Pathogens have co-evolved with mosquitoes to optimize transmission to hosts. Mosquito salivary-gland extract is known to modulate host immune responses and facilitate pathogen transmission, but the underlying molecular mechanisms of this have remained unknown. In this study, we identified and characterized a prominent 15-kilodalton protein, LTRIN, obtained from the salivary glands of the mosquito Aedes aegypti. LTRIN expression was upregulated in blood-fed mosquitoes, and LTRIN facilitated the transmission of Zika virus (ZIKV) and exacerbated its pathogenicity by interfering with signaling through the lymphotoxin-β receptor (LTβR). Mechanically, LTRIN bound to LTβR and 'preferentially' inhibited signaling via the transcription factor NF-κB and the production of inflammatory cytokines by interfering with the dimerization of LTβR during infection with ZIKV. Furthermore, treatment with antibody to LTRIN inhibited mosquito-mediated infection with ZIKV, and abolishing LTβR potentiated the infectivity of ZIKV both in vitro and in vivo. This study provides deeper insight into the transmission of mosquito-borne diseases in nature and supports the therapeutic potential of inhibiting the action of LTRIN to disrupt ZIKV transmission.

Breast cancer resistance protein (BCRP/ABCG2) is a membranebound efflux transporter important in cellular detoxification and multidrug resistance. Some aryl hydrocarbon receptor (AHR) agonists were reported to induce BCRP expression in human colon carcinoma cells. However, a direct involvement of AHR transcriptional regulation remains unexplored. In this study, we show that BCRP induction by AHR ligands occurs in human intestinal, liver, and mammary carcinoma cells and in primary colonocytes and hepatocytes. Increased BCRP transporter activity consistent with gene induction was also evident in the Caco2 subclone C2bbe1 cells. Using RNA interference and ectopic expression techniques to manipulate cellular AHR status, we confirmed AHR dependence of ABCG2 gene regulation. By gene promoter analysis, chromatin immunoprecipitation, and electrophoretic mobility shift assays, an active, proximal dioxin-response element at Ϫ194/ Ϫ190 base pairs upstream of the transcription start site of the human ABCG2 gene was identified. Despite a common observation in human-derived cells, our in vitro and in vivo studies supported by phylogenetic footprinting analysis did not find that mouse Abcg2 is subject to AHR regulation. We conclude that AHR is a direct transcriptional regulator of human BCRP and provide an unprecedented role of AHR in cellular adaptive response and cytoprotection by up-regulating an important ATP-binding cassette efflux transporter.Breast cancer resistance protein (BCRP) is an ATP-binding cassette (ABC) transporter encoded by the ABCG2 gene, which attracts growing research efforts directed at its involvement in toxicity and elimination of various drugs and xenobiotics (Doyle et al., 1998;Ishikawa, 2009). BCRP is a promiscuous cellular efflux pump of a broad spectrum of drugs (e.g., topotecan, acyclovir, mitoxantrone), carcinogens [e.g., aflatoxin, benzo(a)pyrene, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine], nutrients and phytochemicals (e.g., riboflavin, folate, daidzein, flavonoids), and metabolites (e.g., sulfated estrogens, eicosanoids). The apical domain of intestinal mucosa, mammary ductal epithelia, liver, kidney, and sanctuary barrier tissues (blood-brain barrier, blood-testis barrier, and blood-placental barrier) is an important site of BCRP expression (Ishikawa, 2009;Robey et al., 2009). Thus, BCRP has important pharmacological and toxicological implications in systemic pharmacokinetics, tissue distribution,

No abstract

No abstract