Herold, B. | bioRxiv Science

bioRxiv2025

Neutralizing Activity of Cervicovaginal Secretions against Herpes Simplex Virus is Mediated by Mucosal IgG and Viral Glycoprotein E and Adversely Impacted by Vaginal Dysbiosis

Genital herpes simplex virus (HSV) recurrences are more common in women with bacterial vaginosis (BV). Prior studies demonstrated that genital tract secretions exhibit variable neutralizing activity against HSV, independent of serostatus, but the relationship of this activity to the vaginal microbiome and underlying mechanisms have not been defined. To test the hypothesis that cervicovaginal antiviral activity is lower in women with BV, we took advantage of cervicovaginal lavage (CVL) available from two studies conducted among women with symptomatic BV and healthy controls. CVL obtained from women with BV had significantly less antiviral activity than controls (p< 0.001). Inhibitory activity correlated negatively and most strongly with Shannon diversity index (p<0.0001). The innate activity did not differ comparing HSV-seropositive versus seronegative participants and no HSV-specific antibodies were detected in CVL. Activity was enriched in the immunoglobulin fraction but was lost when IgG (but not IgA) was depleted. Increasing doses of an anti-glycoprotein E (gE) monoclonal antibody overcame the neutralizing activity, suggesting that interactions between the Fc region of IgG and gE, a viral Fc gamma receptor (Fc{gamma}R), contribute. Consistent with this notion, CVL had less HSV inhibitory activity against a gE-null virus. Glycan analysis demonstrated a decrease in mature glycans in IgG from CVL with low antiviral activity and treatment of CVL with peptide N-glycanase F, which cleaves N-glycans in IgG, resulted in a loss of HSV inhibitory activity. We speculate that glycosidases elaborated by anaerobic bacteria cleave Fc glycans, resulting in decreased affinity for gE and a reduction in protective activity. IMPORTANCE: This study provides a mechanistic link for the increased risk of HSV infection and replication in the setting of symptomatic bacterial vaginosis and asymptomatic vaginal dysbiosis. Independent of Fab antigen specificity, the Fc region of mucosal IgG may neutralize HSV by binding to glycoprotein E, a viral Fc receptor. Vaginal dysbiosis leads to a loss of Fc glycans and a concomitant decrease in this innate antiviral activity. These findings suggest that viral Fc receptors, previously thought to function only in immune evasion, may also play a protective role. The results highlight the importance of developing and implementing strategies to protect against vaginal dysbiosis.

microbiology↗

bioRxiv2020

Deaf intermarriage does not increase the prevalence of deafness alleles

The idea that deaf intermarriage increases deafness was forcefully pushed in the late 19th century by Alexander Graham Bell, in proceedings published by the National Academy of Science. Bells hypothesis was not supported by a 19th century study by Edward Allen Fay, which was funded by Bells own organization, the Volta Bureau. The Fay study showed through an analysis of 4,471 deaf marriages that the chances of having deaf children did not increase significantly when both parents were deaf. In light of an apparent increase in non-complementary pairings when a recent dataset of Gallaudet alumni was compared with the 19th century Fay dataset, Bells argument has been resurrected that residential schools for the deaf, which concentrate signing deaf individuals together, have promoted assortative mating and increased the prevalence of both phenotypic deafness and the commonest recessive deafness allele. Because this hypothesis persists, even though it contradicts classical models introduced by R.A. Fisher and Sewell Wright, it is critically important that this hypothesis be thoroughly re-investigated. In this study, we used an established forward-time genetics simulator with parameters and measurements collected from the published literature. Compared to mathematical equations, simulations allowed for more complex modeling, operated without assumptions of parametricity, and captured ending distributions and variances. Our simulation results affirm predictions from classical equations and show that assortative mating only modestly increases the prevalence of phenotypically deaf individuals, with this effect mostly completed by the third generation. Most importantly, our data show that even intense assortative mating does not increase allelic frequency under reported conditions. These results are not locus-specific and are generalizable to other forms of recessive deafness. We offer alternative explanations for the higher rate of non-complementary pairings measured in the contemporary Gallaudet alumni sample as compared to the Fay dataset.

genetics↗