BCG vaccine

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/BCG_vaccine 

 

BCG vaccine

Microscopic image of the Calmette-Guérin bacillus, Ziehl–Neelsen stain, magnification:1,000nn
Vaccine description
Target disease	Tuberculosis
Type	Live bacteria
Clinical data
AHFS/Drugs.com	FDA Professional Drug Information
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Percutaneous
ATC code	J07AN01 (WHO)
Legal status
Legal status	US: ℞-only
Identifiers
DrugBank	DB12768
ChemSpider	none

Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB). In countries where tuberculosis or leprosy is common, one dose is recommended in healthy babies as close to the time of birth as possible. In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated. Adults who do not have tuberculosis and have not been previously immunized but are frequently exposed may be immunized as well. BCG also has some effectiveness against Buruli ulcer infection and other nontuberculous mycobacteria infections. Additionally it is sometimes used as part of the treatment of bladder cancer.

Rates of protection against tuberculosis infection vary widely and protection lasts up to twenty years. Among children it prevents about 20% from getting infected and among those who do get infected it protects half from developing disease. The vaccine is given by injection into the skin. Additional doses are not supported by evidence.

Serious side effects are rare. Often there is redness, swelling, and mild pain at the site of injection. A small ulcer may also form with some scarring after healing. Side effects are more common and potentially more severe in those with poor immune function. It is not safe for use during pregnancy. The vaccine was originally developed from Mycobacterium bovis which is commonly found in cows. While it has been weakened, it is still live.

The BCG vaccine was first used medically in 1921. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system. Between 2011 and 2014 the wholesale price was US$0.16 to US$1.11 a dose in the developing world. In the United States it costs US$100 to US$200. As of 2004 the vaccine is given to about 100 million children per year globally.

Medical uses

Tuberculosis

The main use of BCG is for vaccination against tuberculosis. BCG vaccine can be administered after birth intradermally. BCG vaccination can cause a false positive Mantoux test, although a very high-grade reading is usually due to active disease.

The most controversial aspect of BCG is the variable efficacy found in different clinical trials, which appears to depend on geography. Trials conducted in the UK have consistently shown a protective effect of 60 to 80%, but those conducted elsewhere have shown no protective effect, and efficacy appears to fall the closer one gets to the equator.

A 1994 systematic review found that BCG reduces the risk of getting TB by about 50%. There are differences in effectiveness, depending on region, due to factors such as genetic differences in the populations, changes in environment, exposure to other bacterial infections, and conditions in the lab where the vaccine is grown, including genetic differences between the strains being cultured and the choice of growth medium.

A systematic review and meta analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19–27% and reduced progression to active TB by 71%. The studies included in this review were limited to those that used interferon gamma release assay. 

The duration of protection of BCG is not clearly known. In those studies showing a protective effect, the data are inconsistent. The MRC study showed protection waned to 59% after 15 years and to zero after 20 years; however, a study looking at Native Americans immunized in the 1930s found evidence of protection even 60 years after immunization, with only a slight waning in efficacy.

BCG seems to have its greatest effect in preventing miliary TB or TB meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible.

Reasons

A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None have been proven, some have been disproved, and none can explain the lack of efficacy in both low-TB burden countries (US) and high-TB burden countries (India). The reasons for variable efficacy have been discussed at length in a World Health Organization (WHO) document on BCG.

1. Genetic variation in BCG strains: Genetic variation in the BCG strains used may explain the variable efficacy reported in different trials.
2. Genetic variation in populations: Differences in genetic make-up of different populations may explain the difference in efficacy. The Birmingham BCG trial was published in 1988. The trial, based in Birmingham, United Kingdom, examined children born to families who originated from the Indian Subcontinent (where vaccine efficacy had previously been shown to be zero). The trial showed a 64% protective effect, which is very similar to the figure derived from other UK trials, thus arguing against the genetic variation hypothesis.
3. Interference by nontuberculous mycobacteria: Exposure to environmental mycobacteria (especially M. avium, M. marinum and M. intracellulare) results in a nonspecific immune response against mycobacteria. Administering BCG to someone who already has a nonspecific immune response against mycobacteria does not augment the response already there. BCG will therefore appear not to be efficacious, because that person already has a level of immunity and BCG is not adding to that immunity. This effect is called masking, because the effect of BCG is masked by environmental mycobacteria. Clinical evidence for this effect was found in a series of studies performed in parallel in adolescent school children in the UK and Malawi. In this study, the UK school children had a low baseline cellular immunity to mycobacteria which was increased by BCG; in contrast, the Malawi school children had a high baseline cellular immunity to mycobacteria and this was not significantly increased by BCG. Whether this natural immune response is protective is not known. An alternative explanation is suggested by mouse studies; immunity against mycobacteria stops BCG from replicating and so stops it from producing an immune response. This is called the block hypothesis.
4. Interference by concurrent parasitic infection: In another hypothesis, simultaneous infection with parasites changes the immune response to BCG, making it less effective. As Th1 response is required for an effective immune response to tuberculous infection, concurrent infection with various parasites produces a simultaneous Th2 response, which blunts the effect of BCG.

Mycobacteria

BCG has protective effects against some non-tuberculosis mycobacteria.

• Leprosy: BCG has a protective effect against leprosy in the range of 20 to 80%.
• Buruli ulcer: BCG may protect against or delay the onset of Buruli ulcer.

Cancer

Micrograph showing granulomatous inflammation of bladder neck tissue due to Bacillus Calmette-Guérin used to treat bladder cancer, H&E stain

BCG has been one of the most successful immunotherapies. BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)" since 1977. By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of non–muscle-invasive bladder cancer (NMIBC).

• A number of cancer vaccines use BCG as an additive to provide an initial stimulation of the person's immune systems.
• BCG is used in the treatment of superficial forms of bladder cancer. Since the late 1970s, evidence has become available that instillation of BCG into the bladder is an effective form of immunotherapy in this disease. While the mechanism is unclear, it appears a local immune reaction is mounted against the tumor. Immunotherapy with BCG prevents recurrence in up to 67% of cases of superficial bladder cancer.
• BCG has been evaluated in a number of studies as a therapy for colorectal cancer. The US biotech company Vaccinogen is evaluating BCG as an adjuvant to autologous tumour cells used as a cancer vaccine in stage II colon cancer.

Method of administration

An apparatus (4–5 cm length, with 9 short needles) used for BCG vaccination in Japan, shown with ampules of BCG and saline

Except in neonates, a tuberculin skin test should always be done before administering BCG. A reactive tuberculin skin test is a contraindication to BCG. Someone with a positive tuberculin reaction is not given BCG, because the risk of severe local inflammation and scarring is high, not because of the common misconception that tuberculin reactors "are already immune" and therefore do not need BCG. People found to have reactive tuberculin skin tests should be screened for active tuberculosis. BCG is also contraindicated in certain people who have IL-12 receptor pathway defects.

BCG is given as a single intradermal injection at the insertion of the deltoid. If BCG is accidentally given subcutaneously, then a local abscess may form (a "BCG-oma") that can sometimes ulcerate, and may require treatment with antibiotics immediately, otherwise without treatment it could spread the infection causing severe damage to vital organs. An abscess is not always associated with incorrect administration, and it is one of the more common complications that can occur with the vaccination. Numerous medical studies on treatment of these abscesses with antibiotics have been done with varying results, but the consensus is once pus is aspirated and analysed, provided no unusual bacilli are present, the abscess will generally heal on its own in a matter of weeks.

The characteristic raised scar that BCG immunization leaves is often used as proof of prior immunization. This scar must be distinguished from that of smallpox vaccination, which it may resemble.

Adverse effects

BCG immunization generally causes some pain and scarring at the site of injection. The main adverse effects are keloids—large, raised scars. The insertion of deltoid is most frequently used because the local complication rate is smallest when that site is used. Nonetheless, the buttock is an alternative site of administration because it provides better cosmetic outcomes.

