Mouse Norovirus Uses Host Metabolites to Enhance Receptor Binding and Evade Immune Recognition

Main Article Content

Michael B Sherman Alexis N Williams Hong Qiu Smith Christiane E Wobus Thomas James Smith


Noroviruses are the major cause of epidemic gastroenteritis in humans, causing ~20 million cases annually, resulting in more than 70,000 hospitalizations and 570-800 deaths in the United States alone. The T=3 icosahedral calicivirus capsid is composed of viral protein 1 (VP1) with three major domains: the N-terminus (N), shell (S), and C-terminal protruding (P) domains. The S domain forms a shell around the viral RNA genome, while the P domains dimerize to form protrusions on the capsid surface. The P domain is subdivided into P1 and P2 subdomains, with the latter containing the binding sites for cellular receptors and neutralizing antibodies. Mouse norovirus (MNV) is a widely used system for study of norovirus biology since we have a cell culture system, reverse genetic tools, and small animal model to eventually correlate structural information to whole animal pathology

Mouse norovirus is a surprisingly dynamic virus that switches between receptor and antibody binding structures depending upon the in-vivo environment. In the circulation, the P domain floats above the shell by more than 15Å and the P domain loops (A’B’/E’F’) at the very tip are splayed apart in an ‘open’ conformation that antibodies learn to recognize. Upon ingestion, the low pH environment with high metal and bile salt concentrations in the alimentary canal each independently trigger the P domains to rotate 90° and contract by 15 Å onto the capsid surface. This hides any epitopes at base of the P domain. During this reversible collapse, the two P domains within the dimer rotate about each other and the A’B’/E’F’ loops adopt the ‘closed’ conformation. This opens the receptor binding site while burying the epitopes at the tip of the P domain. Therefore, rather than only depending on escape mutations to block antibody binding, MNV aggressively uses host conditions to remodel itself to enhance receptor binding while blocking antibody recognition.

This review will describe the structural processes and biological consequences of the virus responding to activating host cues in the gut while these same triggers bury the epitopes presented in the circulation. This is an aggressive and unique mode of immune escape that has been subsequently shown in other viruses such as COVID-19. Therefore, a deeper understanding of the dynamic processes of virus capsids will improve vaccine design by understanding how to present the epitope conformations at the site of infection rather than what is presented to the immune system.

Article Details

How to Cite
SHERMAN, Michael B et al. Mouse Norovirus Uses Host Metabolites to Enhance Receptor Binding and Evade Immune Recognition. Medical Research Archives, [S.l.], v. 10, n. 11, nov. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 23 apr. 2024. doi:
Research Articles


