Milk IgAs of early life origin B cells have cross-neutralizing antiviral properties

Hannah Karen Labayo, NIH-NHLBI

Hannah Karen Mina Labayo1, Graham Brogden1, Madeleine Rochon1 Anastasia Du Halgouet2, Dan Corral3,Inta Gribonika3, Yasmine Belkaid3, Roxanne Tussiwand2, Joan Yuan4,Nihal Altan-Bonnet1 1. Laboratory of Host-Pathogen Dynamics, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA 2. Immune Regulation Unit, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA 3. Microbiome Metaorganism Immunity Section, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA 4. Developmental Immunology Unit, Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Lund University, 22242 Lund, Sweden.

Vaccines and immunity

IgA is a key immune component found in mother's milk. It is vertically transmitted to infants' immature mucosal system providing protection from viral and bacterial infections including those caused by the enteric noroviruses and rotaviruses. While enteric viruses have traditionally been understood to transmit via the fecal–oral route, we recently demonstrated that noroviruses and rotaviruses can also be transmitted through saliva (Ghosh et al., Nature 2022). Using a lactating mouse model, we showed that viral infection in suckling pups can be transmitted via saliva to the mother’s mammary glands, rapidly inducing a robust IgA response in milk. Now, we demonstrate that these milk-derived IgAs are protective and are primarily produced by early-life origin (ELO) B cells residing in the mammary gland and in their absence the infection in infants is enhanced in viral load and prolonged. Notably, these IgAs display broad cross-neutralizing activity, despite the mothers having no prior exposure to the infecting viruses. We showed that this neutralization is mediated by IgA binding to phosphatidylserine lipids—membrane components enriched in enveloped viruses such as coronaviruses and in vesicle-associated forms of traditionally “non-enveloped” viruses like noroviruses, rotaviruses, and picornaviruses. These vesicles facilitate en bloc transmission and are similarly rich in phosphatidylserine. Our findings have broad implications for not only understanding immune responses in the context of mammalian biology but also for designing antiviral treatments based on manipulating these broadly neutralizing IgA’s in milk.