At the American Association for the Advancement of Science meeting in Boston last weekend, Emory Vaccine Center researcher Mark Mulligan presented some limited findings on immune responses in Zika-infected humans, who were returned US travelers or expatriates.
The results were intriguing, despite the small number of study participants: five, two of whom were pregnant. Detailed information has not been available about immune responses against Zika in humans, especially T cell responses.
Highlights from Mulligan’s abstract:
*All five seemed to have a hole in their immune systems – functional antiviral “killer” CD8 T cells were rare, despite activation of CD8 T cells in general and strong responses from other cell types.
*Cross-reactive immune responses, based on previous exposure to dengue and/or yellow fever vaccine, may have blunted Zika’s peak.
*”Even with prolonged maternal viremia, both pregnancies resulted in live births of apparently healthy babies.” Read more
An ongoing collaboration between the Emory Vaccine Center and the ICGEB (International Centre for Genetic Engineering and Biotechnology) in New Delh, investigating immune responses to dengue virus, is getting some attention.
A Journal of Virology paper published by the collaboration was highlighted by Nature Asia. In that paper, the researchers show that in dengue infection, the group of antiviral immune cells known as CD8+ T cells undergoes a massive expansion. That could be dangerous if all of the CD8 T cells were making inflammatory cytokines, but they do not. Only a small fraction are making cytokines.
The authors point out that this phenomenon is “somewhat reminiscent of T-cell exhaustion seen under the conditions of prolonged antigenic stimulus in chronic viral infections [which has been studied in detail by Rafi Ahmed and colleagues] or closely resembles the ‘stunned’ phenotype reported in febrile phase of other acute infections such as HIV and viral hepatitis… The IFN-γ unresponsiveness acquired during the massive antigen-driven clonal expansion is likely to ensure that these cells do not cause excessive inflammation at the time that their numbers are high during the febrile phase of dengue disease.” Read more
Scientists have revealed molecular differences between how the African and Asian strains of Zika virus infect neural progenitor cells. The results could provide insights into the Zika virus’ recent emergence as a global health emergency, and also point to inhibitors of the p53 pathway as potential leads for drugs that could protect brain cells from cell death.
The findings, from the Emory/Johns Hopkins/Florida State team that showed this spring that neural progenitor cells are particularly vulnerable to Zika infection (related paper), were published this week in Nucleic Acid Research. The manuscript was also posted on BioRxiv before publication.
Overlap in gene expression changes when neural progenitor cells are infected by African or Asian strains of Zika virus. Diagram from Nucleic Acids Research via Creative Commons.
Zika virus was first discovered in Uganda in the 1940s, and two distinct lineages of Zika diverged sometime in the second half of the 20th century: African and Asian. The strains currently circulating in the Western Hemisphere, which have been linked to microcephaly in infants and Guillain-Barre syndrome in adults, are more closely related to the Asian lineage.
The research team catalogued and compared genes turned on and off by Asian and African strains of Zika virus, as well as dengue virus, in human neural progenitor cells. The authors describe dengue as inducing more robust changes in gene expression than either strain of Zika. Although they show that dengue can infect neural progenitor cells like Zika can, dengue infection does not stunt the cells’ growth or lead to cell death.
“This shows that the differences between Zika and dengue are not at the level of being able to infect neural progenitors, but more about the harm Zika causes when it does infect those cells,” says senior author Peng Jin, PhD, professor of human genetics at Emory University School of Medicine. Read more
Emory Vaccine Center director Rafi Ahmed, is a co-author on a recent Science paper advocating a â€œHuman Vaccines Projectâ€. Wayne Koff, chief scientific officer of IAVI (International Aids Vaccine Initiative) is lead author and several other vaccine experts are co-authors.
The idea behind a â€œHuman Vaccine Projectâ€ is to combine efforts at developing vaccines for major (but very different) diseases such as influenza, dengue, HIV, hepatitis C, tuberculosis and malaria, with the rationale that what scientists working on those diseases have in common is the challenge of working with the human immune system.
Technology has advanced to the point where whole genome-type approaches can be brought to bear on vaccine problems. The authors cite work by Bali Pulendranâ€™s laboratory on â€œsystems vaccinologyâ€ and their analysis of the yellow fever vaccine as an example.
One major puzzle confronting vaccine designers is to coax the immune system into producing broadly neutralizing antibodies against a rapidly mutating virus, whether it is influenza or HIV. Our own Cynthia Derdeyn has been analyzing this problem through painstaking work following how the immune system pursues a twisting and turning HIV.
An interesting related tidbit:
There are hints that the reverse engineering of vaccines has taken a leap forward in the case of RSV (respiratory syncytial virus): Scientists at Scripps Research Institute have designed vaccine components by computer and have used them to provoke neutralizing antibodies in monkeys.
Also check out Mike Kingâ€™s feature in Emory Health on HIV vaccine research.