Interferon Response Factors 3 and 7 Protect against Chikungunya Virus Hemorrhagic Fever and Shock

Abstract

f Chikungunya virus (CHIKV) infections can produce severe disease and mortality. Here we show that CHIKV infection of adult mice deficient in interferon response factors 3 and 7 (IRF3/7 ؊/؊ ) is lethal. Mortality was associated with undetectable levels of alpha/beta interferon (IFN-␣/␤) in serum, ϳ50-and ϳ10-fold increases in levels of IFN-␥ and tumor necrosis factor (TNF), respectively, increased virus replication, edema, vasculitis, hemorrhage, fever followed by hypothermia, oliguria, thrombocytopenia, and raised hematocrits. These features are consistent with hemorrhagic shock and were also evident in infected IFN-␣/␤ receptor-deficient mice. In situ hybridization suggested CHIKV infection of endothelium, fibroblasts, skeletal muscle, mononuclear cells, chondrocytes, and keratinocytes in IRF3/7 ؊/؊ mice; all but the latter two stained positive in wild-type mice. Vaccination protected IRF3/7 ؊/؊ mice, suggesting that defective antibody responses were not responsible for mortality. IPS-1-and TRIF-dependent pathways were primarily responsible for IFN-␣/␤ induction, with IRF7 being upregulated >100-fold in infected wild-type mice. These studies suggest that inadequate IFN-␣/␤ responses following virus infection can be sufficient to induce hemorrhagic fever and shock, a finding with implications for understanding severe CHIKV disease and dengue hemorrhagic fever/dengue shock syndrome.

Interferon regulatory factor 7- (IRF7-) mediated immune response affects Newcastle disease virus replication in chicken embryo fibroblasts

“…Overexpression of IRF7 can result in the enhancement of viral replication, while the knockdown of IRF7 in macrophages can significantly reduce viral production (Sirois et al, 2011). Ruddy et al (2012) have demonstrated that Chikungunya virus (CHIKV) infection of IRF3-or IRF7-deficient adult mice is lethal, and the mortality is associated with undetectable serum IFN-α/β, and with increased virus replication.…”

Recent progress on chikungunya virus research

“…These mouse models are suitable for testing the effectiveness of vaccine or treatment and helping to understand CHIKV pathogenesis. Nevertheless, partial knock out of IFN pathway in IFN--α/βR +/-, IRF3 -/-, or IRF7 -/-mice only lead to non-lethal acute disease during CHIKV infection, reflecting the dose effect of IFN response in restricting CHIKV infection (Rudd et al, 2012). In addition, C57BL/6 mice inoculated with CHIKV subcutaneously exhibited low-level of virus replication in some tissues for a prolonged period, contributing to cartilage necrosis and periosteal bone proliferation, and thus they are used in a chronic infection model (Goupil et al, 2016).…”

The role of type I interferon in the immunobiology of chikungunya virus

“…Experimentally-induced overexpression of RIG-1 was also found to prevent viral replication of VEEV in the human embryonic kidney (HEK293) cell line (Wu, Huang et al 2008). MDA5 and RIG-1 signal through the adaptor molecule IPS-1 (see section 1.4.3.3), which has been found to play an important role in initiation of the type I IFN response to CHIKV (Schilte, Couderc et al 2010, Schilte, Buckwalter et al 2012, Rudd, Wilson et al 2012, and is discussed further Chapter 2.…”

“…The interferon-induced transmembrane proteins 1/2/3 (IFITM1/2/3) restrict viral entry by sequestering 5'-triphosphate RNA produced by enveloped ssRNA viruses, (Liu, Sanchez et al 2011, Pichlmair, Lassnig et al 2011. Zinc antiviral protein (ZAP), which disrupts viral RNA translation, has been shown to work synergistically with ISG20, an ssRNA-specific RNAse that disrupts RNA synthesis, to inhibit yellow fever virus more effectively than if expressed alone (Zhang, Burke et al 2007, Karki, Li et al 2012 (Gardner, Anraku et al 2010, Rudd, Wilson et al 2012 and CHIKV patients (Jaffar-Bandjee, Ramful et al 2010, Schwartz andAlbert 2010). In vitro, pre-treatment in an epithelial cell line with doses as low as 10 IU/ml of IFNα is known to effectively inhibit CHIKV infection (Sourisseau, Schilte et al 2007).…”

“…CHIKV infection is lethal in type I IFN deficient mice (see Chapter 2) (Couderc, Chrétien et al 2008, Rudd, Wilson et al 2012. Thus, only mice that retained one WT allele (and therefore, the capacity to produce type I IFNs), in addition to the inserted eGFP transgene were suitable for analysing type I IFN production in vivo, following CHIKV infection.…”