Epithelial Cells’ Sensitivity to Interferon Gamma May Shape Genital Herpes Outcomes

Genital herpes is one of the most common chronic viral infections in the world, yet people who carry herpes simplex virus type 2 experience it in strikingly different ways. Some individuals shed virus from the genital tract frequently and suffer recurrent, painful ulcerative lesions, while others harbor the same infection with few or no noticeable symptoms. For decades, researchers have tried to understand why the clinical course of HSV-2 varies so dramatically from person to person. A new study published in PLOS Pathogens points to an unexpected contributor: the epithelial cells that line the genital tract themselves, and specifically how sensitive they are to interferon gamma, a signaling molecule released by resident immune cells during viral reactivation.

The research team, led by Angelina Zimenko and Jia Zhu with colleagues at the University of Washington and the Fred Hutchinson Cancer Center, set out to examine a question that has been surprisingly underexplored. Interferon gamma is well established as a critical weapon in the antiviral arsenal of tissue-resident T cells, the immune sentinels that patrol mucosal surfaces and respond when HSV-2 attempts to reactivate from its latent state in sensory neurons. What has remained murky is how the target cells of that signal, the epithelial cells of the genital skin and mucosa, respond to it, and whether differences in that response could help explain why some people develop lesions while others do not.

To address this, the investigators worked with primary keratinocytes, the dominant epithelial cell type of the outer genital tissue, obtained from donors with well-characterized HSV-2 infection. Crucially, the donors fell into two clinically distinct groups: those with asymptomatic infection, who shed virus without developing lesions, and those with ulcerative disease, who experience recurrent genital sores. The researchers also isolated donor-matched fibroblasts, the structural cells of the underlying dermis, allowing them to compare epithelial and stromal responses within the same individual. This paired design gave the team a way to isolate cell-type-specific behavior from person-to-person variation.

The first major finding concerned sheer sensitivity. Keratinocytes turned out to be remarkably responsive to interferon gamma, altering their gene expression at concentrations far lower than those typically used in laboratory studies of the cytokine. This matters because the doses commonly employed in cell culture experiments have often been orders of magnitude higher than what immune cells are thought to deliver locally in tissue. By probing responses across a range of physiologically relevant interferon gamma concentrations, the researchers revealed that epithelial cells are tuned to detect and react to very faint cytokine signals, a property that previous work had substantially underestimated.

The comparison with fibroblasts sharpened the picture. Across donors, keratinocytes showed greater sensitivity to interferon gamma stimulation than their matched fibroblasts, and the epithelial response was dominated by robust induction of chemokines, the secreted proteins that act as homing beacons for circulating immune cells. Among these, CXCL10 stood out. It was the most sensitive and most strongly induced gene in the dataset, ramping up rapidly even at the lowest interferon gamma doses tested. CXCL10 is a well-known ligand for the chemokine receptor CXCR3, which is expressed on activated T cells and other immune populations, making it a plausible molecular bridge between cytokine signaling and the recruitment of antiviral lymphocytes to sites of viral reactivation.

The most clinically significant result emerged when the researchers compared keratinocytes from the two donor groups. Epithelial cells from individuals with asymptomatic HSV-2 infection mounted significantly stronger responses to interferon gamma than cells from donors with ulcerative disease, and the difference was most pronounced at the low, physiologically relevant cytokine concentrations. The heightened responsiveness was evident both at the messenger RNA level and at the protein level, indicating that the cells from asymptomatic donors were not merely transcribing chemokine genes more vigorously but actually secreting more of the corresponding proteins. In effect, the epithelial barrier of people who never develop lesions appeared intrinsically better wired to broadcast an immune-recruitment alarm when interferon gamma arrives.

Delving into the signaling machinery, the team found that the enhanced response correlated with increased nuclear localization of phosphorylated STAT1, the transcription factor that carries the interferon gamma signal from the cell surface receptor into the nucleus. Interestingly, this difference was not explained by higher baseline expression of the interferon gamma receptor or of STAT1 itself, which were similar across donor groups. Instead, the asymptomatic donors’ keratinocytes appeared to process the incoming signal more efficiently, amplifying the downstream transcriptional output. This suggests that the variation lies in the dynamics of the JAK-STAT signaling pathway rather than in the simple abundance of its components, a distinction that could guide future mechanistic studies of interferon responsiveness in epithelial barriers.

An important nuance concerns the direct antiviral effect of the cytokine. When the researchers pretreated keratinocytes with interferon gamma before exposing them to HSV, the cytokine suppressed viral replication to a similar degree in cells from both donor cohorts. In other words, the intrinsic antiviral state that interferon gamma induces in epithelial cells was not obviously stronger in the asymptomatic group. What differed was the chemokine output. The authors propose, therefore, that the advantage enjoyed by asymptomatic individuals may lie less in the epithelium’s ability to block the virus directly and more in its capacity to summon antiviral immune cells to the tissue through vigorous chemokine production, particularly CXCL10, thereby containing reactivation events before they escalate into visible lesions.

Taken together, the findings reframe the epithelium as an active participant in the immunology of genital herpes rather than a passive substrate for viral replication. Tissue-resident T cells clearly supply the interferon gamma signal, but the study indicates that the clinical outcome of that signal depends on how loudly the epithelial target cells answer. Intrinsic variation in epithelial interferon gamma responsiveness emerges as a candidate host factor associated with whether HSV-2 infection runs a symptomatic or silent course, and CXCL10-mediated immune recruitment is highlighted as a key mechanism potentially linking T cell cytokine signaling to epithelial antiviral defense. The researchers caution that their work identifies an association and a plausible mechanism, and that establishing causation in human infection will require further study.

The implications extend beyond basic virology. Therapeutic vaccines for genital herpes, which aim to boost T cell responses in the genital tract, implicitly rely on the responsiveness of target tissues to the cytokines those T cells produce. If a substantial fraction of the population has epithelial cells that respond weakly to interferon gamma, strategies that amplify chemokine signaling or sensitize the JAK-STAT pathway in epithelial cells could complement vaccine approaches. Conversely, measuring epithelial interferon gamma responsiveness might eventually help stratify patients by their likelihood of symptomatic disease. As the authors note, understanding variability in the immune defenses of the epithelial barrier may prove crucial for improving both therapies and vaccine strategies against one of the world’s most prevalent chronic infections.

Subject of Research: Epithelial interferon gamma signaling and chemokine responses in herpes simplex virus type 2 infection outcomes

Article Title: Epithelial interferon-γ responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection

Article References: Zimenko, A., Hayman, I., Fong, Y., Monroe, L. D., Mills, M. G., Greninger, A., Johnston, C., Corey, L., & Zhu, J. (2026). Epithelial interferon-γ responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection. PLOS Pathogens, 22(9), e1014612. https://doi.org/10.1371/journal.ppat.1014612

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014612

Keywords: HSV-2, genital herpes, interferon gamma, keratinocytes, CXCL10, chemokines, STAT1, tissue-resident T cells, epithelial immunity, viral reactivation, PLOS Pathogens, antiviral defense