Noroviruses are a significant cause of epidemic and sporadic gastroenteritis worldwide. They are the leading cause of severe childhood diarrhea in the United States and a major cause of severe childhood diarrhea in developing nations. Thus, development of effective vaccines and therapeutics is a critical need. The major barrier to this development has been the inability to culture human noroviruses. We have made two remarkable discoveries to overcome this obstacle - (1) human noroviruses infect B cells; and (2) they require enteric bacteria for optimal infection. Using the well-developed murine model of norovirus infection, we have validated both of these features of infection in an in vivo setting. Moreover, both of these findings provide fundamentally important clues to understanding norovirus pathogenesis and to developing effective strategies to combat infection. We speculate that human noroviruses interact with commensal bacteria in the gut lumen and virus:bacteria complexes are transcytosed across the intestinal epithelium in order to access the underlying B cell targets. During this process, the commensal bacteria should be recognized by mucosal immune cells and stimulate a tolerogenic microenvironment. In this environment, development of immune responses to the virus should be curbed through a process termed bystander suppression. This model is supported by the long- standing knowledge that norovirus infections are noninflammatory and they fail to elicit robust protective immunity. Understanding the basis for this apparent weak immunogenicity is key to designing effective treatment approaches. The objectives of the proposed research are thus to elucidate the mechanism by which enteric bacteria facilitate norovirus infection of B cells (Specific Aim 1); and the immune consequences of this interaction (Specific Aim 2).

Public Health Relevance

Human noroviruses are the leading cause of severe childhood diarrhea in the United States, and likely worldwide, but development of effective therapeutics and vaccines has been hampered by the lack of an in vitro viral propagation system. We have identified B cells are norovirus targets and enteric bacteria as a stimulatory factor of in vitro and in vivo infections. The objectives of the proposed studies are to elucidate the underlying mechanism by which bacteria facilitate norovirus infection of B cells, and the immune consequences of this interaction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116892-05
Application #
9621356
Study Section
Immunity and Host Defense (IHD)
Program Officer
Alarcon, Rodolfo M
Project Start
2015-02-16
Project End
2020-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Grau, Katrina R; Roth, Alexa N; Zhu, Shu et al. (2017) The major targets of acute norovirus infection are immune cells in the gut-associated lymphoid tissue. Nat Microbiol 2:1586-1591
Zhu, S; Jones, M K; Hickman, D et al. (2016) Norovirus antagonism of B-cell antigen presentation results in impaired control of acute infection. Mucosal Immunol 9:1559-1570
Karst, Stephanie M (2016) The influence of commensal bacteria on infection with enteric viruses. Nat Rev Microbiol 14:197-204
Roth, Alexa N; Karst, Stephanie M (2016) Norovirus mechanisms of immune antagonism. Curr Opin Virol 16:24-30
Karst, Stephanie M; Tibbetts, Scott A (2016) Recent advances in understanding norovirus pathogenesis. J Med Virol 88:1837-43
Zhu, Shu; Watanabe, Makiko; Kirkpatrick, Ericka et al. (2015) Regulation of Norovirus Virulence by the VP1 Protruding Domain Correlates with B Cell Infection Efficiency. J Virol 90:2858-67
Karst, Stephanie M (2015) Identification of a novel cellular target and a co-factor for norovirus infection - B cells & commensal bacteria. Gut Microbes 6:266-71
Jones, Melissa K; Grau, Katrina R; Costantini, Veronica et al. (2015) Human norovirus culture in B cells. Nat Protoc 10:1939-47