Reovirus triggers cell type-specific proinflammatory responses dependent on the autocrine action of IFN-β

Abstract

Resident cells of the respiratory and gastrointestinal tracts, including epithelial and fibroblast cells, are the initial sites of entry for many viral pathogens. We investigated the role that these cells play in the inflammatory process in response to infection with reovirus 1/L. In A549 human bronchial or HT-29 human colonic epithelial cells, interferon (IFN)-beta, regulated on activation T cell expressed and secreted (RANTES), IFN-gamma-inducible protein (IP)-10, and interleukin-8 were upregulated regardless of whether cells were infected with replication-competent or replication-deficient reovirus 1/L. However, in CCD-34Lu human lung fibroblast cells, IFN-beta, IP-10, and RANTES were expressed only after infection with replication-competent reovirus 1/L. Expression of interleukin-8 in CCD-34Lu fibroblast cells was viral replication independent. This differential expression of IFN-beta, RANTES, and IP-10 was shown to be due to the lack of induction of IFN regulatory factor-1 and -2 in CCD-34Lu fibroblast cells treated with replication-deficient reovirus 1/L. We have shown that cytokine and/or chemokine expression may not be dependent on viral replication. Therefore, treatment of viral infections with inhibitors of replication may not effectively alleviate inflammatory mediators because most viral infections result in the generation of replication-competent and replication-deficient virions in vivo.

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

“…Expression profiling analysis of RNA isolated from U266 cells revealed that reovirus treatment induced a strong anti-viral response, which was characterized by interferon (IFN) stimulation (Supplementary Tables 1 and 2). Consistent with prior reports, reovirus exposure induces an IFN-b response (Hamamdzic et al, 2001;Holm et al, 2007;Steele et al, 2011). While IFN production has been reported to decrease viral spread and efficacy, IFNs have also been shown to elicit anti-tumor effects via inhibition of angiogenesis and stimulation of apoptosis (Sidky and Borden, 1987;Taylor et al, 2008;Shmulevitz et al, 2010).…”

Upregulation of the TLR3 Pathway by Kaposi's Sarcoma-Associated Herpesvirus during Primary Infection

“…IRF-1 has previously been shown to respond to TLR3 stimulation via poly(I:C) treatment in HT29 human intestinal epithelial cells (52). Furthermore, IRF-1 is essential for IFN-␤1 and CXCL10 expression after reovirus infection in human lung fibroblasts (28). This evidence points to a pivotal role for IRF-1 in TLR3 signaling, directly contributing to the upregulation of CXCL10.…”

“…IRF-1 is known to exert transcriptional control over CXCL10, TLR3, and IFN-␤1 (16,28), all of which were observed to be upregulated in KSHV-infected monocytes. It is possible that TLR3 activation stimulates IRF-1, which in turn activates both CXCL10 and IFN-␤1, leading to the promotion of the inflammatory response and a positive feedback loop.…”

Oncolytic Viral Therapy for Prostate Cancer: Efficacy of Reovirus as a Biological Therapeutic

“…Moreover, it has also been shown that T cells will home to the peripheral margin of recurring mammary tumors without infiltrating the tumor proper and that these immuneeffector cells are likely inhibited by the immunosuppressive nature of the tumor microenvironment (38). Promisingly, reovirus has been shown to induce secretion of proinflammatory factors mediating T-cell infiltration in a number of epithelial-derived cancer cell lines (39). It is plausible that a chemokine repertoire may be induced by reovirus infection in the patients of this study and that this provides a platform for overcoming inefficient T-cell homing.…”