Zika fever

From Wikipedia, the free encyclopedia

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

 

Zika fever
Other names	Zika virus disease, Zika, Zika virus infection
Rash during Zika fever infection
Pronunciation	Zika /ˈziːkə/
Specialty	Infectious disease
Symptoms	Fever, red eyes, joint pain, headache, maculopapular rash
Complications	Guillain–Barré syndrome, during pregnancy can cause microcephaly in the baby
Duration	Less than a week
Causes	Zika virus mainly spread by mosquitoes
Diagnostic method	Testing blood, urine, or saliva for viral RNA or blood for antibodies
Differential diagnosis	Chikungunya, malaria, dengue, leptospirosis, measles
Prevention	Decreasing mosquito bites, condoms
Treatment	Supportive care
Deaths	None during initial infection

Zika fever, also known as Zika virus disease or simply Zika, is an infectious disease caused by the Zika virus. Most cases have no symptoms, but when present they are usually mild and can resemble dengue fever. Symptoms may include fever, red eyes, joint pain, headache, and a maculopapular rash. Symptoms generally last less than seven days. It has not caused any reported deaths during the initial infection. Mother-to-child transmission during pregnancy can cause microcephaly and other brain malformations in some babies. Infections in adults have been linked to Guillain–Barré syndrome (GBS).

Zika fever is mainly spread via the bite of mosquitoes of the Aedes type. It can also be sexually transmitted and potentially spread by blood transfusions. Infections in pregnant women can spread to the baby. Diagnosis is by testing the blood, urine, or saliva for the presence of the virus's RNA when the person is sick, or the blood for antibodies after symptoms are present more than a week.

Prevention involves decreasing mosquito bites in areas where the disease occurs and proper use of condoms. Efforts to prevent bites include the use of insect repellent, covering much of the body with clothing, mosquito nets, and getting rid of standing water where mosquitoes reproduce. There is no effective vaccine. Health officials recommended that women in areas affected by the 2015–16 Zika outbreak consider putting off pregnancy and that pregnant women not travel to these areas. While there is no specific treatment, paracetamol (acetaminophen) may help with the symptoms. Admission to hospital is rarely necessary.

The virus that causes the disease was first isolated in Africa in 1947. The first documented outbreak among people occurred in 2007 in the Federated States of Micronesia. An outbreak started in Brazil in 2015, and spread to the Americas, Pacific, Asia, and Africa. This led to the World Health Organization declared it a Public Health Emergency of International Concern in February 2016. The emergency was lifted in November 2016, but 84 countries still reported cases as of March 2017. The last proven case of Zika spread in the Continental United States was in 2017.

Signs and symptoms

Rash on an arm due to Zika fever

Most people who are infected have no or few symptoms. Otherwise the most common signs and symptoms of Zika fever are fever, rash, conjunctivitis (red eyes), muscle and joint pain, and headache, which are similar to signs and symptoms of dengue and chikungunya fever. The time from a mosquito bite to developing symptoms is not yet known, but is probably a few days to a week. The disease lasts for several days to a week and is usually mild enough that people do not have to go to a hospital.

Due to being in the same family as dengue, there has been concern that it could cause similar bleeding disorders. However that has only been documented in one case, with blood seen in semen, also known as hematospermia.

Guillain–Barré syndrome

Zika virus infections have been strongly associated with Guillain–Barré syndrome (GBS), which is a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system, and which can progress to paralysis. While both GBS and Zika infection can simultaneously occur in the same individual, it is difficult to definitively identify Zika virus as the cause of GBS. Though Zika virus has been shown to infect human Schwann cells. Several countries affected by Zika outbreaks have reported increases in the rate of new cases of GBS. During the 2013–2014 outbreak in French Polynesia there were 42 reported cases of GBS over a 3-month period, compared to between 3 and 10 annually prior to the outbreak.

Pregnancy

Microcephaly

The disease spreads from mother to child in the womb and can cause multiple problems, most notably microcephaly, in the baby. The full range of birth defects caused by infection during pregnancy is not known, but they appear to be common, with large scale abnormalities seen in up to 42% of live births. The most common observed associations have been abnormalities with brain and eye development such as microcephaly and chorioretinal scarring. Less commonly there have been systemic abnormalities such as hydrops fetalis, where there is abnormal accumulation of fluid in the fetus. These abnormalities can lead to intellectual problems, seizures, vision problems, hearing problems, problems feeding and slow development.

Whether the stage of pregnancy at which the mother becomes infected affects the risk to the fetus is not well understood, nor is whether other risk factors affect outcomes. One group has estimated the risk of a baby developing microcephaly at about 1% when the mother is infected during the first trimester, with the risk of developing microcephaly becoming uncertain beyond the first trimester. Affected babies might appear normal but actually have brain abnormalities; infection in newborns could also lead to brain damage.

Cause

Reservoir

Zika virus is a mosquito-borne flavivirus closely related to the dengue and yellow fever viruses. While mosquitoes are the vector, the main reservoir species remains unknown, though serological evidence has been found in both West African monkeys and rodents.

Transmission

Transmission is via the bite of mosquitoes from the genus Aedes, primarily Aedes aegypti in tropical regions. It has also been isolated from Ae. africanus, Ae. apicoargenteus, Ae. luteocephalus, Ae. Albopictus, Ae. vittatus and Ae. furcifer. During the 2007 outbreak on Yap Island in the South Pacific, Aedes hensilli was the vector, while Aedes polynesiensis spread the virus in French Polynesia in 2013.

Zika virus can also spread by sexual transmission from infected men to their partners. Zika virus has been isolated from semen samples, with one person having 100,000 times more virus in semen than blood or urine, two weeks after being infected. It is unclear why levels in semen can be higher than other body fluids, and it is also unclear how long infectious virus can remain in semen. There have also been cases of men with no symptoms of Zika virus infection transmitting the disease. The CDC has recommended that all men who have travelled to affected areas should wait at least 6 months before trying to attempt conception, regardless of if they were ill. To date there have been no reported sexual transmissions from women to their sexual partners. Oral, anal or vaginal sex can spread the disease.

