Peripheral immune response in the African green monkey model following Nipah-Malaysia virus exposure by intermediate-size particle aerosol

The ability to appropriately mimic human disease is critical for using animal models as a tool for understanding virus pathogenesis. In the case of Nipah virus (NiV), infection of humans appears to occur either through inhalation, contact with or consumption of infected material. In two of these circumstances, respiratory or sinusoidal exposure represents a likely route of infection. In this study, intermediate-size aerosol particles (similar to 7 mu m) of NiV-Malaysia were used to mimic potential routes of exposure by focusing viral deposition in the upper respiratory tract. Our previous report showed this route of exposure extended the disease course and a single animal survived the infection. Here, analysis of the peripheral immune response found minimal evidence of systemic inflammation and depletion of B cells during acute disease. However, the animal that survived infection developed an early IgM response with rapid development of neutralizing antibodies that likely afforded protection. The increase in NiV-specific antibodies correlated with an expansion of the B cell population in the survivor. Cell-mediated immunity was not clearly apparent in animals that succumbed during the acute phase of disease. However, CD4+ and CD8+ effector memory cells increased in the survivor with correlating increases in cytokines and chemokines associated with cell-mediated immunity. Interestingly, kinetic changes of the CD4+ and CD8(bright) T cell populations over the course of acute disease were opposite from animals that succumbed to infection. In addition, increases in NK cells and basophils during convalescence of the surviving animal were also evident, with viral antigen found in NK cells. These data suggest that a systemic inflammatory response and cytokine storm are not major contributors to NiV-Malaysia pathogenesis in the AGM model using this exposure route. Further, these data demonstrate that regulation of cell-mediated immunity, in addition to rapid production of NiV specific antibodies, may be critical for surviving NiV infection. Author summary Nipah virus (NiV) infection in Malaysia, Bangladesh and India has been correlated with severe respiratory and neurological disease that led to death in over 50% of known cases. In this study, we used a nonhuman primate model for NiV infection to evaluate the peripheral immune response to virus infection in an effort to identify aspects of the immune response that may be important for survival. An aerosol exposure that targeted virus deposition in sinuses and upper respiratory tract was used in an effort to mimic a probable human exposure route. Following exposure, five of six animals included in the study succumbed to the infection. The survivor developed a virus-specific antibody response and showed clear evidence of cell-mediated immunity. Interestingly, the rate of change in CD4+ and CD8(bright) T cell populations in the survivor over the course of the acute disease, were the reverse of animals that succumbed to infection. These data suggest that rapid development of virus-specific adaptive immunity is critical for survival of NiV infection.