CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus

Autoři: Vincent R. Graziano aff001;  Forrest C. Walker aff002;  Elizabeth A. Kennedy aff002;  Jin Wei aff001;  Khalil Ettayebi aff003;  Madison S. Strine aff001;  Renata B. Filler aff001;  Ebrahim Hassan aff002;  Leon L. Hsieh aff004;  Arthur S. Kim aff002;  Abimbola O. Kolawole aff005;  Christiane E. Wobus aff005;  Lisa C. Lindesmith aff006;  Ralph S. Baric aff006;  Mary K. Estes aff003;  Robert C. Orchard aff007;  Megan T. Baldridge aff002;  Craig B. Wilen aff001
Působiště autorů: Departments of Laboratory Medicine and Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America aff001;  Department of Medicine, Division of Infectious Diseases, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, Saint Louis, Missouri, United States of America aff002;  Departments of Medicine and Molecular Virology & Microbiology, Baylor College of Medicine, Houston, Texas, United States of America aff003;  Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America aff004;  Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America aff005;  Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America aff006;  Department of Immunology, University of Texas Southwestern Medical School, Dallas, Texas, United States of America aff007
Vyšlo v časopise: CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus. PLoS Pathog 16(4): e1008242. doi:10.1371/journal.ppat.1008242
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008242


Murine norovirus (MNoV) is an important model of human norovirus (HNoV) and mucosal virus infection more broadly. Viral receptor utilization is a major determinant of cell tropism, host range, and pathogenesis. The bona fide receptor for HNoV is unknown. Recently, we identified CD300lf as a proteinaceous receptor for MNoV. Interestingly, its paralogue CD300ld was also sufficient for MNoV infection in vitro. Here we explored whether CD300lf is the sole physiologic receptor in vivo and whether HNoV can use a CD300 ortholog as an entry receptor. We report that both CD300ld and CD300lf are sufficient for infection by diverse MNoV strains in vitro. We further demonstrate that CD300lf is essential for both oral and parenteral MNoV infection and to elicit anti-MNoV humoral responses in vivo. In mice deficient in STAT1 signaling, CD300lf is required for MNoV-induced lethality. Finally, we demonstrate that human CD300lf (huCD300lf) is not essential for HNoV infection, nor does huCD300lf inhibit binding of HNoV virus-like particles to glycans. Thus, we report huCD300lf is not a receptor for HNoV.

Klíčová slova:

Colon – Ileum – Mammalian genomics – Norovirus – Receptor physiology – RNA extraction – Spleen – Viral genome


1. Graziano VR, Wei J, Wilen CB. Norovirus Attachment and Entry. Viruses. 2019;11(6).

2. Lopman BA, Steele D, Kirkwood CD, Parashar UD. The Vast and Varied Global Burden of Norovirus: Prospects for Prevention and Control. PLoS Med. 2016;13(4):e1001999. doi: 10.1371/journal.pmed.1001999 27115709

3. Ahmed SM, Hall AJ, Robinson AE, et al. Global prevalence of norovirus in cases of gastroenteritis: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14(8):725–730. doi: 10.1016/S1473-3099(14)70767-4 24981041

4. Ahmed SM, Lopman BA, Levy K. A systematic review and meta-analysis of the global seasonality of norovirus. PLoS One. 2013;8(10):e75922. doi: 10.1371/journal.pone.0075922 24098406

5. Marsh M, Helenius A. Virus entry: open sesame. Cell. 2006;124(4):729–740. doi: 10.1016/j.cell.2006.02.007 16497584

6. Estes MK, Ettayebi K, Tenge VR, et al. Human Norovirus Cultivation in Nontransformed Stem Cell-Derived Human Intestinal Enteroid Cultures: Success and Challenges. Viruses. 2019;11(7).

7. Kilic T, Koromyslova A, Hansman GS. Structural Basis for Human Norovirus Capsid Binding to Bile Acids. J Virol. 2019;93(2).

8. Ettayebi K, Crawford SE, Murakami K, et al. Replication of human noroviruses in stem cell-derived human enteroids. Science. 2016.

