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Monday, March 13, 2023

Protozoan infection

From Wikipedia, the free encyclopedia
 
Giardia lamblia, an infectious protozoan

Protozoan infections are parasitic diseases caused by organisms formerly classified in the kingdom Protozoa. They are usually contracted by either an insect vector or by contact with an infected substance or surface and include organisms that are now classified in the supergroups Excavata, Amoebozoa, SAR, and Archaeplastida.

Protozoan infections are responsible for diseases that affect many different types of organisms, including plants, animals, and some marine life. Many of the most prevalent and deadly human diseases are caused by a protozoan infection, including African sleeping sickness, amoebic dysentery, and malaria.

The species originally termed "protozoa" are not closely related to each other and only have superficial similarities (eukaryotic, unicellular, motile, though with exceptions). The terms "protozoa" (and protist) are usually discouraged in the modern biosciences. However, this terminology is still encountered in medicine. This is partially because of the conservative character of medical classification and partially due to the necessity of making identifications of organisms based upon morphology.

Within the taxonomic classification, the four protist supergroups (Amoebozoa, Excavata, SAR, and Archaeplastida) fall under the domain Eukarya. Protists are an artificial grouping of over 64,000 different single-celled life forms. This means that it is difficult to define protists due to their extreme differences and uniqueness. Protists are a polyphyletic [(of a group of organisms) derived from more than one common evolutionary ancestor or ancestral group and therefore not suitable for placing in the same taxon] a collection of organisms and they are unicellular, which means that they lack the level of tissue organization which is present in more complex eukaryotes. Protists grow in a wide variety of moist habitats and a majority of them are free-living organisms. In these moist environments, plankton and terrestrial forms can also be found. Protists are chemoorganotrophic [organisms which oxidize the chemical bonds in organic compounds as their energy source and are responsible for recycling nitrogen and phosphorus. Parasites also are responsible for causing disease in humans and domesticated animals.

Protozoa are chemoorganotrophic protists and have three different ways of acquiring nutrients. The first method of acquiring nutrients is through saprotrophic nutrition. In saprotrophic nutrition, nutrients are obtained from dead organic matter through enzymatic degradation. The second method of acquiring nutrients is through osmotrophic nutrition. In osmotrophic nutrition, nutrients are obtained through absorbing soluble products. The third method of acquiring nutrients is through holozoic nutrition. In holozoic nutrition, solid nutrients are absorbed through phagocytosis.

Some protozoa are photoautotrophic protists. These protists include strict aerobes, and use photosystems I and II in order to carry out photosynthesis which produces oxygen.

Diagram of Plasmodium structure

Mixotrophic protists obtain nutrients through organic and inorganic carbon compounds simultaneously.

All cells have a plasma membrane. In a protist, the plasma membrane is also known as the plasmalemma. Just below the plasma membrane, and in the inner fluid region, cytoplasm can be found. The pellicle structure in the protist is a thin layer of protein that helps provide the cell with some support and protection.  In addition to the plasma membrane, protists contain two different types of vacuoles. Contractile vacuoles help to maintain osmoregulation, and phagocytic vacuoles allow select protists to ingest food. In some protists, flagella or cilia may be present to help with motility and nutrient intake. The flagella or cilia create water currents that assist in feeding and respiration. Energy intake is necessary for protists’ survival. Aerobic chemoorganotrophic protists produce energy through the use of their mitochondria. The mitochondria then generate energy for the protist to keep up with cellular life functions. Photosynthetic protists produce energy through the use of their mitochondria and chloroplasts. Finally, anaerobic chemoorganotrophs produce energy through the use of hydrogenosomes, which are membrane-enclosed organelles that release molecular hydrogen (H2).

Encystment is when a protist becomes a dormant cyst with a cell wall; during encystment, the cyst has decreased complexity and metabolic activity relative to the protist. Encystment protects the protist from environmental changes, the cyst can be a site for nuclear reorganization and cell division, and it can act as a host cell in order to transfer parasitic species. Excystment is when a return to favorable conditions may cause a cyst to return to its original state. In parasitic protists, excystment may occur when the cyst is ingested by a new host.

Protists reproduce asexually or sexually. If the protists reproduce asexually, they do so through binary fission, multiple fission, budding, and fragmentation. If the protists reproduce sexually, they do so through a syngamy process where there is a fusion of the gametes. If this occurs in an individual it is recognized as autogamy. If this occurs between individuals, it is known as conjugation.

Supergroup Excavata


Excavata are considered primitive eukaryotes. They are characterized by a feeding groove with a posteriorly located flagella, which allows them to create a current that captures small food particles. The cytostome is the specialized structure that allows the protists this function. This supergroup Excavata includes the subgroups Diplomonads (Fornicata), Parabasalids, and Euglenozoans.

Diplomonads

Diplomonads used to be defined as Fornicata, but their characteristics remain the same despite their renaming. They are microaerophilic protists. Diplomonads were previously defined by the lack of a mitochondrion, but recent studies have found that they have a nonfunctional, mitochondrial remnant organelle called a mitosome. Most are harmless except for Giardia, Hexamita salmonis, and Histomonas meleagridis. Giardia causes diarrhea, Hexamita salmonis is a fish parasite, and Histomonas meleagridis is a turkey pathogen.

Giardia intestinalis is a human pathogen, which is transmitted by cyst-contaminated water. It causes epidemic diarrhea from contaminated water. One can tell one may be infected by the observation of cysts or trophozoites in stools and ELISA (enzyme-linked immunosorbent assay) test. To prevent contamination, avoid any possibly contaminated water, and if contaminated water is the only thing available to drink, a slow sand filter should be used. A study found that the chlorination of water and nutritional intervention had no effect on childhood giardia infection. Only handwashing and hygienic sanitation interventions reduced infection rates in children.

Hexamita salmonis is a common flagellated fish pathogen. Infected fish are weak and emaciated, and typically swim on their sides.

Histomonas meleagridis is a common bird pathogen that causes histomoniasis. Signs of histomoniasis include reduced appetite, drooping wings, unkempt feathers, and yellow fecal droppings.

