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According to extensive investigations, male in many species are more vulnerable than female to infectious diseases causing by viruses, bacteria, fungi, and parasites. The mechanisms for this phenomenon could be explained by differences in steroid hormones, immune responses, or even in genetic susceptibility between genders. Among that, various studies which have been investigated this disparity in term of sex-based hormones shown that male hormones contribute to the male prevalence in particular infectious disease through either seizing immune system or by direct interaction with pathogens. Recently, a finding that has been published by Ke Lan’s group shown for the first time that male hormones may facilitate infection of Kaposi’sarcoma-associated herpesvirus, could help explain why men have an increased risk of developing Kaposi’s sarcoma.To study, they use RNA interference technique which knockdown the expression of membrane-localized androgen receptor (mAR) to or pretreatment with 5?-dihydrotestosterone (DHT)- the AR agonist.  As result, mAR inhibition led to much lower levels of detected KSHV DNA genetic in cells as well as perinuclear-accumulated virus particles during early KSHV entry stage than in control cells.

In contrast, DHT-treated cells had increased levels of KSHV copies and genetic materials. This suggests that both the membrane androgen receptor and its ligand promote KSHV infection. Moreover, AR can activate the kinase p90 ribosomal S6 kinase 1 (RSK1) by mediating for its upstream signal-Src recruitment which led to phosphorylate RSK1. Activated RSK1 directly phosphorylates ephrin receptor A2 (EphA2), one of the major KSHV entry receptors, at residue Ser897, which was specifically upregulated upon KSHV infection. Finally, Ser897Asn mutant eliminated the EphA2-mediated entry of KSHV. These findings demonstrate that the activation of Src/RSK1/EphA2 signaling cascade by membrane-associated AR facilitate for KSHV infection of both endothelial and epithelial cells and may suggest a mechanism for gender disparity in KS prevalence.

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Considering that EphA2 is also the receptor for some other viruses such as hepatitis C virus (HCV) (32) and Eppstin- Barr virus (13) together with the disparity in those infectious diseases, this finding could be relevant to other viral infection.Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV 8) is one of the seven currently known human oncogenic viruses (7). This virus is etiologically associated with Kaposi’s sarcoma (KS) , a angiogenic and inflammatory malignancy of endothelial cell origin, often appear on the skin, oral cavity, and subcutaneous tissues. In addition to KS, KSHV is also causally involved with lymphoproliferative diseases such as primary effusion lymphoma (PEL) (11) and some types of multicentric Castleman’s disease (MCD) (22). As other herpesviruses, the life cycle of KSHV also consists latent and lytic replication phases (38). In immunocompetent individuals, KSHV enters into the cells via macropinosomes where it establishes a latent state following an acute infection.

Latent infection is characterized by persistence as a naked circular double-stranded DNA molecule (episome) in the host’s nucleus of KSHV genome with the silence of most of viral genes except a limited number of latent genes such as LANA. in consequence, no production of infectious virions is made (5). Staying in latent stage allows KSHV to elude the surveillance of host immune system and facilitate the development of a lifetime persistent infection and induction of KSHV-related malignancies. KSHV infected cells can be reactivated into lytic stage with the expression of most or all of viral genes, KSHV DNA genome replication in the form of linear DNA molecules as well as assembling and releasing infectious virions (24, 38).

 Reactivation of KSHV from latent to lytic stage results in modulation of diverse cellular pathway and microenvironment which promotes cell proliferation, angiogenesis and local inflammation following by the development of KS tumors (37, 45, 48) and other KSHV-associated diseases such as multicentric Castleman’s disease (MCD) (14, 25, 34) or primary effusion lymphoma. KSHV lytic DNA replication requires the expression of at least eight viral genes including: ORF9 (DNA polymerase), ORF6 (single-stranded DNA binding protein), ORF40/41 (primase-associated factor), ORF44 (helicase), ORF56 (primase), ORF59 (processivity factor), ORF50 (replication and transcription activator or RTA), and ORF K8 (K-bZIP)(4, 24). Among a number of candidate KSHV genes, the primary viral protein responsible for the activation of lytic replication is known as RTA. When cell signaling conditions activate the generation of RTA, it binds directly to the DNA of several KSHV promoters it in turn, then, activates synthesis of a stereotypic cascade of secondary and tertiary viral proteins that ultimately make components of the virus capsid and also the DNA synthesis enzymes required to replicate the virus genome (9). However, direct DNA binding by Rta to all of these promoters is insufficient to specify them as targets for transactivation; instead, Rta requires combinatorial interactions with cellular factors and signalings. Results from various researches strongly suggest the contribution of different types of cellular signalling pathways and several physiological factors in KSHV reactivation by activating the RTA promoter (2).

