Inflammation and HSV-2 in human foreskin

Maria Röhl1, Annelie Tjernlund1, Supriya D. Mehta2, Pernilla Pettersson1, Robert C. Bailey2, Kristina Broliden1
Affiliates: 1Department of Medicine Solna, Unit of Infectious Diseases, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden 2Division of Epidemiology, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA

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Objectives
Skin biopsies from local sites of HSV-2-induced ulcers can show infiltrates of inflammatory cells several months after macroscopic healing. We here hypothesized that foreskin tissue samples of asymptomatic HSV-2 seropositive men had remaining signs of inflammation at the molecular level. Even in the absence of clinical lesions, genital inflammation may contribute to increased HIV susceptibility upon sexual exposure to the virus.

Methods
Tissue samples (n=86) collected from men undergoing circumcision were stratified into study groups based on HSV-2 serology and assessed for mRNA expression of inflammatory markers. Markers of interest were further assessed by immunohistochemical staining within the tissue samples.

Results
The two study groups had comparable levels of all molecular markers (E-cadherin, ZO-1, occludin, CD3, CD4, CD8, CD69, CCR5, HLA-DR, Langerin, DC-SIGN, Mannose Receptor 1, IL-1, IL-6, TNF-α, β7, IgA, IFN-α and CCL5), except for lower mRNA levels of the epithelial junction protein claudin-1 in the HSV-2 seropositive group (p=0.008). Although mRNA levels of claudin-1 were lower in HSV-2 seropositive individuals, the corresponding protein could be visualized in the foreskin epithelium of all samples tested.

Conclusion
Whereas no general inflammation was demonstrated in the foreskin of asymptomatic HSV-2 seropositive individuals, a decreased expression of claudin-1 indicates a less robust genital epithelial barrier. An intact epithelial barrier is essential for blocking mucosal entry of genital infections including HIV.