# Genital herpes shedding episodes associate with altered spatial organization and activation of mucosal immune cells

## TL;DR

This study shows that active genital herpes shedding changes the organization and activity of immune cells in the vaginal mucosa, possibly to protect tissue.

## Contribution

The study reveals how HSV-2 shedding affects immune cell spatial organization and gene expression in the genital tract.

## Key findings

- HSV-2 shedding is linked to altered localization of T cells, macrophages, and dendritic cells in the vaginal mucosa.
- Active shedding correlates with immune cell gene expression patterns suggesting increased surveillance and tissue homeostasis.
- Immune responses during shedding include both inflammatory and regulatory signals to limit tissue damage.

## Abstract

Herpes Simplex Virus 2 (HSV-2) infection results in variable rates of local viral shedding in anogenital skin. The effect of episodic viral exposures on immune cells in adjacent mucosal tissues, including the genital tract, is unknown. However, any immune responses at this site could affect protective mucosal immunity, tissue homeostasis, and adverse health outcomes. To investigate the effect of HSV-2 on cervicovaginal tract immunity, we applied flow cytometry, immunofluorescence imaging, analysis of soluble immune factors, and spatial transcriptomics to cervicovaginal tissue and blood samples provided by a total of 232 HSV-2–seropositive and seronegative participants, with genital HSV-2 shedding evaluated at the time of biopsy. This unique dataset was used to define and spatially map immune cell subsets and localized gene expression via spatial transcriptomics. HSV-2 seropositivity alone was associated with minimal differences in cervicovaginal and circulating T cell phenotypes. However, the vaginal mucosa during active HSV-2 shedding was associated with alterations in T cell, macrophage, and DC localization and gene expression, consistent with increased immune surveillance, with immune activating and suppressing signals potentially reinforcing mucosal tissue homeostasis.

In context of episodic HSV-2 shedding, immune cells mobilize and co-localize in the vaginal epithelium, expressing cytotoxic and inflammatory plus immunoregulatory genes that collectively may promote tissue homeostasis to limit damage.