IgG in cervicovaginal mucus traps HSV and prevents vaginal herpes infections.
IgG is the predominant immunoglobulin in cervicovaginal mucus (CVM), yet how immunoglobulin G (IgG) in mucus can protect against infections is not fully understood. IgG diffuses rapidly through cervical mucus, slowed only slightly by transient adhesive interactions with mucins. We hypothesize that this almost unhindered diffusion allows IgG to accumulate rapidly on pathogen surfaces, and the resulting IgG array forms multiple weak adhesive crosslinks to mucus gel that effectively trap (immobilize) pathogens, preventing them from initiating infections. Here, we report that herpes simplex virus serotype 1 (HSV-1) readily penetrated fresh, pH-neutralized ex vivo samples of CVM with low or no detectable levels of anti-HSV-1 IgG but was trapped in samples with even modest levels of anti-HSV-1 IgG. In samples with little or no endogenous anti-HSV-1 IgG, addition of exogenous anti-HSV-1 IgG, affinity-purified from intravenous immunoglobulin, trapped virions at concentrations below those needed for neutralization and with similar potency as endogenous IgG. Deglycosylating purified anti-HSV-1 IgG, or removing its Fc component, markedly reduced trapping potency. Finally, a non-neutralizing IgG against HSV-gG significantly protected mice against vaginal infection, and removing vaginal mucus by gentle lavage abolished protection. These observations suggest that IgG-Fc has a glycan-dependent "muco-trapping" effector function that may provide exceptionally potent protection at mucosal surfaces.
Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, USA.
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Wang
UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
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A
Kannan
UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
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Nunn
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
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Murphy
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
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Subramani
ReProtect, Baltimore, Maryland, USA.
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Moench
Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, USA.
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Cone
1] UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA [2] Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
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Lai
D000328:Adult; D000818:Animals; D002582:Cervix Mucus / Q000276:immunology*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005260:Female; D036681:Fluorescence Recovery After Photobleaching; D006566:Herpesviridae Infections / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology; D018258:Herpesvirus 2, Human / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018139:Simplexvirus / Q000276:immunology*; D014621:Vagina / Q000276:immunology* / Q000821:virology; D014709:Vero Cells; D055815:Young Adult
D007074:Immunoglobulin G