The TWiV team reveal the origin of the poxvirus membrane, and how a retrovirus drove the development of the placenta of a lizard.
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Show notes at microbe.tv/twiv
The protein syncytin, which is essential for formation of the placenta, originally came to the genome of our ancestors, and those of other mammals, via a retrovirus infection. Placental structures have also developed in non-mammalian vertebrates. The Mabuya lizard (pictured: image credit), which emerged 25 million years ago, has a placenta very much like those in mammals, and its development was likely driven by capture of a retroviral gene.
The latest Zika virus news from the ConTWiVstadors, including a case of female to male transmission, risk of infection at the 2016 summer Olympics, a DNA vaccine, antibody-dependent enhancement by dengue antibodies, and sites of replication in the placenta.
You can find TWiV #399 at microbe.tv/twiv, or listen below.
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Four virologists discuss our current understanding of Zika virus biology, pathogenesis, transmission, and prevention, in this special live episode recorded at the American Society for Microbiology in Washington, DC.
You can find TWiV #392 at microbe.tv/twiv, or listen/watch below.
I am convinced that Zika virus causes microcephaly in humans, but it would be valuableÂ to have an animal model to study how the virus crosses the placenta and damages the fetus. As with manyÂ questions aboutÂ Zika virus, answers are coming very rapidly, and three different groups have now provided substantial insight into this problem.
When a Samoan isolate of Zika virus was injected into the brain of embryonic day 13.5 mice, the virus replicated mainly in neural progenitor cells, but also in many other brain cells (link to paper). At 5 days after infection, brain size was markedly reduced compared with uninfected littermates. Infection of neural progenitor cells disrupted their normal differentiation program which leads to the production of mature neurons. Gene expression profiling of infected brains showed an increase in the production of cytokines, suggesting that these proteins might play a role in disease development. The expression of genes that have been previously associated with microcephaly was reduced. The authors conclude that “these effects are likely to account for microcephaly in human fetuses or newborn babies.”
In a different approach (link to paper), pregnant mice (not fetuses as in the previous study) were infected with a Brazilian Zika virus strain, and newborns were studied. Zika virus was detected in many tissues of newborns, especially in brain. Newborn mice displayed overall reduced growth, cortical malformations, and reduced cortical cell number and cortical layer thickness, all defects associated with microcephaly in humans. The infected mice also had ocular abnormalities similar to those that have been observed in babies with congenital Zika virus syndrome. Of note was the observation that the ability of Zika virus to cross the placenta was dependent on the strain of mouse used. I would not be surprised if the ability of viruses (or any microbe) to cross the human placenta is also determined in part by the genetics of the host.
The authors of this study suggest that human to human passage of Zika virus in humans for ~60 years led to a strain that can cross the placenta and infect the fetus. Consistent with their hypothesis, they show thatÂ replication of a Brazilian Zika virus strain in human brain organoids (three-dimensional models of the human brain produced from human pluripotent stem cells), greater morphological abnormalities and a reduction in size compared with effects cause by infection with an African strain of the virus. Furthermore, they find that a Brazilian Zika virus strain does not replicate in chimpanzee organoids, while the African strain does well. However, they do not address theirÂ hypothesis directly by determining in their mouse model whether an African strain of Zika virus can cross the placenta and infect the fetus.
A third report provides insight into how Zika virus might cross the placenta (paper link). This model consists of immunocompromised mice in which the type I interferon response has been ablated either genetically or by the administration of antibodies to the receptor for this cytokine. Pregnant mice areÂ infected subcutaneously in the footpad with a French Polynesian Zika virus strain at embryonic days 6.5 and 7.5; embryos are then sacrificed 7 or 8 days later. No microcephaly wasÂ observed, but virus was detected in the head of the fetus. Replication was also detected in placenta and is accompanied by placental damage. Infected placentas are smaller, have damaged blood vessels, and display evidence of cell death and virus replication in various types of trophoblasts that make up placental tissues. In contrast, dengue virus did not replicate in the placenta or in the fetus.
These observations suggest that Zika virus can cross the placenta and move from the maternal blood into the fetus. The authors conclude that “The cellular and ultrastructural evidence of ZIKV infection in trophoblasts and fetal endothelium suggests that maternal viremia leads to compromise of the placental barrier by infecting fetal trophoblasts and entering the fetal circulation.â€
Previously it was shown that term placentas are resistant to Zika virus infection due to the production of type III interferon (paper link). The authors of the mouse study described above suggest that Zika virus may cross the placenta early in pregnancy due to infection of extravillous trophoblasts. These cells are abundant early but not later in pregnancy.