9. Jones MK, Watanabe M, Zhu S, et al. Enteric bacteria promote human and mouse norovirus infection of B cells. Science. 2014;346(6210):755–759. doi: 10.1126/science.1257147 25378626

10. Karst SM, Wobus CE, Goodfellow IG, Green KY, Virgin HW. Advances in norovirus biology. Cell Host Microbe. 2014;15(6):668–680. doi: 10.1016/j.chom.2014.05.015 24922570

11. Walker FC, Baldridge MT. Interactions between noroviruses, the host, and the microbiota. Curr Opin Virol. 2019;37:1–9. doi: 10.1016/j.coviro.2019.04.001 31096124

12. Sherman MB, Williams AN, Smith HQ, et al. Bile salts alter the mouse norovirus capsid conformation; possible implications for cell attachment and immune evasion. J Virol. 2019.

13. Nelson CA, Wilen CB, Dai YN, et al. Structural basis for murine norovirus engagement of bile acids and the CD300lf receptor. Proc Natl Acad Sci U S A. 2018;115(39):E9201–E9210. doi: 10.1073/pnas.1805797115 30194229

14. Karst SM, Wobus CE, Lay M, Davidson J, Virgin HW. STAT1-dependent innate immunity to a Norwalk-like virus. Science. 2003;299(5612):1575–1578. doi: 10.1126/science.1077905 12624267

15. Orchard RC, Wilen CB, Doench JG, et al. Discovery of a proteinaceous cellular receptor for a norovirus. Science. 2016;353(6302):933–936. doi: 10.1126/science.aaf1220 27540007

16. 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. Proc Natl Acad Sci U S A. 2016;113(41):E6248–E6255. doi: 10.1073/pnas.1605575113 27681626

17. Prasad BV, Rothnagel R, Jiang X, Estes MK. Three-dimensional structure of baculovirus-expressed Norwalk virus capsids. J Virol. 1994;68(8):5117–5125. 8035511

18. Jiang X, Wang M, Graham DY, Estes MK. Expression, self-assembly, and antigenicity of the Norwalk virus capsid protein. J Virol. 1992;66(11):6527–6532. 1328679

19. Kilic T, Koromyslova A, Malak V, Hansman GS. Atomic Structure of the Murine Norovirus Protruding Domain and Soluble CD300lf Receptor Complex. J Virol. 2018;92(11).

20. Strong DW, Thackray LB, Smith TJ, Virgin HW. Protruding domain of capsid protein is necessary and sufficient to determine murine norovirus replication and pathogenesis in vivo. J Virol. 2012;86(6):2950–2958. doi: 10.1128/JVI.07038-11 22258242

21. Thackray LB, Wobus CE, Chachu KA, et al. Murine noroviruses comprising a single genogroup exhibit biological diversity despite limited sequence divergence. J Virol. 2007;81(19):10460–10473. doi: 10.1128/JVI.00783-07 17652401

22. Ward JM, Wobus CE, Thackray LB, et al. Pathology of immunodeficient mice with naturally occurring murine norovirus infection. Toxicol Pathol. 2006;34(6):708–715. doi: 10.1080/01926230600918876 17074739

23. Nice TJ, Strong DW, McCune BT, Pohl CS, Virgin HW. A single-amino-acid change in murine norovirus NS1/2 is sufficient for colonic tropism and persistence. J Virol. 2013;87(1):327–334. doi: 10.1128/JVI.01864-12 23077309

24. Van Winkle JA, Robinson BA, Peters AM, et al. Persistence of Systemic Murine Norovirus Is Maintained by Inflammatory Recruitment of Susceptible Myeloid Cells. Cell Host Microbe. 2018;24(5):665–676.e664. doi: 10.1016/j.chom.2018.10.003 30392829

25. Borrego F. The CD300 molecules: an emerging family of regulators of the immune system. Blood. 2013;121(11):1951–1960. doi: 10.1182/blood-2012-09-435057 23293083

26. Voss OH, Tian L, Murakami Y, Coligan JE, Krzewski K. Emerging role of CD300 receptors in regulating myeloid cell efferocytosis. Mol Cell Oncol. 2015;2(4):e964625. doi: 10.4161/23723548.2014.964625 27308512

