Tomorrow begins a Special President’s Edition ASM Conference, hosted by the American Society for Microbiology in collaboration with the American Society for Virology. The conference, “What Does the Biology of Flaviviruses Tell Us About Zika: The Importance of Fundamental Virus Biology” highlights the value of fundamental virology. In this evening prior to the one-day conference, a panel of flavivirus experts convened before members of the press to briefly outline their research, its application to Zika virus and disease, and then opened the floor to questions related to recent research developments.
“The rapid progress that we’re making, which is truly phenomenal, is possible only because of the fundamental research that has been done on flaviviruses before,” said ASM President Lynn Enquist in his opening remarks. The panelists were all established experts on Flaviviridae, the family of single-stranded RNA viruses that includes Zika as well as other human pathogenic viruses such as dengue, chikagunya, yellow fever, Japanese encephalitis, and Hepatitis C viruses. The scientists included were:
Dr. Michael Diamond, Professor in the Departments of Medicine, Molecular Microbiology, Pathology, and Immunology at Washington University, works on a variety of flaviviruses. Diamond says that the questions focused on remain the same: “What cell types does the virus infect, how does it injure cells, and how does this cause disease in an organism?” His lab uses mouse models to investigate disease, taking advantage of the powerful genetic manipulation available to researchers that allows them to investigate the role of single genes during infection by flaviviruses.
Viral immunity, infectivity, and communication have been the three major concentrations of Zika-related research in the Diamond lab. Over the past year, the lab has worked toward developing not only a mouse model of Zika infection, but an in utero infection model to study the transmission of infection from pregnant mother to fetus. The lab also works on antibody immunity, which Diamond sees as vital to vaccine development.
Dr. Mehul Suthar, Assistant Professor in the Department of Pediatrics at Emory University, and whose lab is part of the Emory Vaccine Center*, wants to understand how emerging viruses, such as West Nile virus and Zika virus, cause disease in humans, and how the innate immune system can restrict these infections. His lab recently published a report on how the virus is able to cross the placental barrier to infect the fetus by looking at infection of different fetal cell types. His research shows that Zika virus replicates very efficiently in Hofbauer cells, which are macrophage-like cells of the placenta. The virus also relicates, though less efficiently, in cytotrophoblasts, which make up one of the cell layers surrounding the developing embryo.
“Zika virus is very unique in its ability to cross the placenta, and there are specific cell types in which the virus can replicate through mechanisms we aren’t too familiar with yet,” Suthar says. He hopes to uncover more about intrauterine transmission and these early target cells of the virus.
Dr. Kristen Bernard, Associate Professor of Virology at the University of Wisconsin, Madison, focuses her research on mosquito-borne viruses, which include the flaviviruses, and how they cause disease. She focuses on the role of the mosquito – which is “not just a flying needle,” she explains – in influencing the disease process. Her lab has shown that the West Nile virus replicates better in the presence of mosquito saliva, and she hopes to investigate whether it has the same effect on Zika virus. The Bernard lab also studies how the virus persists, which will be important to understand viral transmission.
Although a universal flavivirus vaccine is a stretch, deciphering the role of mosquito saliva could add components that might acts as an adjuvant in the presence of a virus-specific vaccine. And if the immune response to mosquito saliva is strong enough, it might even produce a quasi-pan-flavivirus vaccine, able to halt infection of any viruses transmitted by a specific mosquito species (flaviviruses are transmitted by multiple mosquito species and genera).
Dr. Charles Rice, the Maurice R. and Corinne P. Greenberg Professor in Virology at the Rockefeller University, has studied flavivirus replication for many years. His lab has worked on the molecular basis for the yellow fever virus vaccine, which has become the backbone for the first approved dengue virus vaccine and may play a role in Zika virus vaccine development.
Dr. John Schoggins, Assistant Professor of Microbiology at University of Texas Southwestern Medical Center, is interested in how the cell can control viral infections. As the Zika story unfolded, he identified a collaborator on campus who works on primary neural progenitor cells, with their results being published in a report on Friday (so stay tuned, readers, for an update once the embargo has been lifted!).
