Genital herpes shedding episodes associate with altered spatial organization and activation of mucosal immune cells
Finn MacLean, Rachael M. Zemek, Adino Tesfahun Tsegaye, Jessica B. Graham, Jessica L. Swarts, Sarah C. Vick, Nicole B. Potchen, Irene Cruz Talavera, Lakshmi Warrier, Julien Dubrulle, Lena K. Schroeder, Anna Elz, David Sowerby, Ayumi Saito, Katherine K. Thomas, Matthias Mack, Joshua T. Schiffer, R. Scott McClelland, Keith R. Jerome, Bhavna H. Chohan, Kenneth Ngure, Nelly Rwamba Mugo, Evan W. Newell, Jairam R. Lingappa, Jennifer M. Lund, Kinga Study Team
Finn MacLean, Rachael M. Zemek, Adino Tesfahun Tsegaye, Jessica B. Graham, Jessica L. Swarts, Sarah C. Vick, Nicole B. Potchen, Irene Cruz Talavera, Lakshmi Warrier, Julien Dubrulle, Lena K. Schroeder, Anna Elz, David Sowerby, Ayumi Saito, Katherine K. Thomas, Matthias Mack, Joshua T. Schiffer, R. Scott McClelland, Keith R. Jerome, Bhavna H. Chohan, Kenneth Ngure, Nelly Rwamba Mugo, Evan W. Newell, Jairam R. Lingappa, Jennifer M. Lund, Kinga Study Team
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Research Article Immunology Infectious disease

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

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.

Authors

Finn MacLean, Rachael M. Zemek, Adino Tesfahun Tsegaye, Jessica B. Graham, Jessica L. Swarts, Sarah C. Vick, Nicole B. Potchen, Irene Cruz Talavera, Lakshmi Warrier, Julien Dubrulle, Lena K. Schroeder, Anna Elz, David Sowerby, Ayumi Saito, Katherine K. Thomas, Matthias Mack, Joshua T. Schiffer, R. Scott McClelland, Keith R. Jerome, Bhavna H. Chohan, Kenneth Ngure, Nelly Rwamba Mugo, Evan W. Newell, Jairam R. Lingappa, Jennifer M. Lund, Kinga Study Team

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Figure 6

Vaginal inflammatory immune response is enhanced in the epithelium during HSV-2 shedding.

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Vaginal inflammatory immune response is enhanced in the epithelium durin...
(A and B) BuildNicheAssay function in Seurat was used to stratify the epithelium (Epi) and lamina propria (LP) layers, and clustering cells in each layer confirmed differences in cell populations in each layer. (A)Scale bar: 500 µm. (C) The average distance and distribution of each cell type from the thin basal epithelium cell layer were measured. (D) The proportion of cell types in the lamina propria and epithelium in Shed– versus Shed+ samples was measured. (E and F) The proportion of T cell subsets and NK cells in Shed– versus Shed+ (n [Shed–] = 2, n [Shed+] = 3) (E), and the heatmap comparing gene expression in T and NK cells in Shed– versus Shed+ (F). (G and H) The proportion of macrophage subset (MP) in Shed– versus Shed+ (G), and the heatmap comparing gene expression in macrophage subsets in Shed– versus Shed+ (H). (I and J) The proportion of DC subsets in Shed– versus Shed+ (I), and the heatmap comparing gene expression in DC subsets in Shed– versus Shed+ (J). **P < 0.01, calculated using a nonparametric permutation test, with Benjamini-Hochberg correction for multiple comparisons.