Parabasilia

Most Parabasalia are flagellated endosymbionts of animals. They lack a distinct cytostome, which means they must use phagocytosis to engulf food. There are two subgroups: Trichonympha and Trichomonadida. Trichonympha are obligate mutualists of wood-eating insects such as termites. They secrete cellulase, which is used for digesting wood. The next subgroup, Trichomonadida, does not require oxygen and possesses hydrogenosomes. They only reproduce through asexual reproduction and some strains are human pathogens. There are three types of pathogenic parabasalia: Trichomonas foetus, Dientamoeba fragilis, and Trichomonas vaginalis. Trichomonas foetus causes spontaneous abortion in cattle, Dientamoeba fragilis causes diarrhea in humans, and Trichomonas vaginalis is a sexually transmitted disease.

Image of a cultured Tritrichomonas foetus

Trichomonas foetus is a parasite that resides in the urogenital tract of cattle and causes bovine trichomoniasis. Trichomoniasis is a sexually transmitted disease that causes infertility in heifers. Most infertility is caused by sudden embryonic death. Various imidazoles have been used to treat infected bulls, but none are safe and effective. Ipronidazole is probably most effective but it frequently causes sterile abscesses at injection sites.

Dientamoeba fragilis is a parasite that lives in the large intestine of humans. No one knows how D. fragilis is spread; one possibility is from swallowing contaminated water or food. Many people who are infected with this parasite show no signs of being infected. Sometimes the infection can be observed; the most common symptoms include diarrhea, stomach pains, loss of appetite, nausea, and fatigue.

Trichomonas vaginalis is a sexually transmitted disease. Men who are infected rarely show any symptoms (asymptomatic). Women who are infected usually show signs of soreness, inflammation, and redness around the vagina and a possible change in vaginal discharge. Trichomonas vaginalis can be treated with a course of antibiotics.

Euglenozoa

Most Euglenozoa are photoautotrophic, but some are chemoorganotrophs (saprophytic). They are commonly found in freshwater. The members of the phylum Euglenozoa have a pellicle for support, a red eye spot called a stigma to orient the cell toward light, chlorophyll a and b to assist in the process of photosynthesis, contractile vacuoles, and flagella.

Leishmaniasis lesion on adult human forearm

One major pathogen from the phylum Euglenozoa is Leishmania. Leishmania causes leishmaniasis. The symptoms of leishmaniasis include systemic and skin/membrane damage. Leishmania parasites spread by phlebotomine sand flies in the tropics, subtropics, and southern Europe. They may manifest cutaneously (cutaneous leishmaniasis) as skin sores with as scab a few weeks after the bite or internally (visceral leishmaniasis), affecting the organs, which can be life-threatening. Cutaneous leishmaniasis can spread to the mucus membranes and cause mucosal leishmaniasis even years after the initial infection. Cutaneous leishmaniasis heals on its own and leaves bad scars. Only FDA approved for visceral leishmaniasis is amphotericin B and oral miltefosine for cutaneous and mucosal leishmaniasis diagnosis- tissue specimen, bone marrow, blood tests detect antibody to parasite for visceral leishmaniasis.

Reduviid Bug

The second pathogen from this phylum is Trypanosoma cruzi. Trypanosoma cruzi causes Chagas disease and is transmitted by the reduviid bug, also known as the “kissing bug.”  Chagas disease is diagnosed using a physical exam and blood test. The only treatment includes antiparasitics only from the CDC, which are not FDA approved. Acute Chagas disease has a quick onset, the trypanosomes enter the bloodstream, they become amastigotes, and replicate. Acute Chagas disease can be treated using benznidazole or nifurtimox. Chronic chagas disease is asymptomatic and causes heart and gastrointestinal cells to be affected. Currently, there are only investigational treatments for this disease. Unfortunately, vaccines are not effective with Chagas disease due to antigenic variation. This pathogen causes damage to the nervous system.

African Sleeping Sickness is caused by Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense, and is transmitted by the tsetse fly. It is diagnosed by a physical exam and blood test. African sleeping sickness causes interstitial inflammation, lethargy, brain swelling, and death within one to three years. Drug therapy, using Eflornithine and Melarsoprol Pentamidine for T. gambiense and Suramin (Antrypol) for either Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense, or combinations of these medications, can help treat this disease, but vaccines can not be used due to antigenic variation.

Supergroup Amoebozoa

X-ray of colon infected with E. histolytica

Amoebozoa are characterized by the use of pseudopodia for movement and feeding. These protists reproduce by binary or multiple fission.

Entamoebida

Entamoebida lack mitochondria and possess mitosomes. Entamoeba histolytica is a pathogenic parasite known to cause amoebiasis, which is the third leading cause of parasitic deaths. It is diagnosed by the assessment of stool samples. Amoebiasis is caused by the ingestion of food or water contaminated with feces or other bodily wastes of an infected person, which contain cysts, the dormant form of the microbe. These cysts on reaching the terminal ileum region of the gastrointestinal tract give rise to a mass of proliferating cells, the trophozoite form of the parasite, by the process of excystation. Symptoms of this infection include diarrhea with blood and mucus, and can alternate between constipation and remission, abdominal pain, and fever. Symptoms can progress to ameboma, fulminant colitis, toxic megacolon, colonic ulcers, leading to perforation, and abscesses in vital organs like liver, lung, and brain. Amoebiasis can be treated with the administration of anti-amoebic compounds, this often includes the use of Metronidazole, Ornidazole, Chloroquine, Secnidazole, Nitazoxanide and Tinidazole. Tinidazole may be effective in curing children. The usage of conventional therapeutics to treat amoebiasis if often linked with substantial side effects, a threat to the efficacy of these therapeutics, further worsened by the development of drug resistance in the parasite. Amoebic meningoencephalitis and keratitis is a brain-eating amoeba caused by free-living Naeglaria and Acanthomoeba. One way this pathogen can be acquired is by soaking contact lenses in water instead of contact solution. This will result in progressive ulceration of the cornea. This pathogen can be diagnosed by demonstration of amoebae in clinical specimens. There is currently no drug therapy available for amoebic meningoencephalitis and keratitis.