Cases of vertical perinatal transmission have been reported. The CDC recommends that women with Zika fever should wait at least 8 weeks after they start having symptoms of disease before attempting to conceive. There have been no reported cases of transmission from breastfeeding, but infectious virus has been found in breast milk.

Like other flaviviruses it could potentially be transmitted by blood transfusion and several affected countries have developed strategies to screen blood donors. The U.S. FDA has recommended universal screening of blood products for Zika. The virus is detected in 3% of asymptomatic blood donors in French Polynesia.

Pathophysiology

In fruit flies microcephaly appears to be caused by the flavivirid virus protein NS4A, which can disrupt brain growth by hijacking a pathway which regulates growth of new neurons.

Diagnosis

It is difficult to diagnose Zika virus infection based on clinical signs and symptoms alone due to overlaps with other arboviruses that are endemic to similar areas. The US Centers for Disease Control and Prevention (CDC) advises that "based on the typical clinical features, the differential diagnosis for Zika virus infection is broad. In addition to dengue, other considerations include leptospirosis, malaria, rickettsia, group A streptococcus, rubella, measles, and parvovirus, enterovirus, adenovirus, and alphavirus infections (e.g., chikungunya, Mayaro, Ross River, Barmah Forest, O'nyong'nyong, and Sindbis viruses)."

In small case series, routine chemistry and complete blood counts have been normal in most patients. A few have been reported to have mild leukopenia, thrombocytopenia, and elevated liver transaminases.

Zika virus can be identified by reverse transcriptase PCR (RT-PCR) in acutely ill patients. However, the period of viremia can be short and the World Health Organization (WHO) recommends RT-PCR testing be done on serum collected within 1 to 3 days of symptom onset or on saliva samples collected during the first 3 to 5 days. When evaluating paired samples, Zika virus was detected more frequently in saliva than serum. Urine samples can be collected and tested up to 14 days after the onset of symptoms, as the virus has been seen to survive longer in the urine than either saliva or serum. The longest period of detectable virus has been 11 days and Zika virus does not appear to establish latency.

Later on, serology for the detection of specific IgM and IgG antibodies to Zika virus can be used. IgM antibodies can be detectable within 3 days of the onset of illness. Serological cross-reactions with closely related flaviviruses such as dengue and West Nile virus as well as vaccines to flaviviruses are possible. As of 2019, the FDA has authorized two tests to detect Zika virus antibodies.

Screening in pregnancy

The CDC recommends screening some pregnant women even if they do not have symptoms of infection. Pregnant women who have traveled to affected areas should be tested between two and twelve weeks after their return from travel. Due to the difficulties with ordering and interpreting tests for Zika virus, the CDC also recommends that healthcare providers contact their local health department for assistance. For women living in affected areas, the CDC has recommended testing at the first prenatal visit with a doctor as well as in the mid-second trimester, though this may be adjusted based on local resources and the local burden of Zika virus. Additional testing should be done if there are any signs of Zika virus disease. Women with positive test results for Zika virus infection should have their fetus monitored by ultrasound every three to four weeks to monitor fetal anatomy and growth.

Infant testing

For infants with suspected congenital Zika virus disease, the CDC recommends testing with both serologic and molecular assays such as RT-PCR, IgM ELISA and plaque reduction neutralization test (PRNT). RT-PCR of the infants serum and urine should be performed in the first two days of life. Newborns with a mother who was potentially exposed and who have positive blood tests, microcephaly or intracranial calcifications should have further testing including a thorough physical investigation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions. Other recommended tests are cranial ultrasound, hearing evaluation, and eye examination. Testing should be done for any abnormalities encountered as well as for other congenital infections such as syphilis, toxoplasmosis, rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection, and herpes simplex virus. Some tests should be repeated up to 6 months later as there can be delayed effects, particularly with hearing.

Prevention

The virus is spread by mosquitoes, making mosquito avoidance an important element to disease control. The CDC recommends that individuals:

• Cover exposed skin by wearing long-sleeved shirts and long pants treated with permethrin.
• Use an insect repellent containing DEET, picaridin, oil of lemon eucalyptus (OLE), or ethyl butylacetylaminopropionate (IR3535)
• Always follow product directions and reapply as directed
• If you are also using sunscreen, apply sunscreen first, let it dry, then apply insect repellent
• Follow package directions when applying repellent on children. Avoid applying repellent to their hands, eyes, or mouth
• Stay and sleep in screened-in or air-conditioned rooms
• Use a bed net if the area where you are sleeping is exposed to the outdoors
• Cover cribs, strollers and carriers with mosquito netting for babies under 2 months old.

The CDC also recommends strategies for controlling mosquitoes such as eliminating standing water, repairing septic tanks and using screens on doors and windows. Spraying insecticide is used to kill flying mosquitoes and larvicide can be used in water containers.

Because Zika virus can be sexually transmitted, men who have gone to an area where Zika fever is occurring should be counseled to either abstain from sex or use condoms for 6 months after travel if their partner is pregnant or could potentially become pregnant. Breastfeeding is still recommended by the WHO, even by women who have had Zika fever. There have been no recorded cases of Zika transmission to infants through breastfeeding, though the replicative virus has been detected in breast milk.

When returning from travel, with or without symptoms, it is suggested that prevention of mosquito bites continue for 3 weeks in order reduce the risk of virus transmission to uninfected mosquitos.

CDC travel alert

Because of the "growing evidence of a link between Zika and microcephaly", in January 2016, the CDC issued a travel alert advising pregnant women to consider postponing travel to countries and territories with ongoing local transmission of Zika virus. Later, the advice was updated to caution pregnant women to avoid these areas entirely if possible and, if travel is unavoidable, to protect themselves from mosquito bites. Male partners of pregnant women and couples contemplating pregnancy who must travel to areas where Zika is active are advised to use condoms or abstain from sex entirely. The agency also suggested that women thinking about becoming pregnant should consult with their physicians before traveling.

