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Research Project: Viral Ecology of Henipaviruses in Endemic Settings and Intervention Strategies to Prevent their Spread to Domestic Animals

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Title: Monoclonal IgM antibodies mediate potent complement neutralization by targeting cell-derived epitopes on enveloped viruses

Author
item KAINULAINEN, MARKUS - Centers For Disease Control And Prevention (CDC) - United States
item HARMON, JESSICA - Centers For Disease Control And Prevention (CDC) - United States
item BERGERON, ERIC - Centers For Disease Control And Prevention (CDC) - United States
item DAVIES, KATHERINE - Centers For Disease Control And Prevention (CDC) - United States
item DAVIS, MORGAN - Centers For Disease Control And Prevention (CDC) - United States
item CLINES, CHRISTINA - Centers For Disease Control And Prevention (CDC) - United States
item MONTGOMERY, JOEL - Centers For Disease Control And Prevention (CDC) - United States
item SPIROPOULOU, CHRISTINA - Centers For Disease Control And Prevention (CDC) - United States

Submitted to: mBio
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/9/2026
Publication Date: 2/13/2026
Citation: Kainulainen, M.H., Harmon, J.R., Bergeron, E., Davies, K.A., Davis, M., Clines, C., Montgomery, J.M., Spiropoulou, C.F. 2026. Monoclonal IgM antibodies mediate potent complement neutralization by targeting cell-derived epitopes on enveloped viruses. mBio. 17(3). https://doi.org/10.1128/mbio.01709-25.
DOI: https://doi.org/10.1128/mbio.01709-25

Interpretive Summary: A major question in the field of infectious diseases is why the outcome of an infection with a certain organism can vary from severe to benign between individuals. Variability in the microbe or the host arising from genetic or acquired traits can influence the outcome. Individual variance in naïve serum donors’ ability to neutralize Ebola virus and other enveloped viruses was observed. Viral envelope glycoproteins are the main targets of neutralizing antibodies. However, viruses obtain their membranes from cells in which they replicate, and the membranes are known to contain cell-derived markers in addition to virally encoded proteins. Three antibodies that target a cell-derived epitope and mediate potent neutralization were identified. The results highlight the possible role of host-derived epitopes as acquired traits of a virus and suggest they may be targets of potent antibody-mediated immune monitoring.

Technical Abstract: When studying virus neutralization by specific antibodies of the adaptive immune response, serum heat-treatment is a standard procedure done to eliminate any unspecific effects by the complement system. Although unspecific, innate immune responses such as those may be relevant in determining infection outcome. We observed extensive variation between negative control donors in their ability to neutralize Ebola virus and other enveloped viruses in the presence of complement. The effect was mediated by the classical pathway of complement activation, with serum IgM the main initiator in a manner that depended on cell line that produced the virus. To identify the epitope, three monoclonal IgM antibodies were isolated after a neutralization screen and probed against arrayed glycans. The antibodies were found to bind ganglioside GM2, and the test virus was rendered refractory to neutralization when propagated in the presence of an inhibitor of ganglioside synthesis. Gangliosides and other host membrane moieties are known to be carried by viruses in a manner that aids entry to cells. The findings here suggest that under specific circumstances, such moieties on enveloped viruses can be recognized by potent IgM antibodies present in the serum of immunologically naïve individuals.