Rift Valley Fever Virus Clearance and Protection from Neurologic Disease Are Dependent on CD4(+) T Cell and Virus-Specific Antibody Responses

• Type of Material: Article
• Authors: Kimberly A. Dodd, Centers for Disease Control and Prevention; Anita Katherine McElroy, Emory University; Megan E. B. Jones, Centers for Disease Control and Prevention; Stuart T. Nichol, Centers for Disease Control and Prevention; Christina F. Spiropoulou, Centers for Disease Control and Prevention
• Language: English
• Date: 2013-06-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2013, American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.00337-13
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 87
• Issue: 11
• Start Page: 6161
• End Page: 6171
• Keywords: CHALLENGE; LACKING; INFECTION; VIRULENCE; Life Sciences & Biomedicine; BLOOD-BRAIN-BARRIER; Science & Technology; IMMUNITY; Virology; NSS PROTEIN; RHESUS MACAQUES; TRANSCRIPTION; WEST-NILE-VIRUS
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Virology

Abstract

Rift Valley fever virus (RVFV) causes outbreaks of severe disease in people and livestock throughout Africa and the Arabian Peninsula. Human RVFV infections generally manifest as a self-limiting febrile illness, but in some individuals, the disease can progress to a fatal encephalitis or hemorrhagic syndrome. Little is known about the host characteristics that predispose development of more severe disease. Early in infection, interferon-mediated antiviral responses are critical for controlling RVFV replication, but the roles of downstream adaptive immune responses in determining clinical outcome have not been examined. Here, using a C57BL/6 mouse disease model, we evaluated the roles of B cells and T cells in RVFV pathogenesis. Given the profound inhibition of the innate response by the viral NSs protein and rapid course of wild-type infection, we utilized an attenuated RVFV lacking NSs to examine host responses following primary infection. Experiments utilizing B-cell-deficient mice or targeted T cell depletions of wild-type mice demonstrated that B cells and CD4 + T cells, but not CD8 + T cells, were critical for mediating viral clearance, even in the presence of a functional innate response. One-third of CD4 + -depleted mice developed severe neurologic disease following infection, in contrast to virus-infected mock-depleted mice that showed no clinical signs. CD4 + T cells were required for robust IgG and neutralizing antibody responses that correlated with RVFV clearance from peripheral tissues. Furthermore, CD4 + -depleted mice demonstrated significantly stronger proinflammatory 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.