1. Chhabra P, de Graaf M, Parra GI, et al. Updated classification of norovirus genogroups and genotypes. The Journal of general virology. 2019;100(10):1393-1406. doi:10.1099/jgv.0.001318
2. Moe CL, Sobsey MD, Stewart PW, Crawford-Brown D. Estimating the risk of human calicivirus infection from drinking water. . 1999:P4-6.
3. Blanton LH, Adams SM, Beard RS, et al. Molecular and epidemiologic trends of caliciviruses associated with outbreaks of acute gastroenteritis in the United States, 2000-2004. The Journal of infectious diseases. Feb 1 2006;193(3):413-21. doi:10.1086/499315
4. Siebenga JJ, Vennema H, Duizer E, Koopmans MP. Gastroenteritis caused by norovirus GGII.4, The Netherlands, 1994-2005. Emerging infectious diseases. Jan 2007;13(1):144-6. doi:10.3201/eid1301.060800
5. Hall AJ, Lopman BA, Payne DC, et al. Norovirus disease in the United States. Emerging infectious diseases. Aug 2013;19(8):1198-205. doi:10.3201/eid1908.130465
6. Debbink K, Lindesmith LC, Donaldson EF, et al. Emergence of new pandemic GII.4 Sydney norovirus strain correlates with escape from herd immunity. The Journal of infectious diseases. Dec 1 2013;208(11):1877-87. doi:10.1093/infdis/jit37
7. Baldridge MT, Turula H, Wobus CE. Norovirus Regulation by Host and Microbe. Trends Mol Med. Dec 2016;22(12):1047-1059. doi:10.1016/j.molmed.2016.10.003
8. Gonzalez-Hernandez MB, Liu T, Blanco LP, Auble H, Payne HC, Wobus CE. Murine norovirus transcytosis across an in vitro polarized murine intestinal epithelial monolayer is mediated by M-like cells. J Virol. Dec 2013;87(23):12685-93. doi:10.1128/JVI.02378-13
9. Gonzalez-Hernandez MB, Liu T, Payne HC, et al. Efficient norovirus and reovirus replication in the mouse intestine requires microfold (M) cells. J Virol. Jun 2014;88(12):6934-43. doi:10.1128/JVI.00204-14
10. Wobus CE, Thackray LB, Virgin HWI. Murine norovirus: a model system to study norovirus biology and pathogenesis. J Virol. 2006;80:5104-5112.
11. Wobus CE. The Dual Tropism of Noroviruses. J Virol. Aug 15 2018;92(16) doi:10.1128/jvi.01010-17
12. Haga K, Fujimoto A, Takai-Todaka R, et al. Functional receptor molecules CD300lf and CD300ld within the CD300 family enable murine noroviruses to infect cells. Proceedings of the National Academy of Sciences. 2016;113(41):E6248. doi:10.1073/pnas.1605575113
13. Orchard RC, Wilen CB, Doench JG, et al. Discovery of a proteinaceous cellular receptor for a norovirus. Science. 2016;353:933-936.
14. Graziano VR, Walker FC, Kennedy EA, et al. CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus. . PloS Pathogens. 2020;16:e1008242. doi:
15. Barron EL, Sosnovtsev SV, Bok K, et al. Diversity of murine norovirus strains isolated from asymptomatic mice of different genetic backgrounds within a single U.S. research institute. PLoS ONE. 2011;6:e21435. doi: doi: 10.1371/journal.pone.0021435
16. Wobus CE, Karst SM, Thackray LB, et al. Replication of Norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol. Dec 2004;2(12):e432. doi:10.1371/journal.pbio.0020432
17. Vitalle J, Terren I, Orrantia A, Zenarruzabeitia O, Borrego F. CD300 receptor family in viral infections. Eur J Immunol. Mar 2019;49(3):364-374. doi:10.1002/eji.201847951
18. Graziano VR, Walker FC, Kennedy EA, et al. CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus. PLoS Pathog. Apr 2020;16(4):e1008242. doi:10.1371/journal.ppat.1008242
19. Prasad BVV, Hardy ME, Dokland T, Bella J, Rossmann MG, Estes MK. X-ray crystallographic structure of the Norwalk virus capsid. Science. 1999;286:287-290.
20. Prasad BV, Hardy ME, Jiang X, Estes MK. Structure of Norwalk virus. Archives of virology Supplementum. 1996;12:237-42.
21. Prasad BV, Matson DO, Smith AW. Three-dimensional structure of calicivirus. J Mol Biol. 1994;240:256-264.
22. Katpally U, Wobus CE, Dryden K, Virgin HWI, Smith TJ. Structure of antibody-neutralized murine norovirus and unexpected differences from viruslike particles. J Virol. 2008;82:2079-2088.
23. Sherman MB, Williams AN, Smith HQ, et al. Bile salts alter the mouse norovirus capsid conformation; possible implications for cell attachment and immune evasion. Journal of Virology. 2019;12:e00970-19. doi:10.1128/JVI.00970-19
24. Choi J-M, Hutson AM, Estes MK, Prasad BVV. Atomic resolution structural characterization of recognition of histo-blood group antigens by Norwalk virus. Proc Natl Acad Sci. 2008;105:9175-9180.
25. Tan M, Hegde RS, Jiang X. The P domain of norovirus capsid protein forms dimer and binds to histo-blood group antigen receptors. J Virol. Jun 2004;78(12):6233-42. doi:10.1128/JVI.78.12.6233-6242.2004
