1887

Abstract

, the causative agent of Mediterranean spotted fever, preferentially infects human microvascular endothelium and activates pro-inflammatory innate immune responses as evidenced by enhanced expression and secretion of cytokines and chemokines. Our recent studies reveal that human microvascular endothelial cells (HMECs) infected with also launch ‘antiviral’ host defence mechanisms typically governed by type I interferons. To summarize, infected HMECs secrete IFN-β to activate STAT1 in an autocrine/paracrine manner and display increased expression of IFN-stimulated genes, for example , which in turn activate innate responses to interfere with intracellular replication of rickettsiae. We now present evidence that UBP43 and SOCS1, known negative regulators of JAK/STAT signalling, are also induced in infected HMECs, of which UBP43 but not SOCS1 functions to negatively regulate STAT1 activation. Interestingly, UBP43 induction is almost completely abolished in the presence of IFN-β-neutralizing antibody, implicating an important role for UBP43 as a feedback inhibitor for IFN-β-mediated STAT1 activation. In contrast, SOCS1 expression is only partially affected by IFN-β neutralization, implicating potential involvement of as-yet-unidentified IFN-independent mechanism(s) in induction during infection. A number of IFN-stimulated genes, including , , , , and are also induced in an IFN-β-dependent manner, whereas remains unaffected by IFN-β neutralization. Increased STAT1 phosphorylation in HMECs subjected to knockdown led to transcriptional activation of , and , confirming the negative regulatory role of UBP43. Although , and were induced by IFN-β, siRNA-mediated silencing of or did not significantly affect their transcriptional activation. Expression of was, however, increased in HMECs transfected with siRNA for and . Thus, unique regulatory patterns of induced expression of , and IFN-stimulated genes represent pathogen-specific responses underlying IFN-β-mediated host endothelial signalling during the pathogenesis of spotted fever group rickettsiosis.

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2013-07-01
2019-10-20
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