As of September 2016, the CDC travel advisories include:

• Cape Verde
• Many parts of the Caribbean: Anguilla, Antigua and Barbuda, Aruba, The Bahamas, Barbados, Bonaire, British Virgin Islands, Cayman Islands, Cuba, Curaçao, Dominica, Dominican Republic, Grenada, Guadeloupe, Haiti, Jamaica, Martinique, Puerto Rico, Saba, Saint Saint Barthélemy, Saint Lucia, Saint Martin, Saint Vincent and the Grenadines, Sint Eustatius, Sint Maarten, Trinidad and Tobago, and the U.S. Virgin Islands
• Central America: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama
• Mexico
• Most of South America: Argentina, Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Paraguay, Peru, Suriname, and Venezuela
• Several Pacific Islands: American Samoa, Fiji, Marshall Islands, Micronesia, New Caledonia, Papua New Guinea, Samoa, and Tonga
• In Asia: Singapore, Malaysia, Brunei

WHO response

Both the regional Pan American Health Organization (PAHO) as well as the WHO have issued statements of concern about the widespread public health impact of the Zika virus and its links to GBS and microcephaly. The WHO Director-General, Margaret Chan, issued a statement in February 2016 "declaring that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern." The declaration allowed the WHO to coordinate international response to the virus as well as gave its guidance the force of international law under the International Health Regulations. The declaration was ended in November 2016.

Vaccine

As of 2016 there was no available vaccine. Development was a priority of the US National Institutes of Health (NIH), but officials stated that development of a vaccine could take years. To speed new drug development regulatory strategies were proposed by the WHO and NIH. Animal and early human studies were underway as of September 2016. As of December 2019, there were several vaccine candidates in various stages of development.

Mosquito control

Disease control in the affected countries currently centres around mosquito control. Several approaches are available for the management of Aedes aegypti mosquito populations, including the destruction of larval breeding sites (the aquatic pools in which eggs are laid and larvae hatch prior to mosquito development into flying adults); and, insecticides targeting either the larval stages, adult mosquitoes or both. Additionally, a whole host of novel technologies are under current development for mosquito control and the World Health Organization has recently lent its support for the accelerated development of modern methods for mosquito control such as the use of Wolbachia bacteria to render mosquitoes resistant to the virus, and, the release of sterilized male mosquitoes that breed with wild female mosquitoes to give rise to non-viable offspring (offspring that do not survive to the biting, adult stage).

Oxitec’s genetically modified OX513A mosquito was approved by Brazil's National Biosecurity Technical Commission (CTNBio) in April 2014 and it was being used to try to combat mosquitoes carrying the Zika virus in the town of Piracicaba, São Paulo in 2016.

In the 1940s and 1950s, the Aedes aegypti mosquito was eradicated on some Caribbean islands and in at least eighteen Latin American countries. Decreasing political will and presumably available money, mosquito resistance to insecticide, and a pace of urbanization which exceeded eradication efforts led to this mosquito's comeback.

Treatment

There is currently no specific treatment for Zika virus infection. Care is supportive with treatment of pain, fever, and itching. Some authorities have recommended against using aspirin and other NSAIDs as these have been associated with hemorrhagic syndrome when used for other flaviviruses. Additionally, aspirin use is generally avoided in children when possible due to the risk of Reye syndrome.

Zika virus had been relatively little studied until the major outbreak in 2015, and no specific antiviral treatments are available as yet. Advice to pregnant women is to avoid any risk of infection so far as possible, as once infected there is little that can be done beyond supportive treatment.

Outcomes

Most of the time, Zika fever resolves on its own in 2 to 7 days, but rarely, some people develop Guillain–Barré syndrome. The fetus of a pregnant woman who has Zika fever may die or be born with congenital central nervous system malformations, like microcephaly.

Epidemiology

Countries with active Zika virus transmission as of September 2016.

In April 1947, as part of studies sponsored by the Rockefeller Foundation into yellow fever, 6 caged rhesus monkeys were placed in the canopy of the Zika Forest of Uganda. On April 18 one of the monkeys (no. 776) developed a fever and blood samples revealed the first known case of Zika fever. Population surveys at the time in Uganda found 6.1% of individuals to be seropositive for Zika. The first human cases were reported in Nigeria in 1954. A few outbreaks have been reported in tropical Africa and in some areas in Southeast Asia. There have been no documented cases of Zika virus in the Indian subcontinent. Surveys have found antibodies to Zika in healthy people in India which could indicate past exposure, though it could also be due to cross-reaction with other flaviviruses.

By using phylogenetic analysis of Asian strains, it was estimated that Zika virus had moved to Southeast Asia by 1945. In 1977–1978, Zika virus infection was described as a cause of fever in Indonesia. Before 2007, there were only 13 reported natural infections with Zika virus, all with a mild, self-limited febrile illness.

Yap Islands

The first major outbreak, with 185 confirmed cases, was reported in 2007 in the Yap Islands of the Federated States of Micronesia. A total of 108 cases were confirmed by PCR or serology and 72 additional cases were suspected. The most common symptoms were rash, fever, arthralgia, and conjunctivitis, and no deaths were reported. The mosquito Aedes hensilli, which was the predominant species identified in Yap during the outbreak, was probably the main vector of transmission. While the way of introduction of the virus on Yap Island remains uncertain, it is likely to have happened through introduction of infected mosquitoes or a human infected with a strain related to those in Southeast Asia. This was also the first time Zika fever had been reported outside Africa and Asia. Before the Yap Island outbreak, only 14 human cases had ever been reported.

Oceania

In 2013–2014, several outbreaks of Zika were reported in French Polynesia, New Caledonia, Easter Island and the Cook Islands. The source of the virus was thought to be an independent introduction of the virus from Southeast Asia, unrelated to the Yap Islands outbreak.