Supergroup SAR

The supergroup SAR includes Stramenopiles, Alveolata and Rhizaria, and is distinguished by fine pseudopodia which can be branched, simple, or connected.

Stramenopila

Some members of Stramenopila are brown algae, diatoms, and water molds. An example of Stramenopila are Peronosporomycetes. The most well-known example of Peronosporomycetes is Phytophthora infestans. This organism caused the Great Famine of Ireland in the 1850s.

Alveolata

Alveolata is a large group, which includes Dinoflagellata, Ciliophora, and Apicomplexa.

Toxoplasmosis life cycle between humans and animals

Balantidium Coli (Balantidiasis) is an example of a member of the phylum Ciliophora. Balantidiasis is the only ciliate known to be capable of infecting humans, and swine are the primary reservoir host. Balantidiasis is opportunistic and rare in Western countries. Apicomplexans are parasites of animals and contain an arrangement of organelles called the apical complex. One example of an apicomplexan is Malaria. Five species of plasmodium cause malaria in animals. Malaria is transmitted by the bite of an infected female mosquito. Symptoms of malaria include: periodic chills and fever, anemia, and hypertrophy of the liver and spleen. Cerebral malaria can occur in children. In order to diagnose Malaria, doctors will look for parasites in Wright-or-Giemsa-stained red blood cells and serological tests. Treatment includes antimalarial drugs, however, resistance has been observed. New vaccines are being discovered to this day. Preventative measures that can be taken include sleeping with netting and using insecticide to prevent mosquitoes. Eimeria is another example of an apicomplexan pathogen. This pathogen causes cecal coccidiosis in chickens. Coccidiosis is a parasitic disease of the intestinal tract. This disease is treated by placing anticoccidials in the chickens’ feed. It also causes malabsorption, diarrhea, and sometimes bloody diarrhea in animals. Theileria parva & T. annulata are tick-borne parasites which cause fatal East Coast fever in cattle. East Coast fever is transmitted by the bite of the three-host tick Phipicephalus appendiculatus and results in respiratory failure and death in African cattle. Most hosts of P. appendiculatus succumb to pulmonary edema and die within three weeks of infection. The severity of the infection can be lessened by treatment with antiprotozoal drugs like buparvaquone. Toxoplasma causes toxoplasmosis and can be acquired from undercooked meat or cat feces containing Toxoplasma gondii. The majority of the 60 million Americans infected with T. gondii are asymptomatic. The group most vulnerable to this pathogen are the fetuses of mothers who have been infected with the parasite for the first time during pregnancy. This can result in damage to the fetus’s brain, eyes, and other organs. Treatment is available for pregnant women and the immunosuppressed. Cryptosporidiosis can be contracted through contact with water, food, soil, or surfaces contaminated with feces containing the Cryptosporidium. Immunocompromised people are the most susceptible. Cryptosporidiosis causes watery diarrhea and can resolve itself without medical intervention. It is diagnosed by examining stool samples, and diarrhea can be treated using Nitazoxanide.

Rhizaria

Plasmodiophorids and Halosporidians are two examples of parasitic Rhizaria. Plasmodiophorids cause infections in crops such as Spongospora subterranea. They cause powdery scabs and galls and disrupt growth. Halosporidians cause infections in marine invertebrates such as Mikrocytos mackini in Pacific oysters. Mikrocytos mackini are abscesses or green pustules on palps and mantles of certain molluscs.

Archaeplastida

The supergroup Archaeplastida includes red algae, green algae and land plants. Each of these three groups have multicellular species and the green and red algae have many single-celled species. The land plants are not considered protists.

Red algae are primarily multicellular, lack flagella, and range in size from microscopic, unicellular to large, multicellular forms. Some species of red algae contain phycoerythrins, photosynthetic accessory pigments that are red in color and outcompete the green tint of chlorophyll, making these species appear as varying shades of red. This group doesn’t include many pathogens.

Green algae exhibit similar features to the land plants, particularly in terms of chloroplast structure. The green algae are subdivided into the chlorophytes and charophytes. It is very rare for green algae to become parasitic.

Prototheca moriformis belongs to the subdivision Chloroplastida. P. moriformis is a green algae that lacks chlorophyll and has turned to parasitism. It is found in sewage and the soil. P. moriformis causes a disease called protothecosis. This disease mainly infects cattle and dogs. Cattle can be affected by prototheca enteritis and mastitis. Protothecosis is commonly seen in dogs; it enters the body through the mouth or nose and causes infection in the intestines. Treatment with amphotericin B has been reported.

Future Treatment

Scientists have been researching new ways to fight protozoan infections, including targeting channels and transporters involved in the diseases and finding the link between a persons microbiome and their ability to resist a protozoan infection

Pathogen transmission

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Pathogen_transmission

In medicine, public health, and biology, transmission is the passing of a pathogen causing communicable disease from an infected host individual or group to a particular individual or group, regardless of whether the other individual was previously infected. The term strictly refers to the transmission of microorganisms directly from one individual to another by one or more of the following means:

  • airborne transmission – very small dry and wet particles that stay in the air for long periods of time allowing airborne contamination even after the departure of the host. Particle size < 5 μm.
  • droplet transmission – small and usually wet particles that stay in the air for a short period of time. Contamination usually occurs in the presence of the host. Particle size > 5 μm.
  • direct physical contact – touching an infected individual, including sexual contact
  • indirect physical contact – usually by touching a contaminated surface, including soil (fomite)
  • fecal–oral transmission – usually from unwashed hands, contaminated food or water sources due to lack of sanitation and hygiene, an important transmission route in pediatrics, veterinary medicine and developing countries.

Transmission can also be indirect, via another organism, either a vector (e.g. a mosquito or fly) or an intermediate host (e.g. tapeworm in pigs can be transmitted to humans who ingest improperly cooked pork). Indirect transmission could involve zoonoses or, more typically, larger pathogens like macroparasites with more complex life cycles. Transmissions can be autochthonous (i.e. between two individuals in the same place) or may involve travel of the microorganism or the affected hosts.