27. Tian L, Choi SC, Murakami Y, et al. p85α recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression. Nat Commun. 2014;5:3146. doi: 10.1038/ncomms4146 24477292

28. Xi H, Katschke KJ, Helmy KY, et al. Negative regulation of autoimmune demyelination by the inhibitory receptor CLM-1. J Exp Med. 2010;207(1):7–16. doi: 10.1084/jem.20091508 20038601

29. Rozenberg P, Reichman H, Moshkovits I, Munitz A. CD300 family receptors regulate eosinophil survival, chemotaxis, and effector functions. J Leukoc Biol. 2018;104(1):21–29. doi: 10.1002/JLB.2MR1117-433R 29345367

30. Moshkovits I, Reichman H, Karo-Atar D, et al. A key requirement for CD300f in innate immune responses of eosinophils in colitis. Mucosal Immunol. 2017;10(1):172–183. doi: 10.1038/mi.2016.37 27118491

31. Wilen CB, Lee S, Hsieh LL, et al. Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science. 2018;360(6385):204–208. doi: 10.1126/science.aar3799 29650672

32. Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis. N Engl J Med. 2009;361(18):1776–1785. doi: 10.1056/NEJMra0804575 19864676

33. Parrino TA, Schreiber DS, Trier JS, Kapikian AZ, Blacklow NR. Clinical immunity in acute gastroenteritis caused by Norwalk agent. N Engl J Med. 1977;297(2):86–89. doi: 10.1056/NEJM197707142970204 405590

34. Kapikian AZ, Wyatt RG, Dolin R, Thornhill TS, Kalica AR, Chanock RM. Visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis. J Virol. 1972;10(5):1075–1081. 4117963

35. Karst SM, Tibbetts SA. Recent advances in understanding norovirus pathogenesis. J Med Virol. 2016;88(11):1837–1843. doi: 10.1002/jmv.24559 27110852

36. Karst SM, Wobus CE. A working model of how noroviruses infect the intestine. PLoS Pathog. 2015;11(2):e1004626. doi: 10.1371/journal.ppat.1004626 25723501

37. Wobus CE, Karst SM, Thackray LB, et al. Replication of Norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol. 2004;2(12):e432. doi: 10.1371/journal.pbio.0020432 15562321

38. Grau KR, Roth AN, Zhu S, et al. The major targets of acute norovirus infection are immune cells in the gut-associated lymphoid tissue. Nat Microbiol. 2017;2(12):1586–1591. doi: 10.1038/s41564-017-0057-7 29109476

39. Grau KR, Zhu S, Peterson ST, et al. The intestinal regionalization of acute norovirus infection is regulated by the microbiota via bile acid-mediated priming of type III interferon. Nat Microbiol. 2020;5(1):84–92. doi: 10.1038/s41564-019-0602-7 31768030

40. Kolawole AO, Smith HQ, Svoboda SA, et al. Norovirus Escape from Broadly Neutralizing Antibodies Is Limited to Allostery-Like Mechanisms. mSphere. 2017;2(5).

41. Müller B, Klemm U, Mas Marques A, Schreier E. Genetic diversity and recombination of murine noroviruses in immunocompromised mice. Arch Virol. 2007;152(9):1709–1719. doi: 10.1007/s00705-007-0989-y 17533553

42. Niendorf S, Klemm U, Mas Marques A, Bock CT, Höhne M. Infection with the Persistent Murine Norovirus Strain MNV-S99 Suppresses IFN-Beta Release and Activation of Stat1 In Vitro. PLoS One. 2016;11(6):e0156898. doi: 10.1371/journal.pone.0156898 27294868

43. Harrington PR, Vinjé J, Moe CL, Baric RS. Norovirus capture with histo-blood group antigens reveals novel virus-ligand interactions. J Virol. 2004;78(6):3035–3045. doi: 10.1128/JVI.78.6.3035-3045.2004 14990722

