The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online 8 December 2003 doi:10.1084/jem.20031223
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© Rockefeller University Press, 0022-1007/2003/12/1853 $5.00
The Journal of Experimental Medicine, Volume 198, Number 12, 1853-1862

A Critical Role for Induced IgM in the Protection against West Nile Virus Infection

Michael S. Diamond1,2,3, Elizabeth M. Sitati2, Lindzy D. Friend3, Stephen Higgs4, Bimmi Shrestha1 and Michael Engle1

1 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
2 Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110
3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
4 Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555

Address correspondence to Michael S. Diamond, Washington University School of Medicine, 660 S. Euclid Ave., Box 8051, St. Louis, MO 63110. Phone: (314) 362-2842; Fax: (314) 362-9230; email: diamond{at}borcim.wustl.edu

In humans, the elderly and immunocompromised are at greatest risk for disseminated West Nile virus (WNV) infection, yet the immunologic basis for this remains unclear. We demonstrated previously that B cells and IgG contributed to the defense against disseminated WNV infection (Diamond, M.S., B. Shrestha, A. Marri, D. Mahan, and M. Engle. 2003. J. Virol. 77:2578–2586). In this paper, we addressed the function of IgM in controlling WNV infection. C57BL/6J mice (sIgM-/-) that were deficient in the production of secreted IgM but capable of expressing surface IgM and secreting other immunoglobulin isotypes were vulnerable to lethal infection, even after inoculation with low doses of WNV. Within 96 h, markedly higher levels of infectious virus were detected in the serum of sIgM-/- mice compared with wild-type mice. The enhanced viremia correlated with higher WNV burdens in the central nervous system, and was also associated with a blunted anti-WNV IgG response. Passive transfer of polyclonal anti-WNV IgM or IgG protected sIgM-/- mice against mortality, although administration of comparable amounts of a nonneutralizing monoclonal anti-WNV IgM provided no protection. In a prospective analysis, a low titer of anti-WNV IgM antibodies at day 4 uniformly predicted mortality in wild-type mice. Thus, the induction of a specific, neutralizing IgM response early in the course of WNV infection limits viremia and dissemination into the central nervous system, and protects against lethal infection.

Key Words: flavivirus • antibody • innate immunity • encephalitis • risk factor

Abbreviations used in this paper: CNS, central nervous system; PRNT, plaque reduction neutralization titer; WNV, West Nile virus.


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