TGF-β1Regulation In Influenza A Virus Caused Testicular Immune Response

The testis is an organ with immune privilege. Majority of the immune cells (e.g., macrophages, T cells and dendritic cells) and all Leydig cells (LCs) are located in the interstitial compartment, suggesting that there are functional interactions/communications between these cells. In addition to the production of testosterone (T), a body of evidence shows that LCs produce cytokines such as TGF-β1, IL-6and IL-1α. These factors must directly influence the immune cells. While it is an immune privileged organ, testis infection by viruses, bacteria or parasites has been reported, and many male reproductive tract infections are asymptomatic and undiagnosed. Influenza A virus (IAV) is the causative agent of both the seasonal flu and occasional pandemics. The certain unexplained severe pathologies caused by IAVs indicate that they can cause more complex and ill-defined diseases in humans. IAV infection has been hypothesized to cause orchitis, but the early case report supporting this hypothesis was from long before the influenza virus was isolated and characterized, and no direct evidence has been found to support this theory.Our study using mice and ferrets infected with IAV as animal models to study the orchitis caused by IAV and the recovery mechanism. Herein, we demnonstrated that IAVs (WSN,2009H1N1,2009H5N1, H3N2, and H7N9) caused transient-orchitis by directly destroying LCs in different mouse strains and ferrets. IAV receptors:SA-α2,3-Gal-and SA-a2,6-Gal-linked sialic-acid were predominantly localized in LCs. However, due to the lack of IAV-receptors, the spindle-like stem LCs (SLCs) were free of viral-infection, then resumed self-renewal and differentiation upon TGF-β1decreasing due to the depletion of LCs. The resumed self-renewal resulted in viral-free LCs regeneration, followed quick recovery of serum T and simultaneous increased testicular regulatory T cells (Tregs) from the infected testes via TGF-(31signaling in an androgen/androgen receptor (AR)-dependent manner, which in turn led to orchitis recovery. Pretreated-dihydrotestosterone in mice resulted in increased testicular Tregs, prevented orchitis and reduced morbidity and mortality. Furthermore, T levels were decreased in acute-phase and recovered from106pandemic-flu patients (H3N2-,2009-H1N1-, and2013-H7N9-cases), IAV receptors were also detected in human testis. Data reveals the distinct roles of testicular TGF-β1in regulating SLC-activation and Treg induction, orchestrating testicular homeostasis and testicular immune-response, further raise AR as a potential-target for IAVs prevention.