BCG vaccine should be given intradermally. If given subcutaneously, it may induce local infection and spread to the regional lymph nodes, causing either suppurative and nonsuppurative lymphadenitis. Conservative management is usually adequate for nonsuppurative lymphadenitis. If suppuration occurs, it may need needle aspiration. For nonresolving suppuration, surgical excision may be required. Evidence for the treatment of these complications is scarce.

Uncommonly, breast and gluteal abscesses can occur due to haematogenous and lymphangiomatous spread. Regional bone infection (BCG osteomyelitis or osteitis) and disseminated BCG infection are rare complications of BCG vaccination, but potentially life-threatening. Systemic antituberculous therapy may be helpful in severe complications.

If BCG is accidentally given to an immunocompromised patient (e.g., an infant with SCID), it can cause disseminated or life-threatening infection. The documented incidence of this happening is less than one per million immunizations given. In 2007, The World Health Organization (WHO) stopped recommending BCG for infants with HIV, even if there is a high risk of exposure to TB, because of the risk of disseminated BCG infection (which is approximately 400 per 100,000 in that higher risk context).

Usage

The age of the person and the frequency with which BCG is given has always varied from country to country.

• WHO BCG policy: The World Health Organization (WHO) recommends BCG be given to all children born in countries with a high incidence of TB and/or high leprosy burden.
• Brazil: Brazil introduced universal BCG immunization in 1967–1968, and the practice continues until now. According to Brazilian law, BCG is given again to professionals of the health sector and to people close to patients with tuberculosis or leprosy.
• Central and South America: Most countries in Central and South America have universal BCG immunizations. In Ecuador, a child cannot receive their birth certificate without having the BCG vaccine in their medical record along with other vaccinations.
• France: The BCG was mandatory for school children between 1950 and 2007, and for healthcare professionals between 1947 and 2010. Vaccination is still available for French healthcare professionals and social workers but is now decided on a case by case basis.
• Hong Kong: BCG is given to all newborns.
• India and Pakistan: India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so.
• Japan: In Japan, BCG is administered between five and eight months after birth, and no later than a child's first birthday. BCG was administered no later than the fourth birthday until 2005, and no later than six months from birth from 2005 to 2012; the schedule was changed in 2012 due to reports of osteitis side effects from vaccinations at 3–4 months. Some municipalities recommend an earlier immunization schedule.
• Mongolia: All newborns are vaccinated with BCG. Previously, the vaccine was also given at ages 8 and 15, although this is no longer common practice.
• Norway: In Norway the BCG vaccine was mandatory from 1947 to 1995. It is still available and recommended for high-risk groups.
• Philippines: BCG vaccine started in the Philippines in 1979 with the Expanded Program on Immunization
• South Africa: In South Africa, the BCG Vaccine is given routinely at birth, to all newborns, except those with clinically symptomatic AIDS. The vaccination site in the right shoulder.
• Sri Lanka: In Sri Lanka, The National Policy of Sri Lanka is to give BCG vaccination to all newborn babies immediately after birth. BCG vaccination is carried out under the Expanded Programme of Immunisation (EPI).
• Thailand: In Thailand, the BCG Vaccine is given routinely at birth.
• United Kingdom: The UK introduced universal BCG immunization in 1953, and until July 2005, the UK policy was to immunize all school children between 10 and 14 years of age, and all neonates born into high-risk groups. The injection was given only once during an individual's lifetime (as there is no evidence of additional protection from more than one vaccination). BCG was also given to protect people who had been exposed to tuberculosis. The peak of tuberculosis incidence is in adolescence and early adulthood, and the MRC trial showed efficacy lasted a maximum of 15 years. Routine immunization with BCG for all school children was scrapped in July 2005 because of falling cost-effectiveness: whereas in 1953, 94 children would have to be immunized to prevent one case of TB, by 1988, the annual incidence of TB in the UK had fallen so much, 12,000 children would have to be immunized to prevent one case of TB. The vaccine is still given to certain healthcare professionals, however.
• United States: The US has never used mass immunization of BCG, relying instead on the detection and treatment of latent tuberculosis.
• Other countries: In some countries, such as the former Soviet Union, BCG was given regularly throughout life. In South Korea, Singapore, Taiwan and Malaysia, BCG was given at birth and again at age 12. But in Malaysia and Singapore, from 2001, this policy was changed to once only at birth. South Korea also stopped the re-vaccination in 2008. In the Canadian province of Quebec, the BCG vaccine was provided to children until the early 1960s.

Manufacture

BCG is prepared from a strain of the attenuated (virulence-reduced) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its ability to cause disease in humans. Because the living bacilli evolve to make the best use of available nutrients, they become less well-adapted to human blood and can no longer induce disease when introduced into a human host. Still, they are similar enough to their wild ancestors to provide some degree of immunity against human tuberculosis. The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for a duration of 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown.

A number of different companies make BCG, sometimes using different genetic strains of the bacterium. This may result in different product characteristics. OncoTICE, used for bladder instillation for bladder cancer, was developed by Organon Laboratories (since acquired by Schering-Plough, and in turn acquired by Merck & Co.). Pacis BCG, made from the Montréal (Institut Armand-Frappier) strain, was first marketed by Urocor in about 2002. Urocor was since acquired by Dianon Systems. Evans Vaccines (a subsidiary of PowderJect Pharmaceuticals). Statens Serum Institut in Denmark markets BCG vaccine prepared using Danish strain 1331.^[52] Japan BCG Laboratory markets its vaccine, based on the Tokyo 172 substrain of Pasteur BCG, in 50 countries worldwide.

According to a UNICEF report published in December 2015 on BCG vaccine supply security, global demand increased in 2015 from 123 to 152.2 million doses. In order to improve security and to [diversify] sources of affordable and flexible supply," UNICEF awarded seven new manufacturers contracts to produce BCG. Along with supply availability from existing manufacturers, and a "new WHO prequalified vaccine" the total supply will be "sufficient to meet both suppressed 2015 demand carried over to 2016, as well as total forecast demand through 2016-2018."

BCG supply shortage 2012–2017

In the fall of 2011, the Sanofi Pasteur plant flooded causing problems with mold. The facility, located in Toronto, Ontario, Canada, produced BCG vaccine products, made with substrain Connaught, such as a tuberculosis vaccine ImmuCYST, a BCG Immunotherapeutic – a bladder cancer drug. By April 2012 the FDA had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits. The resulting closure of the plant for over two years resulting in shortages of bladder cancer and tuberculosis vaccines. On October 29, 2014 Health Canada gave the permission for Sanofi to resume production of BCG. The global supply situation was analyzed in 2017 and concluded that the global supply is sufficient to meet forecasted BCG vaccine demand but risks for shortages remain mainly due to supply concentration.

Preparation

A weakened strain of bovine tuberculosis bacillus, Mycobacterium bovis is specially subcultured in a culture medium, usually Middlebrook 7H9.

Dried

Some BCG vaccines are freeze dried and become fine powder. Sometimes the powder is sealed with vacuum in a glass ampoule. Such a glass ampoule has to be opened slowly to prevent the airflow from blowing out the powder. Then the powder has to be diluted with saline water before injecting.

History

French poster promoting the BCG vaccine

The history of BCG is tied to that of smallpox. Jean Antoine Villemin first recognized bovine tuberculosis in 1854 and transmitted it, and Robert Koch first distinguished Mycobacterium bovis from Mycobacterium tuberculosis. Following the success of vaccination in preventing smallpox, established during the 18th century, scientists thought to find a corollary in tuberculosis by drawing a parallel between bovine tuberculosis and cowpox: it was hypothesized that infection with bovine tuberculosis might protect against infection with human tuberculosis. In the late 19th century, clinical trials using M. bovis were conducted in Italy with disastrous results, because M. bovis was found to be just as virulent as M. tuberculosis. 