Americas

Areas of active Zika virus transmission, April 2016

Genetic analyses of Zika virus strains suggest that Zika first entered the Americas between May and December 2013. It was first detected in the Western Hemisphere in February 2014, and rapidly spread throughout South and Central America, reaching Mexico in November 2015. In 2016 it established local transmission in Florida and Texas. The first death in the United States due to Zika occurred in February 2016.

In May 2015, Brazil officially reported its first 16 cases of the illness. Although, a case of illness was reported in March 2015 in a returning traveller. According to the Brazilian Health Ministry, as of November 2015 there was no official count of the number of people infected with the virus in Brazil, since the disease is not subject to compulsory notification. Even so, cases were reported in 14 states of the country. Mosquito-borne Zika virus is suspected to be the cause of 2,400 possible cases of microcephaly and 29 infant deaths in Brazil in 2015 (of the 2400 or so notified cases in 2015, 2165 were under investigation in December 2015, 134 were confirmed and 102 were ruled out for microcephaly).

The Brazilian Health Ministry has reported at least 2,400 suspected cases of microcephaly in the country in 2015 as of 12 December, and 29 fatalities. Before the Zika outbreak, only an average of 150 to 200 cases per year were reported in Brazil. In the state of Pernambuco the reported rates of microcephaly in 2015 are 77 times higher than in the previous 5 years. A model using data from a Zika outbreak in French Polynesia estimated the risk of microcephaly in children born to mothers who acquired Zika virus in the first trimester to be 1%.

On 24 January 2016, the WHO warned that the virus is likely to spread to nearly all countries of the Americas, since its vector, the mosquito Aedes aegypti, is found in all countries in the region, except for Canada and continental Chile. The mosquito and dengue fever have been detected in Chile's Easter Island, some 3,500 km (2,200 mi) away from its closest point in mainland Chile, since 2002.

In February 2016, WHO declared the outbreak a Public Health Emergency of International Concern as evidence grew that Zika is a cause of birth defects and neurological problems. In April 2016, WHO stated there is a scientific consensus, based on preliminary evidence, that Zika is a cause of microcephaly in infants and Guillain–Barré syndrome in adults. Studies of this and prior outbreaks have found Zika infection during pregnancy to be associated with early pregnancy loss and other pregnancy problems.

Asia

In 2016 imported or locally transmitted Zika was reported in all the countries of Asia except Brunei, Hong Kong, Myanmar and Nepal. Serological surveys have indicated that Zika virus is endemic in most areas of Asia, though at a low level. While there was a sharp rise in the number of cases of Zika detected in Singapore after the 2016 Summer Olympics in Brazil, genetic analysis revealed that the strains were more closely related to strains from Thailand than from those causing the epidemic in the Americas.

History

Origin of the name

It is named after the Zika Forest near Entebbe, Uganda, where the Zika virus was first identified.

Microcephaly and other infant disorders

Zika virus was first identified in the late 1940s in Kampala, Uganda, Africa but was first confirmed in Brazil. Since it was first identified, Zika has been found in more than 27 countries and territories. Following the initial Zika outbreak in Northeastern Brazil in May 2015, physicians observed a very large surge of reports of infants born with microcephaly, with 20 times the number of expected cases.  Many of these cases have since been confirmed, leading WHO officials to project that approximately 2,500 infants will be found to have born in Brazil with Zika-related microcephaly.

Proving that Zika causes these effects was difficult and complex for several reasons. For example, the effects on an infant might not be seen until months after the mother's initial infection, long after the time when Zika is easily detected in the body. In addition, research was needed to determine the mechanism by which Zika produced these effects.

Since the initial outbreak, studies that use several different methods found evidence of a link, leading public health officials to conclude that it appears increasingly likely the virus is linked to microcephaly and miscarriage. On 1 February 2016, the World Health Organization declared recently reported clusters of microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC). On 8 March 2016, the WHO Committee reconfirmed that the association between Zika and neurological disorders is of global concern.

The Zika virus was first linked with newborn microcephaly during the Brazil Zika virus outbreak. In 2015, there were 2,782 suspected cases of microcephaly compared with 147 in 2014 and 167 in 2013. Confirmation of many of the recent cases is pending, and it is difficult to estimate how many cases went unreported before the recent awareness of the risk of virus infections.

Brazilian President Dilma Rousseff in a videoconference about the Zika virus at the National Center for Disaster Management.

 

In November 2015, the Zika virus was isolated in a newborn baby from the northeastern state of Ceará, Brazil, with microcephaly and other congenital disorders. The Lancet medical journal reported in January 2016 that the Brazilian Ministry of Health had confirmed 134 cases of microcephaly "believed to be associated with Zika virus infection" with an additional 2,165 cases in 549 counties in 20 states remaining under investigation. An analysis of 574 cases of microcephaly in Brazil during 2015 and the first week of 2016, reported in March 2016, found an association with maternal illness involving rash and fever during the first trimester of pregnancy. During this period, 12 Brazilian states reported increases of at least 3 standard deviations (SDs) in cases of microcephaly compared with 2000–14, with the northeastern states of Bahia, Paraíba and Pernambuco reporting increases of more than 20 SDs.

In January 2016, a baby in Oahu, Hawaii, was born with microcephaly, the first case in the United States of brain damage linked to the virus. The baby and mother tested positive for a past Zika virus infection. The mother, who had probably acquired the virus while traveling in Brazil in May 2015 during the early stages of her pregnancy, had reported her bout of Zika. She recovered before relocating to Hawaii. Her pregnancy had progressed normally, and the baby's condition was not known until birth.

In February 2016, ocular disorders in newborns have been linked to Zika virus infection. In one study in Pernambuco state in Brazil, about 40 percent of babies with Zika-related microcephaly also had scarring of the retina with spots, or pigment alteration. On 20 February 2016, Brazilian scientists announced that they had successfully sequenced the Zika virus genome and expressed hope that this would help in both developing a vaccine and in determining the nature of any link to birth defects.