Definition and related terms

An infectious disease agent can be transmitted in two ways: as horizontal disease agent transmission from one individual to another in the same generation (peers in the same age group) by either direct contact (licking, touching, biting), or indirect contact through air – cough or sneeze (vectors or fomites that allow the transmission of the agent causing the disease without physical contact) or by vertical disease transmission, passing the agent causing the disease from parent to offspring, such as in prenatal or perinatal transmission.

The term infectivity describes the ability of an organism to enter, survive and multiply in the host, while the infectiousness of a disease agent indicates the comparative ease with which the disease agent is transmitted to other hosts. Transmission of pathogens can occur by direct contact, through contaminated food, body fluids or objects, by airborne inhalation or through vector organisms.

Transmissibility is the probability of an infection, given a contact between an infected host and a noninfected host.

Community transmission means that the source of infection for the spread of an illness is unknown or a link in terms of contacts between patients and other people is missing. It refers to the difficulty in grasping the epidemiological link in the community beyond confirmed cases.

Local transmission means that the source of the infection has been identified within the reporting location (such as within a country, region or city).

Routes of transmission

The route of transmission is important to epidemiologists because patterns of contact vary between different populations and different groups of populations depending on socio-economic, cultural and other features. For example, low personal and food hygiene due to the lack of a clean water supply may result in increased transmission of diseases by the fecal-oral route, such as cholera. Differences in incidence of such diseases between different groups can also throw light on the routes of transmission of the disease. For example, if it is noted that polio is more common in cities in underdeveloped countries, without a clean water supply, than in cities with a good plumbing system, we might advance the theory that polio is spread by the fecal-oral route. Two routes are considered to be airborne: Airborne infections and droplet infections.

Airborne infection

"Airborne transmission refers to infectious agents that are spread via droplet nuclei (residue from evaporated droplets) containing infective microorganisms. These organisms can survive outside the body and remain suspended in the air for long periods of time. They infect others via the upper and lower respiratory tracts." The size of the particles for airborne infections need to be < 5 μm. It includes both dry and wet aerosols and thus requires usually higher levels of isolation since it can stay suspended in the air for longer periods of time. i.e., separate ventilation systems or negative pressure environments are needed to avoid general contamination. e.g., tuberculosis, chickenpox, measles.

Droplet infection

Droplet image captured under dark background on scattering illumination or tyndall effect
Respiratory droplets are released through talking, coughing, or sneezing.

A common form of transmission is by way of respiratory droplets, generated by coughing, sneezing, or talking. Respiratory droplet transmission is the usual route for respiratory infections. Transmission can occur when respiratory droplets reach susceptible mucosal surfaces, such as in the eyes, nose or mouth. This can also happen indirectly via contact with contaminated surfaces when hands then touch the face. Before drying, respiratory droplets are large and cannot remain suspended in the air for long, and are usually dispersed over short distances. The size of the particles for droplet infections are > 5 μm.

Organisms spread by droplet transmission include respiratory viruses such as influenza virus, parainfluenza virus, adenoviruses, rhinovirus, respiratory syncytial virus, human metapneumovirus, Bordetella pertussis, pneumococci, streptococcus pyogenes, diphtheria, rubella, and coronaviruses. Spread of respiratory droplets from the wearer can be reduced through wearing of a surgical mask.

Direct contact

Direct contact occurs through skin-to-skin contact, kissing, and sexual intercourse. Direct contact also refers to contact with soil or vegetation harboring infectious organisms. Additionally, while fecal–oral transmission is primarily considered an indirect contact route, direct contact can also result in transmission through feces.

Diseases that can be transmitted by direct contact are called contagious (contagious is not the same as infectious; although all contagious diseases are infectious, not all infectious diseases are contagious). These diseases can also be transmitted by sharing a towel (where the towel is rubbed vigorously on both bodies) or items of clothing in close contact with the body (socks, for example) if they are not washed thoroughly between uses. For this reason, contagious diseases often break out in schools, where towels are shared and personal items of clothing accidentally swapped in the changing rooms.

Some diseases that are transmissible by direct contact include athlete's foot, impetigo, syphilis, warts, and conjunctivitis.

Sexual

This refers to any disease that can be caught during sexual activity with another person, including vaginal or anal sex or (less commonly) through oral sex (see below). Transmission is either directly between surfaces in contact during intercourse (the usual route for bacterial infections and those infections causing sores) or from secretions (semen or the fluid secreted by the excited female) which carry infectious agents that get into the partner's blood stream through tiny tears in the penis, vagina or rectum (this is a more usual route for viruses). In this second case, anal sex is considerably more hazardous since the penis opens more tears in the rectum than the vagina, as the vagina is more elastic and more accommodating.

Some diseases transmissible by the sexual route include HIV/AIDS, chlamydia, genital warts, gonorrhea, hepatitis B, syphilis, herpes, and trichomoniasis.

Oral sexual

Sexually transmitted diseases such as HIV and hepatitis B are thought to not normally be transmitted through mouth-to-mouth contact, although it is possible to transmit some STDs between the genitals and the mouth, during oral sex. In the case of HIV this possibility has been established. It is also responsible for the increased incidence of herpes simplex virus 1 (which is usually responsible for oral infections) in genital infections and the increased incidence of the type 2 virus (more common genitally) in oral infections.

Oral

Diseases that are transmitted primarily by oral means may be caught through direct oral contact such as kissing, or by indirect contact such as by sharing a drinking glass or a cigarette. Diseases that are known to be transmissible by kissing or by other direct or indirect oral contact include all of the diseases transmissible by droplet contact and (at least) all forms of herpes viruses, namely Cytomegalovirus infections herpes simplex virus (especially HSV-1) and infectious mononucleosis.