Albert Calmette, a French physician and bacteriologist, and his assistant and later colleague, Camille Guérin, a veterinarian, were working at the Institut Pasteur de Lille (Lille, France) in 1908. Their work included subculturing virulent strains of the tuberculosis bacillus and testing different culture media. They noted a glycerin-bile-potato mixture grew bacilli that seemed less virulent, and changed the course of their research to see if repeated subculturing would produce a strain that was attenuated enough to be considered for use as a vaccine. The BCG strain was isolated after subculturing 239 times during 13 years from virulent strain on glycerine potato medium. The research continued throughout World War I until 1919, when the now avirulent bacilli were unable to cause tuberculosis disease in research animals. Calmette and Guerin transferred to the Paris Pasteur Institute in 1919. The BCG vaccine was first used in humans in 1921.

Public acceptance was slow, and one disaster, in particular, did much to harm public acceptance of the vaccine. In the summer of 1930 in Lübeck, 240 infants were vaccinated in the first 10 days of life; almost all developed tuberculosis and 72 infants died. It was subsequently discovered that the BCG administered there had been contaminated with a virulent strain that was being stored in the same incubator, which led to legal action against the manufacturers of the vaccine.

Dr. R.G. Ferguson, working at the Fort Qu'Appelle Sanatorium in Saskatchewan, was among the pioneers in developing the practice of vaccination against tuberculosis. In 1928, BCG was adopted by the Health Committee of the League of Nations (predecessor to the World Health Organization (WHO)). Because of opposition, however, it only became widely used after World War II. From 1945 to 1948, relief organizations (International Tuberculosis Campaign or Joint Enterprises) vaccinated over 8 million babies in eastern Europe and prevented the predicted typical increase of TB after a major war. 

BCG is very efficacious against tuberculous meningitis in the pediatric age group, but its efficacy against pulmonary tuberculosis appears to be variable. As of 2006, only a few countries do not use BCG for routine vaccination. Two countries that have never used it routinely are the United States and the Netherlands (in both countries, it is felt that having a reliable Mantoux test and therefore being able to accurately detect active disease is more beneficial to society than vaccinating against a condition that is now relatively rare there).

Other names include "Vaccin Bilié de Calmette et Guérin vaccine" and "Bacille de Calmette et Guérin vaccine".

Research

Tentative evidence exists for a beneficial non-specific effect of BCG vaccination on overall mortality in low income countries, or for its reducing other health problems including sepsis and respiratory infections when given early, with greater benefit the earlier it is used.

In rhesus macaques, BCG shows improved rates of protection when given intravenously.

BCG vaccine is in the early stages of being studied in type 1 diabetes.

Mycobacterium tuberculosis

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis

Mycobacterium tuberculosis
M. tuberculosis bacterial colonies
Scientific classification
Domain:	Bacteria
Phylum:	Actinobacteria
Class:	Actinobacteria
Order:	Actinomycetales
Family:	Mycobacteriaceae
Genus:	Mycobacterium
Species:	M. tuberculosis
Binomial name
Mycobacterium tuberculosis Zopf 1883
Synonyms
Tubercle bacillus Koch 1882

M. tuberculosis in the lungs

Mycobacterium tuberculosis (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, M. tuberculosis can appear either Gram-negative or Gram-positive. Acid-fast stains such as Ziehl-Neelsen, or fluorescent stains such as auramine are used instead to identify M. tuberculosis with a microscope. The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, it infects the lungs. The most frequently used diagnostic methods for tuberculosis are the tuberculin skin test, acid-fast stain, culture, and polymerase chain reaction.

The M. tuberculosis genome was sequenced in 1998.

Microbiology

M. tuberculosis is part of a complex that has at least 9 members: M. tuberculosis sensu stricto, M. africanum, M. canetti, M. bovis, M. caprae, M. microti, M. pinnipedii, M. mungi, and M. orygis. It requires oxygen to grow, does not produce spores, and is nonmotile. M. tuberculosis divides every 15–20 hours. This is extremely slow compared with other bacteria, which tend to have division times measured in minutes (Escherichia coli can divide roughly every 20 minutes). It is a small bacillus that can withstand weak disinfectants and can survive in a dry state for weeks. Its unusual cell wall is rich in lipids such as mycolic acid and is likely responsible for its resistance to desiccation and is a key virulence factor.

Microscopy

Other bacteria are commonly identified with a microscope by staining them with Gram stain. However, the mycolic acid in the cell wall of M. tuberculosis does not absorb the stain. Instead, acid-fast stains such as Ziehl-Neelsen stain, or fluorescent stains such as auramine are used. Cells are curved rod-shaped and are often seen wrapped together, due to the presence of fatty acids in the cell wall that stick together. This appearance is referred to as cording, like strands of cord that make up a rope. M. tuberculosis is characterized in tissue by caseating granulomas containing Langhans giant cells, which have a "horseshoe" pattern of nuclei.

Culture

M. tuberculosis can be grown in the laboratory. Compared to other commonly studied bacteria, M. tuberculosis has a remarkably slow growth rate, doubling roughly once per day. Commonly used media include liquids such as Middlebrook 7H9 or 7H12, egg-based solid media such as Lowenstein-Jensen, and solid agar-based such as Middlebrook 7H11 or 7H10. Visible colonies require several weeks to grow on agar plates. It is distinguished from other mycobacteria by its production of catalase and niacin. Other tests to confirm its identity include gene probes and MALDI-TOF.

Pathophysiology

Humans are the only known reservoirs of M. tuberculosis. A misconception is that M. tuberculosis can be spread by shaking hands, making contact with toilet seats, sharing food or drink, sharing toothbrushes, or kissing. It can only be spread through air droplets originating from a person who has the disease either coughing, sneezing, speaking, or singing.

When in the lungs, M. tuberculosis is phagocytosed by alveolar macrophages, but they are unable to kill and digest the bacterium. Its cell wall prevents the fusion of the phagosome with the lysosome, which contains a host of antibacterial factors. Specifically, M. tuberculosis blocks the bridging molecule, early endosomal autoantigen 1 (EEA1); however, this blockade does not prevent fusion of vesicles filled with nutrients. Consequently, the bacteria multiply unchecked within the macrophage. The bacteria also carry the UreC gene, which prevents acidification of the phagosome. In addition, production of the diterpene isotuberculosinol prevents maturation of the phagosome. The bacteria also evades macrophage-killing by neutralizing reactive nitrogen intermediates. More recently, it has been shown that M. tuberculosis secretes and covers itself in 1-tuberculosinyladenosine (1-TbAd), a special nucleoside that acts as an antacid, allowing it to neutralize pH and induce swelling in lysosomes. 1-TbAd is encoded by the gene Rv3378c. 

It was also recently demonstrated that in M. tuberculosis infections, PPM1A levels were upregulated, and this in turn would impact the normal apoptotic response of macrophages to clear pathogens, as PPM1A is involved in the intrinsic and extrinsic apoptotic pathways. Hence, when PPM1A levels were increased, the expression of it would inhibit the two apoptotic pathways. With kinome analysis, the JNK/AP-1 signalling pathway was found to be a downstream effector that PPM1A has a part to play in, and the apoptotic pathway in macrophages are controlled in this manner. As a result of having apoptosis being suppressed, it provides M. tuberculosis with a safe replicative niche, and so the bacteria is able to maintain a latent state for a prolonged period of time.

Protective granulomas are formed due to the production of cytokines and upregulation of proteins involved in recruitment. Granulotomatous lesions are important in both regulating the immune response and minimizing tissue damage. Moreover, T cells help maintain Mycobacterium within the granulomas.

The ability to construct M. tuberculosis mutants and test individual gene products for specific functions has significantly advanced the understanding of its pathogenesis and virulence factors. Many secreted and exported proteins are known to be important in pathogenesis. For example, one such virulence factor is cord factor (trehalose dimycolate), which serves to increase survival within its host. Resistant strains of M. tuberculosis have developed resistance to more than one TB drug, due to mutations in their genes. In addition, pre-existing first-line TB drugs such as rifampicin and streptomycin have decreased efficiency in clearing intracellular M. tuberculosis due not being able to effectively penetrate the macrophage niche.

