Rift valley fever virus: Immunologic determinants of disease severity

The objective of this work was to characterize Rift Valley fever virus (RVFV) immunology and pathogenesis, with a particular emphasis on the role of the host immune response in determining clinical outcome following infection. A greater understanding of these aspects of RVFV infection will provide critical information to help prevent and control RVFV outbreaks through the development of efficacious therapeutics and vaccines.;In Chapter 2, we begin by exploring the importance of innate immunity in controlling RVFV infection. We examined the role of the earliest host immune responses in the development of protective immunity following immunization of mice with a novel replicon-based RVFV vaccine. Subsequent challenge of the vaccinated mice highlighted the remarkable ability of the interferon-mediated immune response to protect against a lethal virus challenge as early as 24 hours after vaccination. These results raised subsequent questions about the mechanism of protection and roles of the adaptive immune response after the initial innate response had waned.;Chapter 3 defines the aspects of the host adaptive immune response required for protective immunity following vaccination, as well as the prevention of RVFV disease in primary infection. A series of targeted depletion studies clearly demonstrate for the first time that functional CD4+ T cells, but not CD8+ T cells, are critical for controlling RVFV infection in vivo and for preventing the development of RVFV neurologic disease in both initial infection and subsequent virus challenge. CD4+ T cells were required for robust IgG and neutralizing antibody responses that correlated with RVFV clearance from peripheral tissues. Further, CD4-depleted mice demonstrated significantly stronger pro-inflammatory responses relative to controls, suggesting CD4+ T cells regulate immune responses to RVFV infection. Together, these results indicate CD4 + T cells are critical determinants of RVFV pathogenesis and play an important role in preventing onset of neurologic disease.;The pathogenesis of RVFV disease in the CNS is examined in more detail in Chapter 4. A uniformly lethal mouse model of RVFV encephalitis is developed to explore virus kinetics, mechanisms of neuroinvasion and host immune responses associated with the development of severe neurologic disease. The onset of RVFV encephalitis is associated with an ineffective systemic immune response characterized by inappropriately activated T cells and reduced antibody titers. End-stage neurologic disease coincides with high CNS viral loads and infiltration of activated T cells into the brain. Surprisingly, depletion of T cells did not reduce overall mortality, and suggested that RVFV disease is a result of direct virus-mediated damage to the CNS. Interestingly, and in contrast to the pathogenesis of other neurotropic viruses, there was no evidence of a pathologic role of the immune response in RVFV encephalitis.;Taken together, these studies provide new insights into mechanisms by which RVFV causes severe disease. I sincerely hope these small contributions will aid in the development of efficacious vaccines and targeted therapeutics for prevention and treatment of RVFV-mediated disease.