To address why dengue infection only occasionally becomes lethal, LJI immunologists Alessandro Sette, Dr. Biol. Sci., and Bjoern Peters, Ph.D., performed “transcriptomic” comparisons of gene expression in immune cells taken from patients with either the mild or hemorrhagic forms of dengue as part of the Human Immunology Project Consortium. Their findings challenge a misconception, namely that the disease becomes lethal once a population of CD4-positive T cells, called “T helpers,” elicits an uncontrolled inflammatory response. Instead, the team observed little difference in number or gene expression pattern of CD4-positive T helpers in blood from either set of patients, suggesting that these cells respond to infection but do not behave differently in benign versus fatal forms of disease.
Other work from Sette’s lab complements these findings. His team has reported that a different type of T cell, CD8-positive “memory T cells,” mobilize after dengue infection and “remember” the virus, likely protecting individuals from severe disease.
LJI’s Sujan Shresta, Ph.D., constructs mouse models to study infection by both dengue and Zika. Mosquitoes that carry both viruses are present in geographically-overlapping regions; thus it is likely that people living in these regions will encounter both viruses in their lifetime. So it makes sense to have pan-flavivirus vaccines that target multiple flaviviruses.
Shresta uses mouse models to study immunological cross-reactivity between flaviviruses. The idea is that pre-existing immunity to one flavivirus can mediate both protection against another flavivirus—or it can lead to more severe infection, depending on the infection scenario. Shresta’s lab has found that which virus a person encounters first makes a difference in protection versus pathogenesis, as does the length of time between infections.
As an illustration, when Shresta infected mice first with dengue virus and then challenged these mice shortly after with Zika virus, the mice remained healthy; in contrast, mice with no prior exposure to dengue virus succumbed to Zika infection. This protective effect of prior dengue immunity was mediated by cross-reactive T cells that recognized both viruses. As another example, when Shresta exposed mouse pups born to Zika-immune mothers to dengue virus, all pups died of lethal dengue disease—an outcome not seen in pups with no Zika immunity. This hyper-lethality occurred because transfer of anti-Zika antibodies from the mother to her offspring made them unusually vulnerable to dengue infection.
The lab continues to dissect the interplay between the cross-reactive T cell and antibody responses to these viruses and trying to understand the rules that govern when they are good and when they are bad. Shresta’s goal is to harness the good effects of cross-reactivity and avoid the bad to develop safe, effective and affordable vaccines against these viruses.
Collaboration is key to LJI’s pioneering dengue research. Working together, Shresta, Sette and Peters have tackled a controversial topic in the field— the role of T cells in dengue infection has been intensely debated for the past several decades. Their human and mouse studies, in collective, have revealed that T cells can play a protective role against dengue infection. This finding may explain the puzzle about the minimally effective dengue vaccine, as the vaccine does not elicit a CD8 T cell response.