Mechanisms of Immunopathology Control by Tregs during HSV-1 Infection

• Grant number: 25/05083-9
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2026
• End date: February 28, 2030
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: José Carlos Farias Alves Filho
• Grantee: Jonatan Constança Silva de Carvalho
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Herpes simplex type 1 (HSV-1) is a virus of the Herpesviridae family and represents a significant public health problem due to its high prevalence, ability to establish latency in sensory neurons, and recurrence of painful lesions. Although frequently associated with mucocutaneous manifestations, such as cold sores, HSV-1 can also affect the central nervous system, resulting in serious complications such as herpetic encephalitis. Regulatory T cells (Tregs) play a complex role during infection, simultaneously containing inflammation and creating an environment permissive to viral persistence. Depletion of these cells exacerbates immunopathology while reducing viral load and latency establishment, highlighting their dual function in balancing tissue protection and antiviral control. Despite this relevance, how HSV-1 modulates the suppressive and reparative functions of Tregs is still poorly understood. Preliminary results from this project show that HSV-1 is capable of infecting and activating Tregs without compromising their viability, suggesting that the direct virus-Treg interaction influences the infection trajectory. Additionally, in vivo studies demonstrate that the absence of HVEM (Herpesvirus Entry Mediator), one of the entry receptors for HSV-1, reduces Treg activation during infection, indicating that this receptor participates in essential pathways regulating the Treg-mediated immune response. On the other hand, recent evidence from cutaneous inflammation models shows that the production of pro-enkephalin (Penk) by Tregs is crucial for these cells to promote tissue repair and pain modulation. Although there are still no studies evaluating Penk in the context of HSV-1, these functions suggest that this axis may contribute to limiting the immunopathology associated with viral infection. Thus, this project will investigate the role of HVEM and Penk cells in Tregs during HSV-1 infection, aiming to elucidate central immunological mechanisms that influence the establishment of primary infection, latency, and tissue damage. Elucidating these processes has the potential to reveal new immunological control points and guide future therapeutic strategies. (AU)