These three reports provide conclusive evidence that Zika virus can cross the placenta and cause fetal defects in mice, and provide models to understand the biology and pathogenesis of infection.
I am astounded at the unprecedented, rapid and frequent publication of new research results on Zika virus biology and pathogenesis. This phenomenon reflects the willingness and ability of large and mature groups of investigators from diverse fields (virology, neurobiology, cell biology) to tackle a new problem and make rapid progress.
I predict that we will learn more about Zika virus in the next year than we have about any other microbe in a similar period of time.
Amidst theÂ fear surrounding Zika virus, rememberÂ that there are over 100,000 children born each year with birth defects caused by infection with rubella virus.
Rubella virus is a member of the TogaviridaeÂ family, which also includesÂ chikungunya virus. The genome is a 9.7 kilobase, positive strand RNA enclosed in a capsid and surrounded by a membrane (illustrated; imageÂ fromÂ ViralZone).
Humans are the only natural host and reservoir of rubellaÂ virus. TheÂ virus is transmitted from human to human by respiratory aerosols. Â Upon entry into the upper respiratory tract, the virus replicates in the mucosa and local lymph nodes. Virus then enters the blood and spreads to regional lymph nodes, where it replicates and a second viremia ensues. The incubation period is approximately 14 days, after which virus is shed by respiratory secretions, allowing transmission to other hosts. The second viremia brings virus to the skin, where a rash appears after 14-21 days.
Signs and Symptoms
Rubella is a mild disease associated with low grade fever, swollen lymph nodes and aÂ morbilliform rash. Before a vaccine was available, infection typically occurred between 5-9 years of age. In 1942 the opthalmologist Norman Gregg found that manyÂ children with cataractsÂ alsoÂ had other serious congenital defects. He noticedÂ that an epidemic of congenital cataracts was preceded by a rubella outbreak, and proposed that cataracts and otherÂ abnormalities were caused byÂ maternal infection during pregnancy. Eventually other investigatorsÂ confirmed that rubellaÂ virus could cause fetal defects when infection ofÂ the mother occurred in the first trimester ofÂ pregnancy.
Congenital rubella syndrome (CRS) is the name give to fetal defects caused by rubella virus infection. These include eye manifestations (cataracts, glaucoma, retinitis), congenital heart defects, hearing loss, microcephaly, bone disease, mental retardation, and diabetes. When a pregnant mother is infected early in pregnancy, the virus crosses the placenta andÂ infects most fetal organ systems. No animal models are available to study how the virusÂ causes tissue damage.
In the US during the pre-vaccine era,Â outbreaks of rubella were routinely accompanied by congenital rubella syndrome. An exampleÂ is theÂ 1962-65 epidemicÂ ofÂ 12.5 million cases of rubella and 20,000 children with congenital abnormalities.Â The incidence of CRS during rubella outbreaks is 1-2 per 1,000 live births
Rubella infection may also lead to encephalopathy or encephalomyelitis in one case per 6,000 infections. In these cases theÂ virus can be found in cerebrospinal fluidÂ and in the central nervous system.
Rubella virus was the first virus shown to be teratogenic in humans. This discovery hastened development of an infectious, attenuated vaccine, which was licensed in the US in 1969. It is now given to children as part of the MMR vaccine – measles, mumps, and rubella. Its use in the US, and in many other countries, has controlled outbreaks of rubella and eliminated congenital rubella syndrome. The Centers for Disease ControlÂ declared in 2005 that endemic congenital rubella syndromeÂ had been eliminated from the US.
Many countries, including much of African, India, Afghanistan, and Pakistan do not include rubella vaccineÂ in routine immunization schedules. As of 2009 less than 40% of the global birth cohort was protected from rubella virus infection. The consequence is thatÂ women of childbearing age are susceptible to rubella.Â In nonepidemic years there are more than 100,000 infants born with CRS every yearÂ (source: WHO)
Rubella is an eradicable disease, because the vaccine produces durable immunity, and humans are the only reservoir of the virus. In contrast, Zika virus probably cannot be eradicated, because there is a non-human reservoir of the virus – possibly non-human primates.
Before immunization, rubella was endemic worldwide, with epidemics taking place every 6-9 years, as pools of susceptibles reached a threshold. I wonder if we will see similar behavior with Zika virus, once the initial wave of spread subsides.
Like the outbreak of microcephaly in Brazil, the 100,000 children born annually with congenital rubella syndrome is a tragedy. It’sÂ important to remember that having an effective vaccine does not guarantee control of disease – the vaccine has to be distributed to all who need it.