Mother-to-child transmission

Brocky, Karoly - Mother and Child (1846-50)
 

This is from mother to child (more rarely father to child), often in utero, during childbirth (also referred to as perinatal infection) or during postnatal physical contact between parents and offspring. In mammals, including humans, it occurs also via breast milk (transmammary transmission). Infectious diseases that can be transmitted in this way include: HIV, hepatitis B and syphilis. Many mutualistic organisms are transmitted vertically.

Iatrogenic

Transmission due to medical procedures, such as touching a wound, an injection or transplantation of infected material. Some diseases that can be transmitted iatrogenically include: Creutzfeldt–Jakob disease by injection of contaminated human growth hormone, MRSA and many more.

Indirect contact

Indirect contact transmission, also known as vehicleborne transmission, involves transmission through contamination of inanimate objects. Vehicles that may indirectly transmit an infectious agent include food, water, biologic products such as blood, and fomites such as handkerchiefs, bedding, or surgical scalpels. A vehicle may passively carry a pathogen, as in the case of food or water may carrying hepatitis A virus. Alternatively, the vehicle may provide an environment in which the agent grows, multiplies, or produces toxin, such as improperly canned foods provide an environment that supports production of botulinum toxin by Clostridium botulinum.

Transmission by other organisms

A vector is an organism that does not cause disease itself but that transmits infection by conveying pathogens from one host to another.

Vectors may be mechanical or biological. A mechanical vector picks up an infectious agent on the outside of its body and transmits it in a passive manner. An example of a mechanical vector is a housefly, which lands on cow dung, contaminating its appendages with bacteria from the feces, and then lands on food prior to consumption. The pathogen never enters the body of the fly. In contrast, biological vectors harbor pathogens within their bodies and deliver pathogens to new hosts in an active manner, usually a bite. Biological vectors are often responsible for serious blood-borne diseases, such as malaria, viral encephalitis, Chagas disease, Lyme disease and African sleeping sickness. Biological vectors are usually, though not exclusively, arthropods, such as mosquitoes, ticks, fleas and lice. Vectors are often required in the life cycle of a pathogen. A common strategy used to control vector-borne infectious diseases is to interrupt the life cycle of a pathogen by killing the vector.

Fecal–oral

1940 US WPA poster encouraging modernized privies
 

In the fecal-oral route, pathogens in fecal particles pass from one person to the mouth of another person. Although it is usually discussed as a route of transmission, it is actually a specification of the entry and exit portals of the pathogen, and can operate across several of the other routes of transmission. Fecal–oral transmission is primarily considered as an indirect contact route through contaminated food or water. However, it can also operate through direct contact with feces or contaminated body parts, such as through anal sex. It can also operate through droplet or airborne transmission through the toilet plume from contaminated toilets.

Main causes of fecal–oral disease transmission include lack of adequate sanitation and poor hygiene practices - which can take various forms. Fecal oral transmission can be via foodstuffs or water that has become contaminated. This can happen when people do not adequately wash their hands after using the toilet and before preparing food or tending to patients.

The fecal-oral route of transmission can be a public health risk for people in developing countries who live in urban slums without access to adequate sanitation. Here, excreta or untreated sewage can pollute drinking water sources (groundwater or surface water). The people who drink the polluted water can become infected. Another problem in some developing countries, is open defecation which leads to disease transmission via the fecal-oral route.

Even in developed countries there are periodic system failures resulting in a sanitary sewer overflow. This is the typical mode of transmission for infectious agents such as cholera, hepatitis A, polio, Rotavirus, Salmonella, and parasites (e.g. Ascaris lumbricoides).

Tracking

Tracking the transmission of infectious diseases is called disease surveillance. Surveillance of infectious diseases in the public realm traditionally has been the responsibility of public health agencies, on an international, national, or local level. Public health staff relies on health care workers and microbiology laboratories to report cases of reportable diseases to them. The analysis of aggregate data can show the spread of a disease and is at the core of the specialty of epidemiology. To understand the spread of the vast majority of non-notifiable diseases, data either need to be collected in a particular study, or existing data collections can be mined, such as insurance company data or antimicrobial drug sales for example.

For diseases transmitted within an institution, such as a hospital, prison, nursing home, boarding school, orphanage, refugee camp, etc., infection control specialists are employed, who will review medical records to analyze transmission as part of a hospital epidemiology program, for example.

Because these traditional methods are slow, time-consuming, and labor-intensive, proxies of transmission have been sought. One proxy in the case of influenza is tracking of influenza-like illness at certain sentinel sites of health care practitioners within a state, for example. Tools have been developed to help track influenza epidemics by finding patterns in certain web search query activity. It was found that the frequency of influenza-related web searches as a whole rises as the number of people sick with influenza rises. Examining space-time relationships of web queries has been shown to approximate the spread of influenza and dengue.

Computer simulations of infectious disease spread have been used. Human aggregation can drive transmission, seasonal variation and outbreaks of infectious diseases, such as the annual start of school, bootcamp, the annual Hajj etc. Most recently, data from cell phones have been shown to be able to capture population movements well enough to predict the transmission of certain infectious diseases, like rubella.

Relationship with virulence and survival

Pathogens must have a way to be transmitted from one host to another to ensure their species' survival. Infectious agents are generally specialized for a particular method of transmission. Taking an example from the respiratory route, from an evolutionary perspective viruses or bacteria that cause their host to develop coughing and sneezing symptoms have a great survival advantage, as they are much more likely to be ejected from one host and carried to another. This is also the reason that many microorganisms cause diarrhea.

The relationship between virulence and transmission is complex and has important consequences for the long term evolution of a pathogen. Since it takes many generations for a microbe and a new host species to co-evolve, an emerging pathogen may hit its earliest victims especially hard. It is usually in the first wave of a new disease that death rates are highest. If a disease is rapidly fatal, the host may die before the microbe can be passed along to another host. However, this cost may be overwhelmed by the short-term benefit of higher infectiousness if transmission is linked to virulence, as it is for instance in the case of cholera (the explosive diarrhea aids the bacterium in finding new hosts) or many respiratory infections (sneezing and coughing create infectious aerosols).