Also in February 2016, rumors that microcephaly is caused by the use of the larvicide pyriproxyfen in drinking water were refuted by scientists. "It's important to state that some localities that do not use pyriproxyfen also had reported cases of microcephaly", read a Brazilian government statement. The Brazilian government also refuted conspiracy theories that chickenpox and rubella vaccinations or genetically modified mosquitoes were causing increases in microcephaly.

Researchers also suspected that Zika virus could be transmitted by a pregnant woman to her babies ("vertical transmission"). This remained unproven until February 2016, when a paper by Calvet et al. was published, showing not only was the Zika virus genome found in the amniotic fluid but also IgM antibodies against the virus. This means that not only can the virus cross the placental barrier, but also the antibodies produced by the mother can reach the fetus, which suggests that vertical transmission is plausible in these cases. One other study published in March 2016 by Mlakar and colleagues analyzed autopsy tissues from a fetus with microcephaly that was probably related to Zika virus; researchers found ZIKV in the brain tissue and suggested that the brain injuries were probably associated with the virus, which also shed a light on the vertical transmission theory. Also in March 2016, first solid evidence was reported on how the virus affects the development of the brain, indicating that it appears to preferentially kill developing brain cells.

The first cases of birth defects linked to Zika in Colombia and in Panama were reported in March 2016. In the same month, researchers published a prospective cohort study that found profound impacts in 29 percent of infants of mothers infected with Zika, some of whom were infected late in pregnancy. This study did not suffer from some of the difficulties of studying Zika: the study followed women who presented to a Rio de Janeiro clinic with fever and rash within the last five days. The women were then tested for Zika using PCR, then the progress of the pregnancies were followed using ultrasound.

Guillain–Barré syndrome

A high rate of the autoimmune disease Guillain–Barré syndrome (GBS), noted in the French Polynesia outbreak, has also been found in the outbreak that began in Brazil. Laboratory analysis found Zika infections in some patients with GBS in Brazil, El Salvador, Suriname and Venezuela, and the WHO declared on 22 March 2016 that Zika appeared to be "implicated" in GBS infection and that if the pattern was confirmed it would represent a global public health crisis.

Research

Mechanism

Research has been ongoing to better understand how Zika virus causes microcephaly and other neurological disorders.

It may involve infection of the primary neural stem cells of the fetal brain, known as neural progenitor cells. The main roles of brain stem cells are to proliferate until the correct number is achieved, and then to produce neurons through the process of neurogenesis. Zika proteins NS4A and NS4B have also been shown to directly suppress neurogenesis. Infection of brain stem cells can cause cell death, which reduces the production of future neurons and leads to a smaller brain. Zika also appears to have an equal tropism for cells of the developing eye, leading to high rates of eye abnormalities as well.

In addition to inducing cell death, infection of neural progenitor cells may alter the process of cell proliferation, causing a depletion in the pool of progenitor cells. A large number of cases of microcephaly have been associated with inherited gene mutations, and specifically with mutations that lead to dysfunction of the mitotic spindle. There is some evidence that Zika virus may directly or indirectly interfere with mitotic function, this may play a role in altering cell proliferation.

Another line of research considers that Zika, unlike other flaviviruses, may target developing brain cells after it crosses the placenta, and considers the resulting damage likely to be the result of inflammation as a byproduct of the immune response to the infection of those cells.

Mosquito control

Some experimental methods of prevention include breeding and releasing mosquitoes that have been genetically modified to prevent them from transmitting pathogens, or have been infected with the Wolbachia bacterium, believed to inhibit the spread of viruses. A strain of Wolbachia helped to reduce the vector competence of the Zika virus in infected Aedes aegypti released in Medellin, Colombia. Gene drive is a technique for changing wild populations, for instance to combat insects so they cannot transmit diseases (in particular mosquitoes in the cases of malaria and Zika). Another method which been researched aims to render male mosquitoes infertile by nuclear radiation in the hope to reduce populations; this is done with a cobalt-60 gamma cell irradiator. In 2016 the World Health Organization encouraged field trials of transgenic male Aedes aegypti mosquitoes developed by Oxitec to try to halt the spread of the Zika virus.

Innate immune system

From Wikipedia, the free encyclopedia

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

 

Innate immune system

The innate immune system is one of the two main immunity strategies found in vertebrates (the other being the adaptive immune system). The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

The major functions of the vertebrate innate immune system include:

• Recruiting immune cells to sites of infection through the production of chemical factors, including specialized chemical mediators called cytokines
• Activation of the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells
• Identification and removal of foreign substances present in organs, tissues, blood and lymph, by specialized white blood cells
• Activation of the adaptive immune system through a process known as antigen presentation
• Acting as a physical and chemical barrier to infectious agents; via physical measures like skin or tree bark and chemical measures like clotting factors in blood or sap from a tree, which are released following a contusion or other injury that breaks through the first-line physical barrier (not to be confused with a second-line physical or chemical barrier, such as the blood-brain barrier, which protects the extremely vital and highly sensitive nervous system from pathogens that have already gained access to the host's body).

Anatomical barriers

Anatomical barrier	Additional defense mechanisms
Skin	Sweat, desquamation, flushing, organic acids
Gastrointestinal tract	Peristalsis, gastric acid, bile acids, digestive enzyme, flushing, thiocyanate, defensins, gut flora
Respiratory airways and lungs	Mucociliary escalator, surfactant, defensins
Nasopharynx	Mucus, saliva, lysozyme
Eyes	Tears
Blood-brain barrier	endothelial cells (via passive diffusion / osmosis & active selection). P-glycoprotein (mechanism by which active transportation is mediated)

Anatomical barriers include physical, chemical and biological barriers. The epithelial surfaces form a physical barrier that is impermeable to most infectious agents, acting as the first line of defense against invading organisms. Desquamation (shedding) of skin epithelium also helps remove bacteria and other infectious agents that have adhered to the epithelial surfaces. Lack of blood vessels, the inability of the epidermis to retain moisture, and the presence of sebaceous glands in the dermis, produces an environment unsuitable for the survival of microbes. In the gastrointestinal and respiratory tract, movement due to peristalsis or cilia, respectively, helps remove infectious agents. Also, mucus traps infectious agents. The gut flora can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces. The flushing action of tears and saliva helps prevent infection of the eyes and mouth.