JNK plays a key role in the control of apoptotic pathways—intrinsic and extrinsic. In addition, it is also found to be a substrate of PPM1A activity, hence the phosphorylation of JNK would cause apoptosis to occur. Since PPM1A levels are elevated during M. tuberculosis infections, by inhibiting the PPM1A signalling pathways, it could potentially be a therapeutic method to kill M. tuberculosis infected macrophages by restoring its normal apoptotic function in defence of pathogens. Therefore, by targeting the PPM1A-JNK signalling axis pathway, it could eliminate M. tuberculosis infected macrophages.

The ability to restore macrophage apoptosis to M. tuberculosis infected ones could improve the current tuberculosis chemotherapy treatment, as TB drugs can gain better access to the bacteria in the niche. Therefore, decreasing the treatment time periods for M. tuberculosis infections.

Symptoms of M. tuberculosis include coughing that lasts for more than three weeks, hemoptysis, chest pain when breathing or coughing, weight loss, fatigue, fever, night sweats, chills, and loss of appetite. M. tuberculosis also has the potential of spreading to other parts of the body. This can cause blood in urine if the kidneys are affected, and back pain if the spine is affected.

Strain variation

Typing of strains is useful in the investigation of tuberculosis outbreaks, because it gives the investigator evidence for or against transmission from person to person. Consider the situation where person A has tuberculosis and believes he acquired it from person B. If the bacteria isolated from each person belong to different types, then transmission from B to A is definitively disproved; however, if the bacteria are the same strain, then this supports (but does not definitively prove) the hypothesis that B infected A.

Until the early 2000s, M. tuberculosis strains were typed by pulsed field gel electrophoresis (PFGE). This has now been superseded by variable numbers of tandem repeats (VNTR), which is technically easier to perform and allows better discrimination between strains. This method makes use of the presence of repeated DNA sequences within the M. tuberculosis genome.

Three generations of VNTR typing for M. tuberculosis are noted. The first scheme, called exact tandem repeat, used only five loci, but the resolution afforded by these five loci was not as good as PFGE. The second scheme, called mycobacterial interspersed repetitive unit, had discrimination as good as PFGE. The third generation (mycobacterial interspersed repetitive unit – 2) added a further nine loci to bring the total to 24. This provides a degree of resolution greater than PFGE and is currently the standard for typing M. tuberculosis. However, with regard to archaeological remains, additional evidence may be required because of possible contamination from related soil bacteria.

Antibiotic resistance in M. tuberculosis typically occurs due to either the accumulation of mutations in the genes targeted by the antibiotic or a change in titration of the drug. M. tuberculosis is considered to be multidrug-resistant (MDR TB) if it has developed drug resistance to both rifampicin and isoniazid, which are the most important antibiotics used in treatment. Additionally, extensively drug-resistant M. tuberculosis (XDR TB) is characterized by resistance to both isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).

M. tuberculosis (stained red) in tissue (blue)

 

Cording M. tuberculosis (H37Rv strain) culture on the luminescent microscopy

Genome

The genome of the H37Rv strain was published in 1998. Its size is 4 million base pairs, with 3,959 genes; 40% of these genes have had their function characterized, with possible function postulated for another 44%. Within the genome are also six pseudogenes.

The genome contains 250 genes involved in fatty acid metabolism, with 39 of these involved in the polyketide metabolism generating the waxy coat. Such large numbers of conserved genes show the evolutionary importance of the waxy coat to pathogen survival. Furthermore, experimental studies have since validated the importance of a lipid metabolism for M. tuberculosis, consisting entirely of host-derived lipids such as fats and cholesterol. Bacteria isolated from the lungs of infected mice were shown to preferentially use fatty acids over carbohydrate substrates. M. tuberculosis can also grow on the lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol use pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis, especially during the chronic phase of infection when other nutrients are likely not available.

About 10% of the coding capacity is taken up by the PE/PPE gene families that encode acidic, glycine-rich proteins. These proteins have a conserved N-terminal motif, deletion of which impairs growth in macrophages and granulomas.

Nine noncoding sRNAs have been characterised in M. tuberculosis, with a further 56 predicted in a bioinformatics screen.

In 2013, a study on the genome of several sensitive, ultraresistant, and multiresistant M. tuberculosis strains was made to study antibiotic resistance mechanisms. Results reveal new relationships and drug resistance genes not previously associated and suggest some genes and intergenic regions associated with drug resistance may be involved in the resistance to more than one drug. Noteworthy is the role of the intergenic regions in the development of this resistance, and most of the genes proposed in this study to be responsible for drug resistance have an essential role in the development of M. tuberculosis.

Evolution

The M. tuberculosis complex evolved in Africa and most probably in the Horn of Africa. In addition to M. tuberculosis, the M. tuberculosis complex (MTBC) has a number of members infecting various animal species, these include M. africanum, M. bovis (Dassie's bacillus), M. caprae, M. microti, M. mungi, M. orygis, and M. pinnipedii. This group may also include the M. canettii clade. These animal strains of MTBC do not strictly deserve species status, as they are all closely related and embedded in the M. tuberculosis phylogeny, but for historic reasons, they currently hold species status.

The M. canettii clade – which includes M. prototuberculosis – is a group of smooth-colony Mycobacterium species. Unlike the established members of the M. tuberculosis group, they undergo recombination with other species. The majority of the known strains of this group have been isolated from the Horn of Africa. The ancestor of M. tuberculosis appears to be M. canettii, first described in 1969.

The established members of the M. tuberculosis complex are all clonal in their spread. The main human-infecting species have been classified into seven lineages. Translating these lineages into the terminology used for spoligotyping, a very crude genotyping methodology, lineage 1 contains the East African-Indian (EAI), the Manila family of strains and some Manu (Indian) strains; lineage 2 is the Beijing group; lineage 3 includes the Central Asian (CAS) strains; lineage 4 includes the Ghana and Haarlem (H/T), Latin America-Mediterranean (LAM) and X strains; types 5 and 6 correspond to M. africanum and are observed predominantly and at high frequencies in West Africa. A seventh type has been isolated from the Horn of Africa. The other species of this complex belong to a number of spoligotypes and do not normally infect humans.

Lineages 2, 3 and 4 all share a unique deletion event (tbD1) and thus form a monophyletic group. Types 5 and 6 are closely related to the animal strains of MTBC, which do not normally infect humans. Lineage 3 has been divided into two clades: CAS-Kili (found in Tanzania) and CAS-Delhi (found in India and Saudi Arabia).

Lineage 4 is also known as the Euro-American lineage. Subtypes within this type include Latin American Mediterranean, Uganda I, Uganda II, Haarlem, X, and Congo.

A much cited study reported that M. tuberculosis has co-evolved with human populations, and that the most recent common ancestor of the M. tuberculosis complex evolved between 40,000 and 70,000 years ago. However, a later study that included genome sequences from M. tuberculosis complex members extracted from three 1,000-year-old Peruvian mummies, came to quite different conclusions. If the most recent common ancestor of the M. tuberculosis complex were 40,000 to 70,000 years old, this would necessitate an evolutionary rate much lower than any estimates produced by genomic analyses of heterochronous samples.

An analysis of over 3000 strains of M. bovis from 35 countries suggested an Africa origin for this species.

Co-evolution with modern humans

There are currently two narratives existing in parallel regarding the age of MTBC and how it has spread and co-evolved with humans through time. One study compared the M. tuberculosis phylogeny to a human mitochondrial genome phylogeny and interpreted these as being highly similar. Based on this, the study suggested that M. tuberculosis, like humans, evolved in Africa and subsequently spread with anatomically modern humans out of Africa across the world. By calibrating the mutation rate of M. tuberculosis to match this narrative, the study suggested that MTBC evolved 40,000 – 70,000 years ago. Applying this time scale, the study found that the M. tuberculosis effective population size expanded during the Neolithic Demographic Transition (around 10,000 years ago) and suggested that M. tuberculosis was able to adapt to changing human populations and that the historical success of this pathogen was driven at least in part by dramatic increases in human host population density. It has also been demonstrated that after emigrating from one continent to another, a human host's region of origin is predictive of which TB lineage they carry, which could reflect either a stable association between host populations and specific M. tuberculosis lineages and/or social interactions that are shaped by shared cultural and geographic histories. 