Anything that reduces the rate of transmission of an infection carries positive externalities, which are benefits to society that are not reflected in a price to a consumer. This is recognized implicitly when vaccines are offered for free or at a cost to the patient less than the purchase price.

Beneficial microorganisms

The mode of transmission is also an important aspect of the biology of beneficial microbial symbionts, such as coral-associated dinoflagellates or human microbiota. Organisms can form symbioses with microbes transmitted from their parents, from the environment or unrelated individuals, or both.

Vertical transmission

Vertical transmission refers to acquisition of symbionts from parents (usually mothers). Vertical transmission can be intracellular (e.g. transovarial), or extracellular (for example through post-embryonic contact between parents and offspring). Both intracellular and extracellular vertical transmission can be considered a form of non-genetic inheritance or parental effect. It has been argued that most organisms experience some form of vertical transmission of symbionts. Canonical examples of vertically transmitted symbionts include the nutritional symbiont Buchnera in aphids (transovarially transmitted intracellular symbiont) and some components of the human microbiota (transmitted during passage of infants through the birth canal and also through breastfeeding).

Horizontal transmission

Some beneficial symbionts are acquired horizontally, from the environment or unrelated individuals. This requires that host and symbiont have some method of recognizing each other or each other's products or services. Often, horizontally acquired symbionts are relevant to secondary rather than primary metabolism, for example for use in defense against pathogens, but some primary nutritional symbionts are also horizontally (environmentally) acquired. Additional examples of horizontally transmitted beneficial symbionts include bioluminescent bacteria associated with bobtail squid and nitrogen-fixing bacteria in plants.

Mixed-mode transmission

Many microbial symbionts, including human microbiota, can be transmitted both vertically and horizontally. Mixed-mode transmission can allow symbionts to have the “best of both worlds” – they can vertically infect host offspring when host density is low, and horizontally infect diverse additional hosts when a number of additional hosts are available. Mixed-mode transmission make the outcome (degree of harm or benefit) of the relationship more difficult to predict, because the evolutionary success of the symbiont is sometimes but not always tied to the success of the host.

Drugs for Neglected Diseases Initiative

The logo of the Drugs for Neglected Diseases initiative (DNDi)

The Drugs for Neglected Diseases initiative (DNDi) is a collaborative, patients' needs-driven, non-profit drug research and development (R&D) organization that is developing new treatments for neglected diseases, notably leishmaniasis, sleeping sickness (human African trypanosomiasis, HAT), Chagas disease, malaria, filarial diseases, mycetoma, paediatric HIV, cryptococcal meningitis, hepatitis C, and dengue. DNDi's malaria activities were transferred to Medicines for Malaria Venture (MMV) in 2015.

Led by Executive Director Luis Pizarro, DNDi has offices in Switzerland (Geneva), Brazil, the Democratic Republic of Congo, India, Japan, Kenya, Malaysia, South Africa, and an affiliate in the United States.

Origins

Despite the major progress achieved in medicine during the past 50 years, many tropical diseases affecting the poorest are still neglected. More than a billion people – more than a seventh of the world's population – are infected with one of the 20 diseases listed by the World Health Organization (WHO) as neglected tropical diseases. Although neglected tropical diseases can be fatal, there is a lack of modern, safe and effective medications to treat these illnesses.

Evidence of the lack of new drugs for diseases that cause high mortality and morbidity among people living in poor areas has been published in the scientific literature. One publication reported that only 1.1% of new drugs were approved specifically for neglected diseases over a period of 25 years (1975 to 1999) despite the fact that these diseases represented 11.4% of the global burden. Another indicated that this trend remained the same between 2000 and 2011 with only 1.2% of the new chemical entities brought to market indicated for neglected diseases.

DNDi was created in 2003 to develop new treatments for neglected diseases. The organization was set up by key research and health institutions, notably from the public sector in neglected-disease-endemic countries – the Oswaldo Cruz Foundation from Brazil, the Indian Council of Medical Research, the Kenya Medical Research Institute, the Ministry of Health of Malaysia and France's Pasteur Institute, with seed funding from Médecins Sans Frontières' (MSF) 1999 Nobel Peace Prize. The WHO Special Programme for Research and Training in Tropical Diseases (TDR) acts as a permanent observer to the initiative.

DNDi's founder Bernard Pécoul led the organization from 2003 until 2022.

Non-profit drug development model

As people with neglected diseases do not represent a lucrative market for pharmaceutical companies, incentives to invest in research and development are lacking for these diseases.

Alternatives to profit-driven drug development emerged in the early 2000s to meet the needs of these neglected patients. Product development partnerships (PDPs), also called public-private partnerships (PPPs) aim to implement and accelerate research and development (R&D) into health tools (diagnostics, vaccines, drugs) for diseases that are neglected, by enabling new collaborations between private industry, academia, and the public sector. Examples of PDPs include the International AIDS Vaccine Initiative, MMV, the Global Alliance for TB Drug Development (TB Alliance), and DNDi.

PDPs act as ‘conductors of a virtual orchestra’, leveraging partners' specific assets, capacities, and expertise to implement projects at all stages of the R&D process, integrating capabilities from academia; public-sector research institutions, particularly in neglected disease-endemic countries; pharmaceutical and biotechnology companies; non-governmental organizations including other PDPs; and governments worldwide.

To overcome the lack of commercial research into drug development, PDPs can apply "delinkage" principles that aim to separate the cost of research and development from the price of products. This allows the incentive for investing in a particular disease to be independent of the price at which any developed products will be sold.

Key achievements

To date, DNDi has delivered eight new treatments and built a large drug pipeline for neglected diseases with both improvements on existing drugs and entirely new chemical entities.

Treatments delivered to date:

ASAQ, fixed-dose combination for malaria, 2007

Launched in 2007, this antimalarial product is a fixed-dose combination of artesunate/amodiaquine (ASAQ). The result of a partnership between DNDi and French pharmaceutical company Sanofi, ASAQ, which is produced in Morocco, is affordable (available for only $0.05 for children, $1 for adults), is administered in a simple regimen (1 or 2 tablets per day for three days), meets the latest WHO guidelines for malaria treatment in Africa and was granted "pre-qualified" status in 2008. Although developed without a patent, ASAQ is included in the WHO Model List of Essential Medicines and Essential Medicines List for Children, is registered in 32 African countries, India, Ecuador, and in Colombia, and more than 437 million treatments have been distributed.