44. Harrington PR, Lindesmith L, Yount B, Moe CL, Baric RS. Binding of Norwalk virus-like particles to ABH histo-blood group antigens is blocked by antisera from infected human volunteers or experimentally vaccinated mice. J Virol. 2002;76(23):12335–12343. doi: 10.1128/JVI.76.23.12335-12343.2002 12414974

45. Jiang C, Parrish NF, Wilen CB, et al. Primary infection by a human immunodeficiency virus with atypical coreceptor tropism. J Virol. 2011;85(20):10669–10681. doi: 10.1128/JVI.05249-11 21835785

46. Wilen CB, Parrish NF, Pfaff JM, et al. Phenotypic and immunologic comparison of clade B transmitted/founder and chronic HIV-1 envelope glycoproteins. J Virol. 2011;85(17):8514–8527. doi: 10.1128/JVI.00736-11 21715507

47. Haber AL, Biton M, Rogel N, et al. A single-cell survey of the small intestinal epithelium. Nature. 2017;551(7680):333–339. doi: 10.1038/nature24489 29144463

48. Clark GJ, Ju X, Tate C, Hart DN. The CD300 family of molecules are evolutionarily significant regulators of leukocyte functions. Trends Immunol. 2009;30(5):209–217. doi: 10.1016/ 19359216

49. Durbin JE, Hackenmiller R, Simon MC, Levy DE. Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell. 1996;84(3):443–450. doi: 10.1016/s0092-8674(00)81289-1 8608598

50. Arias A, Bailey D, Chaudhry Y, Goodfellow I. Development of a reverse-genetics system for murine norovirus 3: long-term persistence occurs in the caecum and colon. J Gen Virol. 2012;93(Pt 7):1432–1441. doi: 10.1099/vir.0.042176-0 22495235

51. Wang GG, Calvo KR, Pasillas MP, Sykes DB, Häcker H, Kamps MP. Quantitative production of macrophages or neutrophils ex vivo using conditional Hoxb8. Nat Methods. 2006;3(4):287–293. doi: 10.1038/nmeth865 16554834

52. Takeshita S, Kaji K, Kudo A. Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts. J Bone Miner Res. 2000;15(8):1477–1488. doi: 10.1359/jbmr.2000.15.8.1477 10934646

53. Baert L, Wobus CE, Van Coillie E, Thackray LB, Debevere J, Uyttendaele M. Detection of murine norovirus 1 by using plaque assay, transfection assay, and real-time reverse transcription-PCR before and after heat exposure. Appl Environ Microbiol. 2008;74(2):543–546. doi: 10.1128/AEM.01039-07 18024676

54. Loisy F, Atmar RL, Guillon P, Le Cann P, Pommepuy M, Le Guyader FS. Real-time RT-PCR for norovirus screening in shellfish. J Virol Methods. 2005;123(1):1–7. doi: 10.1016/j.jviromet.2004.08.023 15582692

55. Mumphrey SM, Changotra H, Moore TN, et al. Murine norovirus 1 infection is associated with histopathological changes in immunocompetent hosts, but clinical disease is prevented by STAT1-dependent interferon responses. J Virol. 2007;81(7):3251–3263. doi: 10.1128/JVI.02096-06 17229692

56. Hsu CC, Riley LK, Wills HM, Livingston RS. Persistent infection with and serologic cross-reactivity of three novel murine noroviruses. Comp Med. 2006;56(4):247–251. 16941951

Článek vyšel v časopise

PLOS Pathogens

2020 Číslo 4
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Deprese u dětí a adolescentů
nový kurz
Autoři: MUDr. Vlastimil Nesnídal

Konsenzuální postupy v léčbě močových infekcí

COVID-19 up to date
Autoři: doc. MUDr. Vladimír Koblížek, Ph.D., MUDr. Mikuláš Skála, prof. MUDr. František Kopřiva, Ph.D., prof. MUDr. Roman Prymula, CSc., Ph.D.

Betablokátory a Ca antagonisté z jiného úhlu
Autoři: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Chronické žilní onemocnění a možnosti konzervativní léčby

Všechny kurzy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se