Regarding the congruence between human and M. tuberculosis phylogenies, a study relying on M. tuberculosis and human Y chromosome DNA sequences to formally assess the correlation between them, concluded that they are not congruent. Also, a more recent study which included genome sequences from M. tuberculosis complex members extracted from three 1,000-year-old Peruvian mummies, estimated that the most recent common ancestor of the M. tuberculosis complex lived only 4,000 – 6,000 years ago. The M. tuberculosis evolutionary rate estimated by the Bos et al. study is also supported by a study on Lineage 4 relying on genomic aDNA sequences from Hungarian mummies more than 200 years old. In total, the evidence thus favors this more recent estimate of the age of the MTBC most recent common ancestor, and thus that the global evolution and dispersal of M. tuberculosis has occurred over the last 4,000–6,000 years. 

Among the seven recognized lineages of M. tuberculosis, only two are truly global in their distribution: Lineages 2 and 4. Among these, Lineage 4 is most well dispersed, and is e.g. almost totally dominating in the Americas. Lineage 4 was shown to have evolved in or in the vicinity of Europe, and to have spread globally with Europeans starting around the 13th century. This study also found that Lineage 4 tuberculosis spread to the Americas shortly after the European discovery of the continent in 1492, and suggests that this represented the first introduction of human TB on the continent (although animal strains have been found in human remains predating Columbus. Similarly, Lineage 4 was found to have spread from Europe to Africa during the Age of Discovery, starting in the early 15th century. Similarly, Lineage 2 was introduced from Asia to Africa multiple times during the past 300 years. M. tuberculosis thus likely evolved in Africa but the two globally distributed lineages evolved later; Lineage 2 in East Asia and Lineage 4 in or around Europe, and has dispersed across the globe from there. 

It has been suggested that ancestral mycobacteria may have infected early hominids in East Africa as early as three million years ago. Even though the MRCA of extant M. tuberculosis seems to have existed as recently as 4,000-6,000 years ago, this does not necessarily suggest that TB did not exist prior to that, it merely means that all M. tuberculosis strains circulating today can be traced back to a common ancestor that lived at that point in time.

Antibiotic resistance (ABR)

M. tuberculosis is a clonal organism and does not exchange DNA via horizontal gene transfer. This, possibly combined with a relatively low rate of evolution, might explain why the evolution of resistance has been relatively slow in the species compared to some other major bacterial pathogens. However, ABR is a very serious and growing challenge. Worst hit are countries in the former Soviet republics, where ABR evolved and spread at explosive levels following the fall of the Soviet Union. An extreme example is Belarus, where a third of all new cases of tuberculosis are multidrug-resistant. Multidrug-resistant tuberculosis requires prolonged treatment with expensive and often toxic drugs, and treatment failure is common.

Multidrug-resistant Tuberculosis (MDR-TB) is caused by an organism that is resistant to at least isoniazid and rifampin, the two most powerful TB drugs. These medications are utilized to treat all people with TB illness. The majority of people with TB are cured by a strictly followed, half-year medicate routine that is provided to patients with support and supervision. Inappropriate or incorrect use of antimicrobial medications, or utilization of ineffectual plans of medications and untimely treatment interruption can cause drug resistance, which can then be transmitted, especially in crowded settings such as prisons and hospitals. In 2016, an estimated 490,000 people worldwide developed MDR-TB, and an additional 110,000 people with rifampicin-resistant TB were also newly eligible for MDR-TB treatment. The countries with the largest numbers of MDR-TB cases (47% of the global total) were China, India and the Russian Federation.

Host genetics

The nature of the host-pathogen interaction between humans and M. tuberculosis is considered to have a genetic component. A group of rare disorders called Mendelian susceptibility to mycobacterial diseases was observed in a subset of individuals with a genetic defect that results in increased susceptibility to mycobacterial infection.

Early case and twin studies have indicated that genetic components are important in host susceptibility to M. tuberculosis. Recent genome-wide association studies (GWAS) have identified three genetic risk loci, including at positions 11p13 and 18q11. As is common in GWAS, the variants discovered have moderate effect sizes. 

DNA repair

As an intracellular pathogen, M. tuberculosis is exposed to a variety of DNA-damaging assaults, primarily from host-generated antimicrobial toxic radicals. Exposure to reactive oxygen species and/or reactive nitrogen species causes different types of DNA damage including oxidation, depurination, methylation, and deamination that can give rise to single- and double-strand breaks (DSBs).

DnaE2 polymerase is upregulated in M. tuberculosis by several DNA-damaging agents, as well as during infection of mice. Loss of this DNA polymerase reduces the virulence of M. tuberculosis in mice. DnaE2 is an error-prone repair DNA repair polymerase that appears to contribute to M. tuberculosis survival during infection. 

The two major pathways employed in repair of DSBs are homologous recombinational repair (HR) and nonhomologous end joining (NHEJ). Macrophage-internalized M. tuberculosis is able to persist if either of these pathways is defective, but is attenuated when both pathways are defective. This indicates that intracellular exposure of M. tuberculosis to reactive oxygen and/or reactive nitrogen species results in the formation of DSBs that are repaired by HR or NHEJ. However deficiency of DSB repair does not appear to impair M. tuberculosis virulence in animal models.

History

M. tuberculosis, then known as the "tubercle bacillus", was first described on 24 March 1882 by Robert Koch, who subsequently received the Nobel Prize in Physiology or Medicine for this discovery in 1905; the bacterium is also known as "Koch's bacillus".

M. tuberculosis has existed throughout history, but the name has changed frequently over time. In 1720, though, the history of tuberculosis started to take shape into what is known of it today; as the physician Benjamin Marten described in his A Theory of Consumption, tuberculosis may be caused by small living creatures transmitted through the air to other patients. This airborne disease is the deadliest infectious disease worldwide, affecting nearly 2 billion people throughout the world currently. M. tuberculosis has been proven to be present in women, children, and individuals with viruses such as HIV or AIDS. It is easily passed through the air by sneezing, coughing, or simply talking. A contaminated droplet can infect any persons and they can become contaminated with M. tuberculosis. Thus, they become a part of the 1.8 billion people worldwide who are currently struggling with this disease.

Vaccine

The BCG vaccine (bacille Calmette-Guerin), which was derived from M. bovis, has had limited success in preventing tuberculosis. This vaccine is used in countries that are notorious for having cases of M. tuberculosis, therefore it is not a recommended vaccine in the United States due to the low risk of infection. To receive this vaccine, the individual is required to go through a consultation process with an expert in M. tb and is only given to those who meet the specific criteria.

Upton Sinclair

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Upton_Sinclair

Upton Sinclair
Born	Upton Beall Sinclair Jr. September 20, 1878 Baltimore, Maryland, U.S.
Died	November 25, 1968 (aged 90) Bound Brook, New Jersey, U.S.
Occupation	Novelist, writer, journalist, political activist, politician
Alma mater	City College of New York
Notable works	The Jungle
Spouse	Meta Fuller (m. 1900; div. 1911) Mary Craig Kimbrough (m. 1913; died 1961) Mary Elizabeth Willis (m. 1961; died 1967)
Signature

Upton Beall Sinclair Jr. (September 20, 1878 – November 25, 1968) was an American writer who wrote nearly 100 books and other works in several genres. Sinclair's work was well known and popular in the first half of the 20th century, and he won the Pulitzer Prize for Fiction in 1943.

In 1906, Sinclair acquired particular fame for his classic muck-raking novel The Jungle, which exposed labor and sanitary conditions in the U.S. meatpacking industry, causing a public uproar that contributed in part to the passage a few months later of the 1906 Pure Food and Drug Act and the Meat Inspection Act. In 1919, he published The Brass Check, a muck-raking exposé of American journalism that publicized the issue of yellow journalism and the limitations of the "free press" in the United States. Four years after publication of The Brass Check, the first code of ethics for journalists was created. Time magazine called him "a man with every gift except humor and silence". He is also well remembered for the line: "It is difficult to get a man to understand something, when his salary depends upon his not understanding it." He used this line in speeches and the book about his campaign for governor as a way to explain why the editors and publishers of the major newspapers in California would not treat seriously his proposals for old age pensions and other progressive reforms.

