title: Rift Valley fever virus clearance and protection from neurologic disease are dependent on CD4+ T cell and virus-specific antibody responses.
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.
authors.affiliation: Viral Special Pathogens Branch, Division of High Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Dodd
authors.forename: Anita K
authors.initials: AK
authors.lastname: McElroy
authors.forename: Megan E B
authors.initials: ME
authors.lastname: Jones
authors.forename: Stuart T
authors.initials: ST
authors.lastname: Nichol
authors.forename: Christina F
authors.initials: CF
authors.lastname: Spiropoulou
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D012295:Rift Valley Fever / Q000276:immunology* / Q000821:virology; D012296:Rift Valley fever virus / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D017361:Viral Nonstructural Proteins
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