Inflammation

Inflammation is one of the first responses of the immune system to infection or irritation. Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens.

The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells, and mast cells. These cells present receptors contained on the surface or within the cell, named pattern recognition receptors (PRRs), which recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). At the onset of an infection, burn, or other injuries, these cells undergo activation (one of their PRRs recognizes a PAMP) and release inflammatory mediators responsible for the clinical signs of inflammation.

Chemical factors produced during inflammation (histamine, bradykinin, serotonin, leukotrienes, and prostaglandins) sensitize pain receptors, cause local vasodilation of the blood vessels, and attract phagocytes, especially neutrophils. Neutrophils then trigger other parts of the immune system by releasing factors that summon additional leukocytes and lymphocytes. Cytokines produced by macrophages and other cells of the innate immune system mediate the inflammatory response. These cytokines include TNF, HMGB1, and IL-1.

The inflammatory response is characterized by the following symptoms:

• redness of the skin, due to locally increased blood circulation;
• heat, either increased local temperature, such as a warm feeling around a localized infection, or a systemic fever;
• swelling of affected tissues, such as the upper throat during the common cold or joints affected by rheumatoid arthritis;
• increased production of mucus, which can cause symptoms like a runny nose or a productive cough;
• pain, either local pain, such as painful joints or a sore throat, or affecting the whole body, such as body aches; and
• possible dysfunction of the organs or tissues involved.

Complement system

The complement system is a biochemical cascade of the immune system that helps, or “complements”, the ability of antibodies to clear pathogens or mark them for destruction by other cells. The cascade is composed of many plasma proteins, synthesized in the liver, primarily by hepatocytes. The proteins work together to:

• trigger the recruitment of inflammatory cells
• "tag" pathogens for destruction by other cells by opsonizing, or coating, the surface of the pathogen
• form holes in the plasma membrane of the pathogen, resulting in cytolysis of the pathogen cell, causing the death of the pathogen
• rid the body of neutralised antigen-antibody complexes.

There are three different complement systems: Classical, alternative, Lectin

• Classical: starts when antibody bind to bacteria
• Alternative: starts "spontaneously"
• Lectin: starts when lectins bind to mannose on bacteria

Elements of the complement cascade can be found in many non-mammalian species including plants, birds, fish, and some species of invertebrates.

White blood cells

A scanning electron microscope image of normal circulating human blood. One can see red blood cells, several knobby white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shape platelets.

 

All white blood cells (WBCs) are known as leukocytes. Most leukocytes differ from other cells of the body in that they are not tightly associated with a particular organ or tissue; thus, their function is similar to that of independent, single-cell organisms. Most leukocytes are able to move freely and interact with and capture cellular debris, foreign particles, and invading microorganisms (although macrophages, mast cells, and dendritic cells are less mobile). Unlike many other cells in the body, most innate immune leukocytes cannot divide or reproduce on their own, but are the products of multipotent hematopoietic stem cells present in the bone marrow.

The innate leukocytes include: natural killer cells, mast cells, eosinophils, basophils; and the phagocytic cells include macrophages, neutrophils, and dendritic cells, and function within the immune system by identifying and eliminating pathogens that might cause infection.

Mast cells

Mast cells are a type of innate immune cell that reside in connective tissue and in the mucous membranes. They are intimately associated with wound healing and defense against pathogens, but are also often associated with allergy and anaphylaxis (serious allergic reactions that can cause death). When activated, mast cells rapidly release characteristic granules, rich in histamine and heparin, along with various hormonal mediators and chemokines, or chemotactic cytokines into the environment. Histamine dilates blood vessels, causing the characteristic signs of inflammation, and recruits neutrophils and macrophages.

Phagocytes

The word 'phagocyte' literally means 'eating cell'. These are immune cells that engulf, or 'phagocytose', pathogens or particles. To engulf a particle or pathogen, a phagocyte extends portions of its plasma membrane, wrapping the membrane around the particle until it is enveloped (i.e., the particle is now inside the cell). Once inside the cell, the invading pathogen is contained inside a phagosome, which merges with a lysosome. The lysosome contains enzymes and acids that kill and digest the particle or organism. In general, phagocytes patrol the body searching for pathogens, but are also able to react to a group of highly specialized molecular signals produced by other cells, called cytokines. The phagocytic cells of the immune system include macrophages, neutrophils, and dendritic cells. 

Phagocytosis of the hosts’ own cells is common as part of regular tissue development and maintenance. When host cells die, either by programmed cell death (also called apoptosis) or by cell injury due to a bacterial or viral infection, phagocytic cells are responsible for their removal from the affected site. By helping to remove dead cells preceding growth and development of new healthy cells, phagocytosis is an important part of the healing process following tissue injury.

A macrophage

Macrophages

Macrophages, from the Greek, meaning "large eaters," are large phagocytic leukocytes, which are able to move outside of the vascular system by migrating through the walls of capillary vessels and entering the areas between cells in pursuit of invading pathogens. In tissues, organ-specific macrophages are differentiated from phagocytic cells present in the blood called monocytes. Macrophages are the most efficient phagocytes and can phagocytose substantial numbers of bacteria or other cells or microbes. The binding of bacterial molecules to receptors on the surface of a macrophage triggers it to engulf and destroy the bacteria through the generation of a “respiratory burst”, causing the release of reactive oxygen species. Pathogens also stimulate the macrophage to produce chemokines, which summon other cells to the site of infection.