Many of his novels can be read as historical works. Writing during the Progressive Era, Sinclair describes the world of industrialized America from both the working man's and the industrialist's points of view. Novels such as King Coal (1917), The Coal War (published posthumously), Oil! (1927), and The Flivver King (1937) describe the working conditions of the coal, oil, and auto industries at the time.

The Flivver King describes the rise of Henry Ford, his "wage reform" and his company's Sociological Department, to his decline into antisemitism as publisher of The Dearborn Independent. King Coal confronts John D. Rockefeller Jr., and his role in the 1913 Ludlow Massacre in the coal fields of Colorado.

Sinclair was an outspoken socialist and ran unsuccessfully for Congress as a nominee from the Socialist Party. He was also the Democratic Party candidate for Governor of California during the Great Depression, running under the banner of the End Poverty in California campaign, but was defeated in the 1934 elections.

Early life and education

Sinclair was born in Baltimore, Maryland, to Upton Beall Sinclair Sr. and Priscilla Harden Sinclair. His father was a liquor salesman whose alcoholism shadowed his son's childhood. Priscilla Harden Sinclair was a strict Episcopalian who disliked alcohol, tea, and coffee. Both of Upton Sinclair's parents were of English ancestry, and all of his ancestors emigrated to America from England during the late 1600s and early 1700s. As a child, Sinclair slept either on sofas or cross-ways on his parents' bed. When his father was out for the night, he would sleep alone in the bed with his mother. Sinclair did not get along with her when he became older because of her strict rules and refusal to allow him independence. Sinclair later told his son, David, that around Sinclair's 16th year, he decided not to have anything to do with his mother, staying away from her for 35 years because an argument would start if they met. His mother's family was very affluent: her parents were very prosperous in Baltimore, and her sister married a millionaire. Sinclair had wealthy maternal grandparents with whom he often stayed. This gave him insight into how both the rich and the poor lived during the late 19th century. Living in two social settings affected him and greatly influenced his books. Upton Beall Sinclair, Sr., was from a highly respected family in the South, but the family was financially ruined by the Civil War, disruptions of the labor system during the Reconstruction era, and an extended agricultural depression. 

As he was growing up, Upton's family moved frequently, as his father was not successful in his career. He developed a love for reading when he was five years old. He read every book his mother owned for a deeper understanding of the world. He did not start school until he was 10 years old. He was deficient in math and worked hard to catch up quickly because of his embarrassment. In 1888, the Sinclair family moved to Queens, New York, where his father sold shoes. Upton entered the City College of New York five days before his 14th birthday, on September 15, 1892. He wrote jokes, dime novels, and magazine articles in boys' weekly and pulp magazines to pay for his tuition. With that income, he was able to move his parents to an apartment when he was seventeen years old.

He graduated in June 1897 and studied for a time at Columbia University. His major was law, but he was more interested in writing, and he learned several languages, including Spanish, German, and French. He paid the one-time enrollment fee to be able to learn a variety of things. He would sign up for a class and then later drop it. He again supported himself through college by writing boys' adventure stories and jokes. He also sold ideas to cartoonists. Using stenographers, he wrote up to 8,000 words of pulp fiction per day. His only complaint about his educational experience was that it failed to educate him about socialism. After leaving Columbia, he wrote four books in the next four years; they were commercially unsuccessful though critically well-received: King Midas (1901), Prince Hagen (1902), The Journal of Arthur Stirling (1903), and a Civil War novel titled Manassas (1904).

Upton became close with Reverend William Wilmerding Moir. Moir specialized in sexual abstinence and taught his beliefs to Sinclair. He was taught to "avoid the subject of sex." Sinclair was to report to Moir monthly regarding his abstinence. Despite their close relationship, Sinclair identified as agnostic.

Career

Upton Sinclair early in his career

Upton Sinclair considered himself a poet and dedicated his time to writing poetry. In 1904, Sinclair spent seven weeks in disguise, working undercover in Chicago's meatpacking plants to research his novel, The Jungle (1906), a political exposé that addressed conditions in the plants, as well as the lives of poor immigrants. When it was published two years later, it became a bestseller. In the spring of 1905, Sinclair issued a call for the formation of a new organization, a group to be called the Intercollegiate Socialist Society.

Upton Sinclair wearing a white suit and black armband, picketing the Rockefeller Building in New York City

With the income from The Jungle, Sinclair founded the utopian—but non-Jewish white only—Helicon Home Colony in Englewood, New Jersey. He ran as a Socialist candidate for Congress. The colony burned down under suspicious circumstances within a year.

In 1913–1914, Sinclair made three trips to the coal fields of Colorado, which led him to write King Coal and caused him to begin work on the larger, more historical The Coal War. In 1914, Sinclair helped organize demonstrations in New York City against Rockefeller at the Standard Oil offices. The demonstrations touched off more actions by the Industrial Workers of the World (IWW) and the Mother Earth group, a loose association of anarchists and IWW members, in Rockefeller's hometown of Tarrytown.

The Sinclairs moved to California in the 1920s and lived there for nearly four decades. During his years with his second wife, Mary Craig, Sinclair wrote or produced several films. Recruited by Charlie Chaplin, Sinclair and Mary Craig produced Eisenstein's ¡Qué viva México! in 1930–32.

Other interests

Aside from his political and social writings, Sinclair took an interest in occult phenomena and experimented with telepathy. His book Mental Radio (1930) included accounts of his wife Mary's telepathic experiences and ability. William McDougall read the book and wrote an introduction to it, which led him to establish the parapsychology department at Duke University.

Political career

Sinclair broke with the Socialist party in 1917 and supported the war effort. By the 1920s, however, he had returned to the party.

In the 1920s, the Sinclairs moved to Monrovia, California, near Los Angeles, where Sinclair founded the state's chapter of the American Civil Liberties Union. Wanting to pursue politics, he twice ran unsuccessfully for United States Congress on the Socialist ticket: in 1920 for the House of Representatives and in 1922 for the Senate. He was the party candidate for governor of California in 1930, winning nearly 50,000 votes.

During this period, Sinclair was also active in radical politics in Los Angeles. For instance, in 1923, to support the challenged free speech rights of Industrial Workers of the World, Sinclair spoke at a rally during the San Pedro Maritime Strike, in a neighborhood now known as Liberty Hill. He began to read from the Bill of Rights and was promptly arrested, along with hundreds of others, by the LAPD. The arresting officer proclaimed: "We'll have none of that Constitution stuff".

In 1934, Sinclair ran in the California gubernatorial election as a Democrat. Sinclair's platform, known as the End Poverty in California movement (EPIC), galvanized the support of the Democratic Party, and Sinclair gained its nomination. Gaining 879,000 votes made this his most successful run for office, but incumbent Governor Frank Merriam defeated him by a sizable margin, gaining 1,138,000 votes. Hollywood studio bosses unanimously opposed Sinclair. They pressured their employees to assist and vote for Merriam's campaign, and made false propaganda films attacking Sinclair, giving him no opportunity to respond.

Upton Sinclair

Sinclair's plan to end poverty quickly became a controversial issue under the pressure of numerous migrants to California fleeing the Dust Bowl. Conservatives considered his proposal an attempted communist takeover of their state and quickly opposed him, using propaganda to portray Sinclair as a staunch communist. Sinclair had been a member of the Socialist Party from 1902 to 1934, when he became a Democrat, though always considering himself a Socialist in spirit. The Socialist party in California and nationwide refused to allow its members to be active in any other party including the Democratic Party and expelled him, along with socialists who supported his California campaign. The expulsions destroyed the Socialist party in California.

At the same time, American and Soviet communists disassociated themselves from him, considering him a capitalist. In later writings, such as his antialcohol book The Cup of Fury, Sinclair scathingly censured communism. Science-fiction author Robert A. Heinlein was deeply involved in Sinclair's campaign, although he attempted to move away from the stance later in his life. In the 21st century, Sinclair is considered an early American democratic socialist.

