Abstract
There is increasing consensus that males are more vulnerable than females to infection by several pathogens. However, the underlying mechanism needs further investigation. Here, it was showed that knockdown of androgen receptor (AR) expression or pre-treatment with 5α-dihydrotestosterone, the AR agonist, led to a considerably dysregulated Kaposi’s sarcoma-associated herpesvirus (KSHV) infection. In endothelial cells, membrane-localized AR promoted the endocytosis and nuclear trafficking of KSHV. The AR interacted with ephrin receptor A2 (EphA2) and increased its phosphorylation at residue Ser897, which was specifically upregulated upon KSHV infection. This phosphorylation resulted from the AR-mediated recruitment of Src, which resulted in the activation of p90 ribosomal S6 kinase 1 (RSK1), which directly phosphorylates EphA2 at Ser897. Finally, the EphA2-mediated entry of KSHV was abolished in a Ser897Asn EphA2 mutant. Taken together, membrane-localized AR was identified as a KSHV entry factor that cooperatively activates Src/RSK1/EphA2 signaling, which subsequently promotes KSHV infection of both endothelial and epithelial cells.
Highlights
Males of many species are more susceptible than females to infections caused by parasites, fungi, bacteria, and viruses
Kaposi’s sarcoma (KS) incidence is higher in males, which correlates with higher seroprevalence and viral DNA levels in the blood, little is known whether male sex steroids contribute to this disparity
As the common function of Lipid Rafts (LRs) in promoting Kaposi’s sarcoma-associated herpesvirus (KSHV) primary infection [27], we speculated that co-localized androgen receptor (AR) may play a concordant role in KSHV infection of target cells
Summary
Males of many species are more susceptible than females to infections caused by parasites, fungi, bacteria, and viruses. There is a reported male predominance in the prevalence and lethality of infections with various pathogens. This may reflect different exposures and immune responses, or even differences in genetic susceptibility between genders [1,2,3]. 17β-Estradiol regulates the activity of immune cells, including lymphocytes, macrophages, granulocytes, and mast cells [4, 5]. A lack of the inhibitory factor CD200R in females leads to Toll-like receptor 7-mediated activation of interferon-α, which accounts for higher immune status in females, at least in a murine model [6,7,8]
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