Rotavirus infection and the ensuing gastroenteritis remain a leading cause of morbidity and mortality worldwide.
The aims of this proposal are to continue and to extend studies of the immune mechanisms responsible for the resolution of primary rotavirus infection and protection from reinfection in a murine model and in humans.
The specific aims are: ? 1) To define the effector mechanisms responsible for protection from rotavirus infection in mice immunized with live virus via the enteric, respiratory and parenteral routes. Immunization via each of these routes can induce short-term protective immunity in mice, but we hypothesize that the effector mechanisms responsible for this immunity, the level of immunity, and its duration may differ depending on the immunization route. We also predict that different routes of antigen delivery will initiate distinct lymphocyte trafficking programs for both T and B cells and that these distinct programs will lead to differences in protection. ? 2) To study people directly in order to better characterize the immune response to rotavirus, with specific emphasis on lymphocytes and lymphocyte trafficking signals in the gut. We hypothesize that rotavirus specific B cells resident in the GI tract will be quantitatively and qualitatively different from such cells in the circulation and that the number and phenotype of these cells will be a better indicator of functional immune status than circulating antibody levels. ? 3) To identify components of the interferon and acquired immune systems responsible for restricting systemic (non-GI tract) replication of rotavirus and to use viral genetics to identify rotavirus genes associated with enhanced systemic replication in the absence of interferon. It is our hypothesis that interferons are critically important in restricting the systemic replication of rotavirus early in infection, especially in organs such as the liver and pancreas, and that specific rotavirus genes can be linked to the restrictive interferon effect. We also predict that specific components of the acquired immune system are involved in modulating systemic rotavirus replication and these may differ from those involved in restricting mucosal replication. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI021362-21
Application #
6780230
Study Section
Special Emphasis Panel (ZRG1-EVR (01))
Program Officer
Berard, Diana S
Project Start
1984-07-01
Project End
2009-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
21
Fiscal Year
2004
Total Cost
$446,658
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Nair, Nitya; Feng, Ningguo; Blum, Lisa K et al. (2017) VP4- and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans. Sci Transl Med 9:
Li, Bin; Ding, Siyuan; Feng, Ningguo et al. (2017) Drebrin restricts rotavirus entry by inhibiting dynamin-mediated endocytosis. Proc Natl Acad Sci U S A 114:E3642-E3651
Sen, Adrish; Sharma, Ayushi; Greenberg, Harry B (2017) Rotavirus degrades multiple type interferon receptors to inhibit IFN signaling and protects against mortality from endotoxin in suckling mice. J Virol :
Nair, N; Newell, E W; Vollmers, C et al. (2016) High-dimensional immune profiling of total and rotavirus VP6-specific intestinal and circulating B cells by mass cytometry. Mucosal Immunol 9:68-82
Sen, Adrish; Rott, Lusijah; Phan, Nguyen et al. (2014) Rotavirus NSP1 protein inhibits interferon-mediated STAT1 activation. J Virol 88:41-53
Uzri, Dina; Greenberg, Harry B (2013) Characterization of rotavirus RNAs that activate innate immune signaling through the RIG-I-like receptors. PLoS One 8:e69825
Deal, Emily M; Lahl, Katharina; Narváez, Carlos F et al. (2013) Plasmacytoid dendritic cells promote rotavirus-induced human and murine B cell responses. J Clin Invest 123:2464-74
Feng, Ningguo; Yasukawa, Linda L; Sen, Adrish et al. (2013) Permissive replication of homologous murine rotavirus in the mouse intestine is primarily regulated by VP4 and NSP1. J Virol 87:8307-16
Newell, Evan W; Sigal, Natalia; Nair, Nitya et al. (2013) Combinatorial tetramer staining and mass cytometry analysis facilitate T-cell epitope mapping and characterization. Nat Biotechnol 31:623-9

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