Update 6/3/16: Schoggins and his collaborators found that these neural progenitor cells, which are primary and not derived from adult skin cells (as used in other studies), are killed by the virus. Cells that survive infection continuously make more virus, and the viral infection does not activate an immune response. This lack of response may be one reason why the viral replication persists for up to four weeks in the neural progenitor cells.
Dr. Eva Harris, Professor in the Division of Infectious Diseases and Vaccinology at University of California, Berkeley, has about 25 years experience of dengue virus research. Her lab studies the mechanisms of viral pathogenesis but she also has collaboration to investigate the clinical aspects of flavivirus disease. One collaboration with scientists at UCSF has demonstrated that many placental cell types can be infected with Zika and has also identified a potent inhibitor of this infection.
Another aspect of her research focuses on antibodies against flaviviruses. There is a question of disease enhancement, especially in regions endemic to both dengue and Zika viruses: “Can anti-dengue virus antibodies can enhance Zika infection or whether anti-Zika virus antibodies can enhance dengue infection,” asks Harris. Her lab uses a sublethal model to investigate antibody-mediated disease enhancement. She is also focused on generating more accurate diagnostic assays, which have been plagued by cross-reactivity issues between these two virus types.
In a non-molecular aspect of her lab, Harris works with communities at risk for Zika infection to help communities generate their own solutions to eliminate places where the Aedes mosquitos that carry the virus might breed. By explaining the role of standing water in the life cycle of the mosquito, household members realize the importance of disrupting this life cycle. As an example, tires are a huge source of water where mosquitos breed, because they accumulate rain water that stands and sustains mosquito larvae. People now fill these old tires with earth to use as planters or staircases, eliminating these potential breeding grounds.
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The Q-and-A session focused on a few important points on general virology and specific Zika virus research.
When asked why scientists were surprised by the fetal neurotropism and sexual transmissibility of Zika virus, the panel was quick to point out that although a flavivirus, the details of its viral biology are yet to be fully discovered. As emphasized by Dr. Rice, Zika virus may be the first flavivirus with neurotropism, but it’s hardly the first neurotropic virus: rubella virus caused large numbers of encephaly until its prevention through the MMR vaccine, and human cytomegalovirus continues to cause congenital birth defects.
Dr. Bernard additionally clarified that some flaviviruses, such as West Nile virus and Japanese encephalitis virus, do cause in utero transmission issues, although at lower numbers. Japanese encephalitis virus also has many fetal effects in pigs, and other flaviviruses cause fetal problem in other veterinary species, so the phenomenon of congenital disease is not a new one.
When the panelists were asked whether they were waiting for federal grants, they laughed good-naturedly. “We’re all waiting for grants,” was the consensus. However, Dr. Harris did emphasize the impressive way that the NIH has used its supplemental mechanism. This has allowed funded researchers to write a supplemental to an existing grant, resulting in an approximately two-week wait for funds. This is quite impressive for an institution that often takes 1-2 years for successful turnaround of a new grant.
All researchers were in unanimous in their support of sustained funding. Dr. Rice illustrated the example of the yellow fever virus vaccine, which resulted in the near abolishment of funding for flavivirus replication in the 1990s. The onset of West Nile virus in 1999 generated more interest, reinvigorating funding for flavivirus infections. This example emphasizes the importance of a diverse research portfolio in a world where we can’t predict the next emerging infectious disease, says Dr. Rice.
The scientific panel also agreed that fighting the spread of Zika has been a collaborative effort. Entire scientific programs have been moved in record time toward this infectious disease. Not only flavivirologists, but many who studied other scientific problems – developmental biologists, neuroscientists, infectious disease experts, epidemiologists – have applied their expertise toward combatting this terrible disease.
Update 6/3/16: Now you can listen to what the experts have to say for yourself! Watch the entire press conference to learn more details about flavivirus and Zika research:
-- Julie Wolf
*The blog previously misidentified Dr. Suthar's affiliation as Assistant Professor at the Emory Vaccine Center.