A technology transfer agreement has been signed with industrial partner Zenufa in Tanzania in order to provide an additional source of ASAQ. ASAQ was handed over to the MMV Access and Product Management Team in May 2015.

ASMQ, fixed-dose combination for malaria, 2008

The second antimalarial treatment developed by DNDi is a fixed-dose combination of artesunate and mefloquine launched in 2008. It was developed by an international collaboration within the FACT Project Consortium. It has a simple and adapted regimen, a three-year shelf-ife and a very high compliance rate. ASMQ is produced in Brazil by Farmanguinhos [pt]/Fiocruz and thanks to a South–South technology transfer, it is now also produced by Cipla. The latter was granted "pre-qualified" status by the WHO in 2012 and included on the WHO Model List of Essential Medicines and Essential Medicines List for Children in 2013. By 2015 it was registered in Brazil, India, Malaysia, Myanmar, Tanzania, Vietnam, Niger, Burkina Faso, Thailand and Cambodia. By the end of 2015 more than one million treatments had been distributed. ASMQ was handed over to the MMV Access and Product Management Team in May 2015.

NECT, improved treatment for sleeping sickness, 2009

Nifurtimox-eflornithine combination treatment (NECT), a combination therapy of nifurtimox and eflornithine, is the first new, improved treatment option in 25 years for stage 2 (advanced stage) human African trypanosomiasis (HAT) also known as sleeping sickness. It is the result of a six-year partnership between NGOs, governments, pharmaceutical companies, and the WHO. It was launched in 2009 and included on the WHO Model List of Essential Medicines and WHO Essential Medicines List for Children in 2009 and 2013 respectively. It requires shorter hospitalization than previous treatment, and is much safer than previously widely used arsenic-based melarsoprol that killed about 5% of patients. NECT is now used to treat 100% of the patients infected with HAT stage 2 in all 13 endemic countries.

SSG&PM, combination treatment for visceral leishmaniasis, 2010

SSG&PM, a sodium stibogluconate plus paromomycin combination therapy, is a shorter-course, cost-efficient treatment option against visceral leishmaniasis (VL) in East Africa available since 2010. It is the result of a six-year partnership between DNDi, the Leishmaniasis East Africa Platform (LEAP), the National Control Programmes of Kenya, Sudan, Ethiopia, and Uganda, Médecins Sans Frontières (MSF) and the WHO. It was recommended by the WHO Expert Committee on the Control of Leishmaniasis in 2010 as the first-line treatment in East Africa, and more than 10,000 patients have been treated. Sudan, Ethiopia, South Sudan and Somalia have released revised guidelines recommending SSG&PM as the first-line treatment for VL.

Combination treatments for visceral leishmaniasis in Asia, 2011

Single dose amphotericin B and paromomycin/miltefosine/amphotericin B combinations were recommended by the WHO Expert Committee on the Control of Leishmaniasis (2010). These treatments are less toxic than previous mainstay treatments, useful in areas of antimonial resistance, are shorter course and their cost is comparable with previous treatments. In 2010, a study investigating the three possible 2-drug combinations of amphotericin B, miltefosine and paromomycin was completed in India. All three combination treatments were shown to be highly efficacious (> 97.5% cure rate). A WHO Expert committee recommended these treatments to be used preferentially to current established monotherapy treatments for VL in South Asia. DNDi is working with TDR and WHO to facilitate their introduction and support VL elimination strategies. DNDi conducted more studies, including a pilot project in the Bihar State of India (2012-2015) that demonstrated the safety and effectiveness of combination therapies based on amphotericin B, miltefosine, and paromomycin at the primary healthcare level, and single dose amphotericin B at the hospital level. Based on the study results, the Indian National Roadmap for Kala-Azar Elimination in August 2014 recommended use of single dose amphotericin B as a first option treatment for the treatment of VL patients, with paromomycin and miltefosine as a second option at all levels; a policy also reflected in Bangladesh and Nepal. This removal of miltefosine monotherapy is an important policy change. This project has been a collaboration with a consortium of partners.

Paediatric Benznidazole for Chagas disease, 2011

This is the only paediatric dosage treatment for Chagas disease, launched in 2011 through a collaboration between DNDi and Laboratório Farmacêutico do Estado de Pernambuco (LAFEPE). In November 2013, the Mundo Sano Foundation and DNDi signed a collaboration agreement to deliver a second source of the treatment in partnership with ELEA. The paediatric dosage form of benznidazole is designed for infants and young children under two years of age (20 kg body weight) infected congenitally. Thanks to its age-adapted, easy-to-use, affordable, and non-patented tablet, the new treatment contributes to improved dosing accuracy, safety, and adherence to treatment. The paediatric dosage form of benznidazole was granted registration by Brazil's National Health Surveillance Agency in 2011, and further endemic countries are targeted for obtaining registration. It was included on the WHO Essential Medicines List for Children in July 2013.

Superbooster therapy for children living with HIV and tuberculosis, 2016

Among the many challenges of treating children co-infected with both tuberculosis (TB) and HIV is the fact that a key TB drug negates the effectiveness of ritonavir, one of the main antiretrovirals to treat HIV. A DNDi-sponsored study at five hospitals in South Africa demonstrated the effectiveness of ‘super-boosting’ or adding extra ritonavir to a child's treatment regimen. WHO has since strengthened recommendations to use super-boosting in TB/HIV co-infected children.

Fexinidazole, 2018

Fexinidazole is the first entirely oral treatment for sleeping sickness (or human African trypanosomiase) due to Trypanosoma brucei gambiense. It was developed in partnership by DNDi, Sanofi, and others. The clinical trials enrolled 749 patients from the Democratic Republic of the Congo and the Central African Republic. Results published in The Lancet showed high efficacy and safety for both stages of the disease. Fexinidazole is administered as oral tablets for 10 days.

