Abstract
Ebola virus (EBOV) causes highly lethal hemorrhagic fever that leads to death in up to 90% of infected humans. Like many other infections, EBOV induces massive lymphocyte apoptosis, which is thought to prevent the development of a functional adaptive immune response. In a lethal mouse model of EBOV infection, we show that there is an increase in expression of the activation/maturation marker CD44 in CD4(+) and CD8(+) T cells late in infection, preceding a dramatic rebound of lymphocyte numbers in the blood. Furthermore, we observed both lymphoblasts and apoptotic lymphocytes in spleen late in infection, suggesting that there is lymphocyte activation despite substantial bystander apoptosis. To test whether these activated lymphocytes were functional, we performed adoptive transfer studies. Whole splenocytes from moribund day 7 EBOV-infected animals protected naive animals from EBOV, but not Marburgvirus, challenge. In addition, we observed EBOV-specific CD8(+) T cell IFN-gamma responses in moribund day 7 EBOV-infected mice, and adoptive transfer of CD8(+) T cells alone from day 7 mice could confer protection to EBOV-challenged naive mice. Furthermore, CD8(+) cells from day 7, but not day 0, mice proliferated after transfer to infected recipients. Therefore, despite significant lymphocyte apoptosis, a functional and specific, albeit insufficient, adaptive immune response is made in lethal EBOV infection and is protective upon transfer to naive infected recipients. These findings should cause a change in the current view of the 'impaired' immune response to EBOV challenge and may help spark new therapeutic strategies to control lethal filovirus disease.
Highlights
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In a lethal mouse model of Ebola virus (EBOV) infection, we show that there is an increase in expression of the activation/ maturation marker CD44 in CD4؉ and CD8؉ T cells late in infection, preceding a dramatic rebound of lymphocyte numbers in the blood
Blood lymphocyte numbers are severely depleted in EBOV infection in BALB/c mice [9, 25], nonhuman primates [11, 12], and likely in humans [15]
Summary
EBOV, Ebola virus; MARV, Marburgvirus; LCMV, lymphocytic choriomeningitis virus. proinflammatory cytokines [16, 21, 22]. The activation status of lymphocyte subsets during the course of EBOV infection have not been functionally studied; for example, the question of whether lymphocytes undergo apoptosis after partial activation, which could occur in the presence of incompletely activated dendritic cells, remains unanswered To address these issues, a lethal mouse model of EBOV virus infection, in which death occurs on or around day 7 postinfection, was used. Increased expression of CD44 correlated with increased lymphocyte numbers in the blood and previously reported lymphoblast presence in the spleen [9], which are indicative of lymphocyte activation and proliferation These data led to a hypothesis that a functional lymphocyte response was being generated in lethal EBOV infection. The data supports the hypothesis that functional adaptive immune responses are present in lethal EBOVinfected mice despite massive lymphocyte apoptosis, suggesting that augmentation of this ongoing response may result in protection against EBOV infection
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