Complement Receptor 3 Promotes Severe Ross River Virus-Induced Disease

Abstract

Alphaviruses such as Ross River virus (RRV) and chikungunya virus are mosquito-transmitted viruses that cause explosive epidemics of debilitating arthritis and myositis affecting millions of humans worldwide. Previous studies using a mouse model of RRV-induced disease demonstrated that viral infection results in a severe inflammatory arthritis and myositis and that complement component 3 (C3) contributes to the destructive phase of the inflammatory disease but not the recruitment of cellular infiltrates to the sites of RRV-induced inflammation. Here, we demonstrate that mice deficient in complement receptor 3 (CR3) (CD11b ؊/؊ ), a signaling receptor activated by multiple ligands including the C3 cleavage fragment iC3b, develop less-severe disease signs and decreased tissue destruction compared to RRV-infected wild-type mice. CR3 deficiency had no effect on viral replication, nor did it diminish the magnitude, kinetics, and composition of the cellular infiltrates at the sites of inflammation. However, the genetic absence of CR3 diminished the expression of specific proinflammatory and cytotoxic effectors, including S100A9/S100A8 and interleukin-6, within the inflamed tissues, suggesting that CR3-dependent signaling at the sites of inflammation contributes to tissue damage and severe disease.

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

“…[22][23][24] In addition, these studies have shown the importance of type I interferons and complement in mice. [25][26][27][28][29] In humans, overlap has been identified between persistent CHIKV and rheumatoid arthritis; and proinflammatory mediators seem to play a role in disease progression and persistence. [30][31][32][33] However, the study of ONNV has received relatively little attention since its discovery, though it was the cause of one of the largest known arboviral outbreaks in the late 1950s and early 1960s in Uganda.…”

Arthrogenic Alphaviruses and Inflammatory Myopathies

“…Several additional soluble factors have also been shown to play a role in the myositis that develops during the sub-acute phase of alphaviral infection. Studies using the RRV mouse model have shown that the complement component 3 (C3) contributes to the destructive phase of the inflammatory disease and promotes the development of severe myositis (Morrison et al, 2008). The main function of the complement system is to eliminate invading organisms.…”

“…In the mouse model of RRV disease, C3 activation products were detected at the sites of RRV-induced inflammation and C3 was found to be critical for myositis and the tissue destruction phase of RRV-induced inflammatory myopathies (Morrison et al, 2007). Furthermore, mice deficient in functional receptor for C3 (CR3; CD11b deficient mice) showed significantly reduced disease symptoms and tissue destruction following RRV infection (Morrison et al, 2008), confirming the critical role of complement in the regulation of inflammatory processes at the site of alphaviral-induced myositis. These studies show complement to be a potential target for anti-viral therapies in treating alphavirus induced myositis.…”

γδ T Cells Play a Protective Role in Chikungunya Virus-Induced Disease

“…Additionally, high levels of proinflammatory cytokines are observed both in humans and in mouse models of CHIKV disease. Finally, the contributions of immune mediators to pathology in closely related alphavirus infections have been well described (52)(53)(54)(55)(56)(57).…”