In November 2018, the European Medicines Agency adopted a positive scientific opinion of fexinidazole. In December 2018, fexinidazole was approved in the Democratic Republic of the Congo.

Other project:

Global Antibiotic Research & Development Partnership (GARDP)

In 2016, the WHO and DNDi collaborated to launch the Global Antibiotic Research & Development Partnership (GARDP), a not-for-profit research and development organization that addresses global public health needs by developing and delivering new or improved antibiotic treatments, while endeavouring to ensure their sustainable access. In 2018, GARDP was organized as an independent legal entity.

Ravidasvir, 2021

Access to affordable hepatitis C treatment with highly efficacious direct-acting antivirals (DAAs) remains extremely limited in many low- and middle-income countries. In 2016, DNDi signed agreements with US biopharmaceutical company Presidio Pharmaceuticals, developer of the DAA drug candidate ravidasvir, and its licensing partner, the Egyptian generic manufacturer Pharco Pharmaceuticals, to enable testing of a new combination treatment optimised for public health use: ravidasvir + sofosbuvir. A Phase II/III study in Malaysia and Thailand, co-sponsored by the Malaysian and Thai Ministries of Health and co-financed by the MSF Transformational Investment Capacity (TIC) initiative, showed that 12 weeks after the end of treatment, 97% of participants were cured. Patients with multiple risk factors were cured, and no unexpected safety signals were detected. In June 2021, Malaysia granted a conditional registration for ravidasvir.

New Treatments for HIV/VL, 2022

Leishmania-HIV coinfection has been reported from 35 endemic countries [http://www.who.int/news-room/fact-sheets/detail/leishmaniasis]. People co-infected with HIV and visceral leishmaniasis have poor response to treatment, higher risk of death, and often experience multiple relapse episodes. Based on the results of two studies, in June 2022 WHO released new treatment guidelines for the treatment of people co-infected with visceral leishmaniasis and HIV, recommending a combination of liposomal amphotericin B with miltefosine.

Leishmaniasis in Latin America, 2022

Previously, first-line treatment recommendations for visceral leishmaniasis in Brazil included the use of meglumine antimoniate, which has serious limitations due to toxicity, parenteral administration, and the need for hospitalization. Results of a trial in partnership with the University of Brasilia and the Oswaldo Cruz Foundation of Brazil showed that due to lower toxicity and acceptable efficacy, liposomal amphotericin B would be a more suitable first-line treatment for visceral leishmaniasis than standard treatment. In June 2022, the Pan American Health Organization (PAHO) published new guidelines for the treatment of leishmaniasis in the Americas, which recommend liposomal amphotericin B for the treatment of visceral leishmaniasis instead of pentavalent antimonials.

4-in-1 for paediatric HIV, 2022

This ‘4-in-1’ fixed-dose combination combines the protease inhibitors lopinavir and ritonavir with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine and abacavir for the treatment of paediatric HIV. The 4-in-1 is a significant improvement over currently available lopinavir-based regimens, because it is formulated as a granule-filled capsule, which is heat-stable, taste-masked, solid, and does not contain alcohol or inappropriate solvents. It was developed for infants and young children weighing from 3 to 25 kg, in partnership with Cipla Limited. It can be administered by opening the capsules and sprinkling the granules on soft food, water, or milk. The South African Health Products Regulatory Authority (SAHPRA) approved the 4-in-1 in June 2022.

Awards

In 2013, DNDi won the BBVA Foundation Frontiers of Knowledge Award in the Development Cooperation category for developing and delivering new treatments for poverty-related diseases including Chagas disease, sleeping sickness, malaria and leishmaniasis.

DNDi received the Carlos Slim Health Award in 2013. Created in 2008 by the Carlos Slim Foundation, the aim of the award is to distinguish the people and institutions who are committed to improving the levels of health among the population of Latin America and the Caribbean.

In 2013, The Rockefeller Foundation asked the global community to nominate organizations and individuals who were making a difference for poor and vulnerable populations through innovation. From those nominations, and the votes of individuals around the world, The Rockefeller Foundation selected three winners of the 2013 Next Century Innovators Award. DNDi was one of the awardees.

On December 11, 2015, DNDi won the national FINEP Award for Innovation. The award was in recognition of an innovative R&D model that has delivered a new antimalarial drug developed in Brazil.

DNDi received the prize for innovation in 2017 and the ‘cuvée 2018 de la Vigne des Nations’ in 2018, both from the Canton of Geneva.

The publication Oral fexinidazole for late-stage African Trypanosoma brucei gambiense trypanosomiasis: a pivotal multicentre, randomised, non-inferiority trial published November 4, 2017 in The Lancet was one of the two winners of the 2018 edition of the Anne Maurer-Cecchini Award.

A short film about fexinidazole, a new treatment for sleeping sickness, was awarded the Grand Prix at the inaugural World Health Organization 'Health for All' film festival in 2020. 'A doctor's dream' was produced by DNDi with Scholars and Gentlemen, a production company from South Africa.

Regional clinical trial platforms

DNDi works with partners in disease-endemic countries to strengthen existing clinical research capacity and build new capacity where necessary. DNDi helped in the setting up of four regional disease-specific platforms in Africa and Latin America including the Leishmaniasis East Africa Platform (LEAP) on leishmaniasis. the HAT Platform on sleeping sickness (human African trypanosomiasis), the Chagas Clinical Research Platform (CCRP), and the RedeLeish Network on leishmaniasis in Latin America and continues to work with them.

Their mission is to define patient needs, taking into consideration the local conditions, bring together key regional actors in the field of health, reinforce clinical capacities in endemic regions, address infrastructural requirements where necessary and provide on-site training.

Long-term objective

As part of its Strategic Plan 2021-2028, DNDi aims to deliver 15 to 18 new treatments, for a total of 25 new treatments in its first 25 years.

Thermodynamic diagrams

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Thermodynamic_diagrams Thermodynamic diagrams are diagrams used to repr...