Neutrophils

A neutrophil

Neutrophils, along with two other cell types (eosinophils and basophils; see below), are known as granulocytes due to the presence of granules in their cytoplasm, or as polymorphonuclear cells (PMNs) due to their distinctive lobed nuclei. Neutrophil granules contain a variety of toxic substances that kill or inhibit growth of bacteria and fungi. Similar to macrophages, neutrophils attack pathogens by activating a respiratory burst. The main products of the neutrophil respiratory burst are strong oxidizing agents including hydrogen peroxide, free oxygen radicals and hypochlorite. Neutrophils are the most abundant type of phagocyte, normally representing 50-60% of the total circulating leukocytes, and are usually the first cells to arrive at the site of an infection. The bone marrow of a normal healthy adult produces more than 100 billion neutrophils per day, and more than 10 times that many per day during acute inflammation.

Dendritic cells

Dendritic cells (DCs) are phagocytic cells present in tissues that are in contact with the external environment, mainly the skin (where they are often called Langerhans cells), and the inner mucosal lining of the nose, lungs, stomach, and intestines. They are named for their resemblance to neuronal dendrites, but dendritic cells are not connected to the nervous system. Dendritic cells are very important in the process of antigen presentation, and serve as a link between the innate and adaptive immune systems.

An eosinophil

Basophils and eosinophils

Basophils and eosinophils are cells related to the neutrophil (see above). When activated by a pathogen encounter, histamine-releasing basophils are important in the defense against parasites and play a role in allergic reactions, such as asthma. Upon activation, eosinophils secrete a range of highly toxic proteins and free radicals that are highly effective in killing parasites, but may also damage tissue during an allergic reaction. Activation and release of toxins by eosinophils are, therefore, tightly regulated to prevent any inappropriate tissue destruction.

Natural killer cells

Natural killer cells (NK cells) are a component of the innate immune system that does not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self." This term describes cells with abnormally low levels of a cell-surface marker called MHC I (major histocompatibility complex) - a situation that can arise in viral infections of host cells. They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells that are "missing self." For many years, it was unclear how NK cell recognize tumor cells and infected cells. It is now known that the MHC makeup on the surface of those cells is altered and the NK cells become activated through recognition of "missing self". Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors (KIR) that, in essence, put the brakes on NK cells. The NK-92 cell line does not express KIR and is developed for tumor therapy.^[11][12]

γδ T cells

Like other 'unconventional' T cell subsets bearing invariant T cell receptors (TCRs), such as CD1d-restricted Natural Killer T cells, γδ T cells exhibit characteristics that place them at the border between innate and adaptive immunity. On one hand, γδ T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and develop a memory phenotype. However, the various subsets may also be considered part of the innate immune system where a restricted TCR or NK receptors may be used as a pattern recognition receptor. For example, according to this paradigm, large numbers of Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted intraepithelial Vδ1 T cells will respond to stressed epithelial cells.

Other vertebrate mechanisms

The coagulation system overlaps with the immune system. Some products of the coagulation system can contribute to the non-specific defenses by their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells. In addition, some of the products of the coagulation system are directly antimicrobial. For example, beta-lysine, a protein produced by platelets during coagulation, can cause lysis of many Gram-positive bacteria by acting as a cationic detergent. Many acute-phase proteins of inflammation are involved in the coagulation system.

Also increased levels of lactoferrin and transferrin inhibit bacterial growth by binding iron, an essential nutrient for bacteria.

Neural regulation

The innate immune response to infectious and sterile injury is modulated by neural circuits that control cytokine production period. The inflammatory reflex is a prototypical neural circuit that controls cytokine production in the spleen. Action potentials transmitted via the vagus nerve to spleen mediate the release of acetylcholine, the neurotransmitter that inhibits cytokine release by interacting with alpha7 nicotinic acetylcholine receptors (CHRNA7) expressed on cytokine-producing cells. The motor arc of the inflammatory reflex is termed the cholinergic anti-inflammatory pathway.

Pathogen-specificity

The parts of the innate immune system have different specificity for different pathogens. 

Pathogen	Main examples	Phagocytosis	complement	NK cells
Intracellular and cytoplasmic virus	influenza mumps measles rhinovirus	yes	no	yes
Intracellular bacteria	Listeria monocytogenes Legionella Mycobacterium Rickettsia	yes (specifically neutrophils, no for rickettsia)	no	yes (no for rickettsia)
Extracellular bacteria	Staphylococcus Streptococcus Neisseria Salmonella typhi	yes	yes	no
Intracellular protozoa	Plasmodium malariae Leishmania donovani	no	no	no
Extracellular protozoa	Entamoeba histolytica Giardia lamblia	yes	yes	no
Extracellular fungi	Candida Histoplasma Cryptococcus	no	yes	yes

Immune evasion

Cells of the innate immune system prevent free growth of microorganisms within the body, but many pathogens have evolved mechanisms to evade it.

One strategy is intracellular replication, as practised by Mycobacterium tuberculosis, or wearing a protective capsule, which prevents lysis by complement and by phagocytes, as in Salmonella. Bacteroides species are normally mutualistic bacteria, making up a substantial portion of the mammalian gastrointestinal flora. Some species like B. fragilis for example are opportunistic pathogens, causing infections of the peritoneal cavity inhibit phagocytosis by affecting the phagocytes receptors used to engulf bacteria. They may also mimick host cells so the immune system does not recognize them as foreign. Staphylococcus aureus inhibits the ability of the phagocyte to respond to chemokine signals. M. tuberculosis, Streptococcus pyogenes, and Bacillus anthracis utilize mechanisms that directly kill the phagocyte.

Bacteria and fungi may form complex biofilms, protecting from immune cells and proteins; biofilms are present in the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.