After his loss to Merriam, Sinclair abandoned EPIC and politics to return to writing. In 1935, he published I, Candidate for Governor: And How I Got Licked, in which he described the techniques employed by Merriam's supporters, including the then popular Aimee Semple McPherson, who vehemently opposed socialism and what she perceived as Sinclair's modernism. Sinclair's line from this book "It is difficult to get a man to understand something, when his salary depends upon his not understanding it" has become well known and was for example quoted by Al Gore in An Inconvenient Truth.

Of his gubernatorial bid, Sinclair remarked in 1951:

The American People will take Socialism, but they won't take the label. I certainly proved it in the case of EPIC. Running on the Socialist ticket I got 60,000 votes, and running on the slogan to 'End Poverty in California' I got 879,000. I think we simply have to recognize the fact that our enemies have succeeded in spreading the Big Lie. There is no use attacking it by a front attack, it is much better to out-flank them.

Personal life

Sinclair's grave in Rock Creek Cemetery, Washington, DC

In April 1900, Sinclair went to Lake Massawippi in Quebec to work on a novel. He had a small cabin rented for three months and then he moved to a farmhouse. Here, he met his first wife, Meta Fuller, and they became close. She was three years younger than he and had aspirations of being more than a housewife. Sinclair gave her direction as to what to read and learn. Fuller had been a childhood friend whose family was one of the First Families of Virginia. Each had warned the other about themselves and would later bring that up in arguments. They married on October 18, 1900. They used abstinence as their main form of birth control. Fuller became pregnant shortly after they married and attempted to abort it multiple times. The child was born on December 1, 1901, and named David. Meta and her family tried to get Sinclair to give up writing and get "a job that would support his family." Around 1911, Meta left Sinclair for the poet Harry Kemp, later known as the "Dunes Poet" of Provincetown, Massachusetts. 

In 1913, Sinclair married Mary Craig Kimbrough (1883–1961), a woman from an elite Greenwood, Mississippi, family. She had written articles and a book on Winnie Davis, the daughter of Confederate States of America President Jefferson Davis. He met her when she attended one of his lectures about The Jungle. In the 1920s, the Sinclair couple moved to California. They were married until her death in 1961. Sinclair married again, to Mary Elizabeth Willis (1882–1967).

Sinclair was opposed to sex outside of marriage and he viewed marital relations as necessary only for procreation. He told his first wife Meta that only the birth of a child gave marriage "dignity and meaning". Despite his beliefs, he had an adulterous affair with Anna Noyes during his marriage to Meta. He wrote a novel about the affair called Love's Progress, a sequel to Love's Pilgrimage. It was never published. His wife next had an affair with John Armistead Collier, a theology student from Memphis; they had a son together named Ben.

In his novel, Mammonart, he suggested that Christianity was a religion that favored the rich and promoted a drop of standards. He was against it.

Late in life Sinclair, with his third wife Mary Willis, moved to Buckeye, Arizona. They returned east to Bound Brook, New Jersey. Sinclair died there in a nursing home on November 25, 1968, a year after his wife. He is buried in Rock Creek Cemetery in Washington, D.C., next to Willis.

Writing

Sinclair devoted his writing career to documenting and criticizing the social and economic conditions of the early 20th century in both fiction and nonfiction. He exposed his view of the injustices of capitalism and the overwhelming effects of poverty among the working class. He also edited collections of fiction and nonfiction.

The Jungle

His novel based on the meatpacking industry in Chicago, The Jungle, was first published in serial form in the socialist newspaper Appeal to Reason, from February 25, 1905, to November 4, 1905. It was published as a book by Doubleday in 1906.

Upton Sinclair selling the "Fig Leaf Edition" of his book Oil! (1927) in Boston

Sinclair had spent about six months investigating the Chicago meatpacking industry for Appeal to Reason, the work which inspired his novel. He intended to "set forth the breaking of human hearts by a system which exploits the labor of men and women for profit". The novel featured Jurgis Rudkus, a Lithuanian immigrant who works in a meat factory in Chicago, his teenaged wife Ona Lukoszaite, and their extended family. Sinclair portrays their mistreatment by Rudkus' employers and the wealthier elements of society. His descriptions of the unsanitary and inhumane conditions that workers suffered served to shock and galvanize readers. Jack London called Sinclair's book "the Uncle Tom's Cabin of wage slavery". Domestic and foreign purchases of American meat fell by half.

Sinclair wrote in Cosmopolitan in October 1906 about The Jungle: "I aimed at the public's heart, and by accident I hit it in the stomach." The novel brought public lobbying for Congressional legislation and government regulation of the industry, including passage of the Meat Inspection Act and the Pure Food and Drug Act. At the time, President Theodore Roosevelt characterized Sinclair as a "crackpot", writing to William Allen White, "I have an utter contempt for him. He is hysterical, unbalanced, and untruthful. Three-fourths of the things he said were absolute falsehoods. For some of the remainder there was only a basis of truth." After reading The Jungle, Roosevelt agreed with some of Sinclair's conclusions, but was opposed to legislation that he considered "socialist". He said, "Radical action must be taken to do away with the efforts of arrogant and selfish greed on the part of the capitalist."

The Brass Check

In The Brass Check (1919), Sinclair made a systematic and incriminating critique of the severe limitations of the "free press" in the United States. Among the topics covered is the use of yellow journalism techniques created by William Randolph Hearst. Sinclair called The Brass Check "the most important and most dangerous book I have ever written."

Sylvia novels

• Sylvia (1913) was a novel about a Southern girl. In her autobiography, Mary Craig Sinclair said she had written the book based on her own experiences as a girl, and Upton collaborated with her. She asked him to publish it under his name. When it appeared in 1913, The New York Times called it "the best novel Mr. Sinclair has yet written–so much the best that it stands in a class by itself."
• Sylvia's Marriage (1914), Craig and Sinclair collaborated on a sequel, also published by John C. Winston Company under Upton Sinclair's name. In his 1962 autobiography, Upton Sinclair wrote: "[Mary] Craig had written some tales of her Southern girlhood; and I had stolen them from her for a novel to be called Sylvia."

I, Governor of California, and How I Ended Poverty

This was a novel he published in 1934 as a preface to running for office in the state of California. In the book he outlined his plans to run as a Democrat instead of a Socialist, and describes his climb to the Democratic nomination, and then subsequent victory by a margin of 100,000 votes.

Lanny Budd series

Between 1940 and 1953, Sinclair wrote a series of 11 novels featuring a central character named Lanny Budd. The son of an American arms manufacturer, Budd is portrayed as holding in the confidence of world leaders, and not simply witnessing events, but often propelling them. As a sophisticated socialite who mingles easily with people from all cultures and socioeconomic classes, Budd has been characterized as the antithesis of the stereotyped "Ugly American".

Sinclair placed Budd within the important political events in the United States and Europe in the first half of the 20th century. An actual company named the Budd Company manufactured arms during World War II, founded by Edward G. Budd in 1912. 

The novels were bestsellers upon publication and were published in translation, appearing in 21 countries. The third book in the series, Dragon's Teeth (1942), won the Pulitzer Prize for the Novel in 1943. Out of print and nearly forgotten for years, ebook editions of the Lanny Budd series were published in 2016.

The Lanny Budd series includes:

• World's End, 1940
• Between Two Worlds, 1941
• Dragon's Teeth, 1942
• Wide Is the Gate, 1943
• Presidential Agent, 1944
• Dragon Harvest, 1945
• A World to Win, 1946
• Presidential Mission, 1947
• One Clear Call, 1948
• O Shepherd, Speak!, 1949
• The Return of Lanny Budd, 1953

Other works

Sinclair was keenly interested in health and nutrition. He experimented with various diets, and with fasting. He wrote about this in his book, The Fasting Cure (1911), another bestseller. He believed that periodic fasting was important for health, saying, "I had taken several fasts of ten or twelve days' duration, with the result of a complete making over of my health".

