ABSTRACT Epithelial cells (ECs) of the female genital tract (FGT) serve as an essential barrier and the first line of defense against sexually transmitted pathogens. Beyond providing a physical barrier, these cells actively contribute to immune responses through pathogen recognition, cytokine release, and modulation of adaptive immune responses. Sexually transmitted viruses such as HIV‐1 and HSV‐2 must overcome the physical and functional barriers of the mucosal surface to establish infection. This review explores the intricate relationship between genital ECs and HIV‐1 and HSV‐2, emphasizing on how these interactions influence infection outcomes. We examine the innate immune responses of ECs in the upper and lower FGT, highlighting both their similarities and differences. Additionally, we delve into the mechanisms of pathogen recognition and virus‐specific innate immune responses of genital ECs to HIV‐1 and HSV‐2. Deepening our understanding of epithelial‐viral interactions is critical for identifying key determinants of susceptibility and resistance to sexually transmitted infections (STIs). Elucidating these mechanisms is essential for developing targeted strategies to enhance mucosal immunity, through novel antiviral therapies, vaccine strategies, or interventions to fortify epithelial defenses. Such advancements have the potential to improve protection against these infections and reduce their global burden.
Jirik et al. (2026) studied this question.