Viruses

Type I interferons (IFN), secreted mainly by dendritic cells, play a central role in antiviral host defense and a cell's antiviral state. Viral components are recognized by different receptors: Toll-like receptors are located in the endosomal membrane and recognize double-stranded RNA (dsRNA), MDA5 and RIG-I receptors are located in the cytoplasm and recognize long dsRNA and phosphate-containing dsRNA respectively. When the cytoplasmic receptors MDA5 and RIG-I recognize a virus the conformation between the caspase-recruitment domain (CARD) and the CARD-containing adaptor MAVS changes. In parallel, when toll-like receptors in the endocytic compartments recognize a virus the activation of the adaptor protein TRIF is induced. Both pathways converge in the recruitment and activation of the IKKε/TBK-1 complex, inducing dimerization of transcription factors IRF3 and IRF7, which are translocated in the nucleus, where they induce IFN production with the presence of a particular transcription factor and activate transcription factor 2. IFN is secreted through secretory vesicles, where it can activate receptors on both the same cell it was released from (autocrine) or nearby cells (paracrine). This induces hundreds of interferon-stimulated genes to be expressed. This leads to antiviral protein production, such as protein kinase R, which inhibits viral protein synthesis, or the 2′,5′-oligoadenylate synthetase family, which degrades viral RNA.

Some viruses evade this by producing molecules which interfere with IFN production. For example, the Influenza A virus produces NS1 protein, which can bind to host and viral RNA, interact with immune signaling proteins or block their activation by ubiquitination, thus inhibiting type I IFN production. Influenza A also blocks protein kinase R activation and establishment of the antiviral state. The dengue virus also inhibits type I IFN production by blocking IRF-3 phosophorylation using NS2B3 protease complex.

In other species

Prokaryotes

Bacteria (and perhaps other prokaryotic organisms), utilize a unique defense mechanism, called the restriction modification system to protect themselves from pathogens, such as bacteriophages. In this system, bacteria produce enzymes, called restriction endonucleases, that attack and destroy specific regions of the viral DNA of invading bacteriophages. Methylation of the host's own DNA marks it as "self" and prevents it from being attacked by endonucleases. Restriction endonucleases and the restriction modification system exist exclusively in prokaryotes.

Invertebrates

Invertebrates do not possess lymphocytes or an antibody-based humoral immune system, and it is likely that a multicomponent, adaptive immune system arose with the first vertebrates. Nevertheless, invertebrates possess mechanisms that appear to be precursors of these aspects of vertebrate immunity. Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with microbial pathogens. Toll-like receptors are a major class of pattern recognition receptor, that exists in all coelomates (animals with a body-cavity), including humans. The complement system, as discussed above, is a biochemical cascade of the immune system that helps clear pathogens from an organism, and exists in most forms of life. Some invertebrates, including various insects, crabs, and worms utilize a modified form of the complement response known as the prophenoloxidase (proPO) system.

Antimicrobial peptides are an evolutionarily conserved component of the innate immune response found among all classes of life and represent the main form of invertebrate systemic immunity. Several species of insect produce antimicrobial peptides known as defensins and cecropins.

Proteolytic cascades

In invertebrates, pattern recognition proteins (PRPs) trigger proteolytic cascades that degrade proteins and control many of the mechanisms of the innate immune system of invertebrates—including hemolymph coagulation and melanization. Proteolytic cascades are important components of the invertebrate immune system because they are turned on more rapidly than other innate immune reactions because they do not rely on gene changes. Proteolytic cascades have been found to function the same in both vertebrate and invertebrates, even though different proteins are used throughout the cascades.

Clotting mechanisms

In the hemolymph, which makes up the fluid in the circulatory system of arthropods, a gel-like fluid surrounds pathogen invaders, similar to the way blood does in other animals. There are various different proteins and mechanisms that are involved in invertebrate clotting. In crustaceans, transglutaminase from blood cells and mobile plasma proteins make up the clotting system, where the transglutaminase polymerizes 210 kDa subunits of a plasma-clotting protein. On the other hand, in the horseshoe crab species clotting system, components of proteolytic cascades are stored as inactive forms in granules of hemocytes, which are released when foreign molecules, like lipopolysaccharides enter.

Plants

Members of every class of pathogen that infect humans also infect plants. Although the exact pathogenic species vary with the infected species, bacteria, fungi, viruses, nematodes, and insects can all cause plant disease. As with animals, plants attacked by insects or other pathogens use a set of complex metabolic responses which lead to the formation of defensive chemical compounds that fight infection or make the plant less attractive to insects and other herbivores.

Like invertebrates, plants neither generate antibody or T-cell responses nor possess mobile cells that detect and attack pathogens. In addition, in case of infection, parts of some plants are treated as disposable and replaceable, in ways that very few animals are able to do. Walling off or discarding a part of a plant helps stop spread of an infection.

Most plant immune responses involve systemic chemical signals sent throughout a plant. Plants use pattern-recognition receptors to recognize conserved microbial signatures. This recognition triggers an immune response. The first plant receptors of conserved microbial signatures were identified in rice (XA21, 1995) and in Arabidopsis (FLS2, 2000). Plants also carry immune receptors that recognize highly variable pathogen effectors. These include the NBS-LRR class of proteins. When a part of a plant becomes infected with a microbial or viral pathogen, in case of an incompatible interaction triggered by specific elicitors, the plant produces a localized hypersensitive response (HR), in which cells at the site of infection undergo rapid programmed cell death to prevent the spread of the disease to other parts of the plant. HR has some similarities to animal pyroptosis, such as a requirement of caspase-1-like proteolytic activity of VPEγ, a cysteine protease that regulates cell disassembly during cell death.

"Resistance" (R) proteins, encoded by R genes, are widely present in plants and detect pathogens. These proteins contain domains similar to the NOD Like Receptors and Toll-like receptors utilized in animal innate immunity. Systemic acquired resistance (SAR) is a type of defensive response that renders the entire plant resistant to a broad spectrum of infectious agents. SAR involves the production of chemical messengers, such as salicylic acid or jasmonic acid. Some of these travel through the plant and signal other cells to produce defensive compounds to protect uninfected parts, e.g., leaves. Salicylic acid itself, although indispensable for expression of SAR, is not the translocated signal responsible for the systemic response. Recent evidence indicates a role for jasmonates in transmission of the signal to distal portions of the plant. RNA silencing mechanisms are also important in the plant systemic response, as they can block virus replication. The jasmonic acid response, is stimulated in leaves damaged by insects, and involves the production of methyl jasmonate.