Sinclair favored a raw food diet of predominantly vegetables and nuts. For long periods of time, he was a complete vegetarian, but he also experimented with eating meat. His attitude to these matters was fully explained in the chapter, "The Use of Meat", in the above-mentioned book.

Representation in popular culture

President Lyndon B. Johnson greets Upton Sinclair as others look on.

• Sinclair is featured as one of the main characters in Chris Bachelder's satirical novel, U.S.! (2005). Repeatedly, Sinclair is resurrected after his death and assassinated again, a "personification of the contemporary failings of the American left". He is portrayed as a quixotic reformer attempting to stir an apathetic American public to implement socialism in America.
• Sinclair Lewis refers to Sinclair and his EPIC plan in Lewis' novel, It Can't Happen Here (1935).
• Joyce Carol Oates refers to Sinclair and his first wife, Meta, in her novel The Accursed (2013).
• Sinclair is extensively featured as a figure in Harry Turtledove's American Empire trilogy (2001–2003) as part of the Southern Victory Series, an alternate history in which the American Socialist Party succeeds in becoming a major force in U.S. politics. This follows two humiliating military defeats to the Confederate States, the United Kingdom, and France and the post-1882 collapse of the Republican Party, with former president Abraham Lincoln leading a large number of Liberal Republicans into the Socialist Party. Sinclair wins the 1920 and 1924 presidential elections and becomes the first Socialist President of the United States. He was also the 28th president in the timeline. On March 4, 1921, his inauguration attended by crowds of jubilant militants waving red flags. However, his policies as portrayed by Turtledove are not particularly radical. Sinclair served as president until 1929, when his Vice President Hosea Blackford is elected in 1928 and becomes the 30th president.
• Sinclair appears in T.C.Boyle's novel The Road to Wellville (1993), which is built around a historical fictionalization of John Harvey Kellogg, the inventor of Corn Flakes and the founder of the Battle Creek Sanitarium. In the book, Sinclair and his first wife, Meta, appear as patients at the Sanitarium. Later, Kellogg is outraged when he discovers that another of his patients has been fasting after reading a typescript of Sinclair's The Fasting Cure.

Films

• The Jungle (1914) is a silent film adaptation of the 1906 novel, with George Nash playing Jurgis Rudkus and Gail Kane playing Ona Lukozsaite. The film is considered lost. Sinclair appears at the beginning and end of the film as a form of endorsement.
• The Wet Parade (1932) is a film adaptation of Sinclair's eponymous 1931 novel, directed by Victor Fleming and starring Lewis Stone, Walter Huston, Dorothy Jordan, Neil Hamilton, Robert Young, and Jimmy Durante. Myrna Loy appears very briefly as an actress who runs an elegant speakeasy.
• Walt Disney Productions adapted The Gnomobile (1937) into the 1967 musical motion picture The Gnome-Mobile.
• Oil! (1927) was adapted as the film There Will Be Blood (2007), starring Daniel Day-Lewis and Paul Dano, and written, produced, and directed by Paul Thomas Anderson. The film received eight Oscar nominations and won two.

Works

Fiction

• Courtmartialed – 1898
• Saved By the Enemy – 1898
• The Fighting Squadron – 1898
• A Prisoner of Morro – 1898
• A Soldier Monk – 1898
• A Gauntlet of Fire – 1899
• Holding the Fort  – 1899
• A Soldier's Pledge – 1899
• Wolves of the Navy – 1899
• Springtime and Harvest – 1901, reissued the same year as King Midas
• The Journal of Arthur Stirling – 1903
• Off For West Point – 1903
• From Port to Port – 1903
• On Guard – 1903
• A Strange Cruise – 1903
• The West Point Rivals – 1903
• A West Point Treasure – 1903
• A Cadet's Honor – 1903
• Cliff, the Naval Cadet – 1903
• The Cruise of the Training Ship – 1903
• Prince Hagen – 1903
• Manassas: A Novel of the War – 1904, reissued in 1959 as Theirs be the Guilt
• A Captain of Industry – 1906
• The Jungle – 1906
• The Overman – 1907
• The Industrial Republic – 1907
• The Metropolis – 1908
• The Moneychangers – 1908, reprinted as The Money Changers
• Samuel The Seeker – 1910
• Love's Pilgrimage – 1911
• Damaged Goods – 1913
• Sylvia – 1913
• Sylvia's Marriage – 1914
• King Coal – 1917
• Jimmie Higgins – 1919
• Debs and the Poets – 1920
• 100% - The Story of a Patriot – 1920
• The Spy – 1920
• They Call Me Carpenter: A Tale of the Second Coming – 1922
• The Millennium – 1924
• The Goslings A Study Of The American Schools – 1924
• The Spokesman's Secretary – 1926
• Money Writes! – 1927
• Oil! – 1927
• Boston, 2 vols. – 1928
• Mountain City – 1930
• Roman Holiday – 1931
• The Wet Parade – 1931
• American Outpost – 1932
• The Way Out (novel) – 1933
• Immediate Epic – 1933
• The Lie Factory Starts – 1934
• The Book of Love – 1934
• Depression Island – 1935
• Co-op: a Novel of Living Together – 1936
• The Gnomobile – 1936, 1962
• Wally for Queen – 1936
• No Pasaran!: A Novel of the Battle of Madrid – 1937
• The Flivver King: A Story of Ford-America  – 1937
• Little Steel – 1938
• Our Lady – 1938
• Expect No Peace – 1939
• Marie Antoinette (novel) – 1939
• Telling The World – 1939
• Your Million Dollars – 1939
• World's End – 1940
• World's End Impending – 1940
• Between Two Worlds – 1941
• Dragon's Teeth – 1942
• Wide Is the Gate – 1943
• Presidential Agent – 1944
• Dragon Harvest – 1945
• A World to Win – 1946
• A Presidential Mission – 1947
• A Giant's Strength – 1948
• Limbo on the Loose – 1948
• One Clear Call – 1948
• O Shepherd, Speak! – 1949
• Another Pamela – 1950
• Schenk Stefan! – 1951
• A Personal Jesus – 1952
• The Return of Lanny Budd – 1953
• What Didymus Did – UK 1954 / It Happened to Didymus – US 1958
• Theirs be the Guilt – 1959
• Affectionately Eve – 1961
• The Coal War – 1976

Autobiographical

• The Autobiography of Upton Sinclair. With Maeve Elizabeth Flynn III. New York: Harcourt, Brace & World, 1962.
• My Lifetime in Letters. Columbia, MO: University of Missouri Press, 1960.
• The Cup of Fury – 1956

Non-fiction

• Good Health and How We Won It: With an Account of New Hygiene (1909) – 1909
• The Fasting Cure – 1911
• The Profits of Religion – 1917
• The Brass Check – 1919
• The McNeal-Sinclair Debate on Socialism – 1921
• The Book of Life – 1921
• The Goose-Step – 1923
• Mammonart. An essay on economic interpretation. – 1925
• Letters to Judd, an American Workingman – 1925
• Mental Radio: Does it work, and how? – 1930, 1962
• Upton Sinclair Presents William Fox – 1933
• We, People of America, and how we ended poverty : a true story of the future – 1933
• I, Governor of California - and How I Ended Poverty – 1933
• The Epic Plan for California – 1934
• I, Candidate for Governor - and How I Got Licked – 1935
• Epic Answers: How to End Poverty in California (1935) – 1934
• What God Means to Me – 1936
• Upton Sinclair on the Soviet Union – 1938^[80]
• Letters to a Millionaire – 1939

Drama

• Plays of Protest: The Naturewoman, The Machine, The Second-Story Man, Prince Hagen – 1912
• The Pot Boiler – 1913
• Hell: A Verse Drama and Photoplay – 1924
• Singing Jailbirds: A Drama in Four Acts – 1924
• Bill Porter: A Drama of O. Henry in Prison – 1925
• The Enemy Had It Too: A Play in Three Acts – 1950

As editor

• The Cry for Justice: An Anthology of the Literature of Social Protest – 1915