These include hypoxia, oxidative stress, reactive oxygen species (ROS) and variety inflammatory cytokines such as oncostatin M, hepatocte growth factor, interferon ? and other soluble factors resulted of other pathogen co-infections (17). Activation of PCK/MAPK/ERK pathway by 2-O-Tetradecanoyl- phorbol-13-acetate (TPA) and sodium butyrate leading to c-Fos accumulation and phospholation of c-Jub, resulted in formation of AP-1 complex or/ and Ras-initiated signal transduction pathways that lead to activation of RTA gene, are demonstrated to trigger lytic KSHV reactivation (15, 49). Furthermore, NF-?B pathway (8), autonomic nervous system (ANS) (16) or intralcellular cancil ion (12) are also play roles in KSHV reactivation.Different types of signaling pathways and several physiological factors including hypoxia, oxidative stress, and reactive oxygen species (ROS) can disrupt KSHV latency and reactivate the virus by activating the RTA promoter.

RTA activation sets up the cascade of gene expression leading to viral lytic replication and virion assembly. RTA auto-regulates its expression at the transcriptional level by using cellular RBP-J? notch signaling pathway repressor and by Oct-1, as well as at post-translational level by self-ubiquitylation. The microPeptide vSP-1 blocks the self-ubiquitylation of RTA and promotes viral lytic replication. Intracellular calcium is considered as one of the cellular factor that regulate KSHV reactivation from latency.

It has been shown that ionomycin and thapsigargin, mobilized intracellular calcium chemicals are known to induce reactivation of KSHV from latency in PEL cells by regulating for ORF 50 protein expression, suggesting that intracellular immobilization of calcium is able to trigger KSHV lytic replication (12, 24). Moreover, blocking calcineurin by cyclosporine , FK506 inhibit calcium-mediated virus reactivation. Retroviral transduction with plasmid that encode for inhibitor protein of calcineurin- NFAT (nuclear factor of activated T cells) interaction also blocked calcium-dependent KSHV reactivation (50). Earlier studies showed involvement of Ca in reactivation of Epstein-Barr virus (EBV), 30 an- other member of the -herpesvirus family (31). Various cellular mechanisms including proliferation, differentiation, and homeostasis are mediated by sex steroid hormones, comprising androgen(20). The classic genomic model for androgenic hormones such as testosterone or dihydrotestosterone  regulation which bind and activate intracellular androgen receptor (iAR),  in cytoplasm (41).

This attachment activate the funtion of iAR as a transcriptional factor which then homodimers or heterodimers, translocates into nucleus  and regulate protein synthesis by specific bindiing ith target gene promoters (33). This genomic-androgen impact normally complete after several hours exposing with androgens.  Conversely, the quick or non-genomic androgens have been shown to exist in cytoplasm membrane which potentially rapid modify cellular signalling through intracellular signaling cascades after seconds to few minutes contact with androgens (21, 33). ZIP9 (Zinc transporter ZIP9) and GPRC6A (G protein-coupled receptor family C group 6 member A) or one of the calcium receptors are known as mAR (36, 44). Androgen receptors have been demonstrated to express in prostate cancer, breast cancer and colon tumor cell (26, 30, 35). In tumor cells, mAR governs the reorganization of actine cytosleleton, cell proliferation, cell death and migration (27-29) In variety investigations, an extensive range of non-genomic reactions of mAR has been reported.

As a cation receptor, the attachment of mAR and it agonist seem to rapid increase Ca2+i by promoting Ca2+ entry or the  release of Ca2+ ions from dense bodies into the cytosol (10, 30). Enhancing in Ca2+i has been shown in different cell types such as Sertoli cells, LNCaP prostate cancer cells, neuroblastoma cells, platelets,  macrophages and T cells (6, 10, 19, 23, 42, 47). The increasing of calcium concentration is recognized by specific Ca2+ sensor molecules including PKC and calmodulin which induce signal transduction cascades and regulation of transcription for example A/C (PKA/PKC) pathway or mitogen-activated protein kinase (MAPK)  (39, 40). Moreover, androgens can also activate calcium downstream kinase pathways, for example, ERK or Src, which could improve AR activity by phosphorylation (10).

Besides the rapid modulation intracellular Ca2+ concentration, membrane AR also activate different signaling cascades and downstream effectors which are independent with the classical androgen receptor (iAR) mechanisms (18, 43)

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