26. Donaldson EF, Lindesmith LC, Lobue AD, Baric RS. Viral shape-shifting: norovirus evasion of the human immune system. Nature reviews Microbiology. Mar 2010;8(3):231-41. doi:10.1038/nrmicro2296
27. Nilsson M, Hedlund KO, Thorhagen M, et al. Evolution of human calicivirus RNA in vivo: accumulation of mutations in the protruding P2 domain of the capsid leads to structural changes and possibly a new phenotype. J Virol. Dec 2003;77(24):13117-24.
28. Taube S, Rubin JR, Smith TJ, Kendall A, Stuckey J, Wobus CE. High resolution X-ray structure and functional analysis of murine norovirus (MNV)-1 capsid protein protruding domain. J Virol. 2010;84:5695-5705.
29. Katpally U, Voss NR, Cavazza T, et al. High-Resolution Cryo-Electron Microscopy Structures of Murine Norovirus 1 and Rabbit Hemorrhagic Disease Virus Reveal Marked Flexibility in the Receptor Binding Domains. J Virol. 2010;84:5836-5841.
30. Taube S, Rubin JR, Katpally U, et al. High-Resolution X-Ray Structure and Functional Analysis of the Murine Norovirus 1 Capsid Protein Protruding Domain. Journal of Virology. June 1, 2010 2010;84(11):5695-5705. doi:10.1128/jvi.00316-10
31. Kolawole AO, Li M, Xia C, et al. Flexibility in surface-exposed loops in a virus capsid mediates escape from antibody neutralization. J Virol. Apr 2014;88(8):4543-57. doi:10.1128/JVI.03685-13
32. Kolawole AO, Xia C, Li M, et al. Newly isolated mAbs broaden the neutralizing epitope in murine norovirus. The Journal of general virology. Sep 2014;95(Pt 9):1958-68. doi:10.1099/vir.0.066753-0
33. Hansman GS, Taylor DW, McLellan JS, et al. Structural basis for broad detection of genogroup II noroviruses by a monoclonal antibody that binds to a site occluded in the viral particle. J Virol. 2012;86:3635-3646.
34. Smith HQ, Smith TJ. The Dynamic Capsid Structures of the Noroviruses. Viruses. 2019;11(3):235. doi:10.3390/v11030235
35. Nelson CA, Wilen CB, Dai Y-N, et al. Structural basis for murine norovirus engagement of bile acids and the CD300lf receptor. Proceedings of the National Academy of Sciences. 2018;115(39):E9201. doi:10.1073/pnas.1805797115
36. Williams AN, Sherman MB, Smith HQ, et al. A norovirus uses bile salts to escape antibody recognition while enhancing receptor binding. J Virol. 2021;95:e00176-21. doi:DOI:10.1128/JVI.00176-21
37. Snowden JS, Hurdiss DL, Adeyemi OO, Ranson NA, Herod MR, Stonehouse NJ. Dynamics in the murine norovirus capsid revealed by high-resolution cryo-EM. PLOS Biology. 2020;18(3):e3000649. doi:10.1371/journal.pbio.3000649
38. Kolawole AO, Smith HQ, Svoboda SA, et al. Norovirus escape from broadly neutralizing antibodies is limited to allosteric-like mechanisms. mSphere. 2017;2:e00334-17. doi: 10.1128/mSphere.00334-17
39. Sherman MB, Williams AN, Smith HQ, Pettitt BM, Wobus CE, Smith TJ. Structural Studies on the Shapeshifting Murine Norovirus. Viruses. 2021;13(11):2162. doi:10.3390/v13112162
40. Williams AN, Sherman MB, Smith HQ, et al. Multiple Signals in the Gut Contract the Mouse Norovirus Capsid To Block Antibody Binding While Enhancing Receptor Affinity. J Virol. Oct 27 2021;95(22):e0147121. doi:10.1128/jvi.01471-21
41. Katpally U, Voss NR, Cavazza T, et al. High-resolution cryo-electron microscopy structures of murine norovirus 1 and rabbit hemorrhagic disease virus reveal marked flexibility in the receptor binding domains. . J Virol. 2010;84:5836-5841.
42. Kolawole AO, Li M, Xia C, et al. Flexibility in Surface-Exposed Loops in a Virus Capsid Mediates Escape from Antibody Neutralization. Journal of Virology. April 15, 2014 2014;88(8):4543-4557. doi:10.1128/jvi.03685-13
43. Goss SL, Lemons KA, Kerstetter JE, Bogner RH. Determination of calcium salt solubility with changes in pH and P(CO(2)), simulating varying gastrointestinal environments. J Pharm Pharmacol. Nov 2007;59(11):1485-92. doi:10.1211/jpp.59.11.0004
44. Hu L, Salmen W, Chen R, et al. Atomic structure of the predominant GII.4 human norovirus capsid reveals novel stability and plasticity. Nature Communications. 2022/03/10 2022;13(1):1241. doi:10.1038/s41467-022-28757-z
45. Rosa A, Pye VE, Graham C, et al. SARS-CoV-2 recruits a haem metabolite to evade antibody immunity. medRxiv. 2021:2021.01.21.21249203. doi:10.1101/2021.01.21.21249203
46. Staufer O, Gupta K, Hernandez Bücher JE, et al. Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein. Nature Communications. 2022/02/14 2022;13(1):868. doi:10.1038/s41467-022-28446-x