Pseudorabies virus inhibits progesterone-induced inactivation of TRPML1 to facilitate viral entry.

Viral infection is a significant risk factor for fertility issues. Here, we demonstrated that infection by neurotropic alphaherpesviruses, such as pseudorabies virus (PRV), could impair female fertility by disrupting the hypothalamus-pituitary-ovary axis (HPOA), reducing progesterone (P4) levels, and consequently lowering pregnancy rates. Our study revealed that PRV exploited the transient receptor potential mucolipin 1 (TRPML1) and its lipid activator, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), to facilitate viral entry through lysosomal cholesterol and Ca2+. P4 antagonized this process by inducing lysosomal storage disorders and promoting the proteasomal degradation of TRPML1 via murine double minute 2 (MDM2)-mediated polyubiquitination. Overall, the study identifies a novel mechanism by which PRV hijacks the lysosomal pathway to evade P4-mediated antiviral defense and impair female fertility. This mechanism may be common among alphaherpesviruses and could contribute significantly to their impact on female reproductive health, providing new insights for the development of antiviral therapies. Author summary: Pseudorabies virus (PRV), an alphaherpesvirus of swine, is the causative agent of Aujeszky's disease and causes a significant economic impact in animal husbandry. Although it is known that PRV infection results in abortion, the mechanism involved in this clinical symptom remains elusive. Here, we reported that PRV infection affected fertility and progesterone (P4) levels through the hypothalamus-pituitary-ovary axis (HPOA). Moreover, PRV activated transient receptor potential mucolipin 1 (TRPML1) to facilitate lysosome-dependent viral entry. However, P4 induced proteasomal degradation of TRPML1 via murine double minute 2 (MDM2), thereby inhibiting viral entry. Overall, we have revealed a novel mechanism by which PRV influences P4 to induce infertility and promote viral replication. [ABSTRACT FROM AUTHOR]