Osteoblasts from osteoarthritis patients show enhanced to Ross River virus infection associated with delayed type I interferon responses

Weiqiang Chen,Paul N Smith,Suresh Mahalingam,Rachel W Li,Suan-Sin Foo

doi:10.1186/preaccept-1303092705136226

Weiqiang Chen, Paul N Smith

Open Access

https://doi.org/10.1186/preaccept-1303092705136226

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Abstract

BackgroundArthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) have caused widespread outbreaks of chronic polyarthritis. The inflammatory responses in alphavirus-induced arthritis and osteoarthritis (OA) share many similar features, which suggests the possibility of exacerbated alphavirus-induced bone pathology in individuals with pre-existing OA. Here, we investigated the susceptibility of osteoblasts (OBs) from OA patients to RRV infection and dissected the immune mechanisms elicited from infection.MethodsPrimary hOBs obtained from trabecular bone of healthy donors and OA patients were infected with RRV. Infectivity and viral replication were determined using flow cytometry and plaque assay, respectively. Real-time PCR was performed to determine expression kinetics of type I interferon (IFN)-related immune mediators and osteotropic factors.ResultsOA hOBs showed enhanced RRV infectivity and replication during infection, which was associated with delayed induction of IFN-β and RIG-I expression. Enhanced susceptibility of OA hOBs to RRV was associated with a more pronounced increase in RANKL/OPG ratio and expression of osteotropic factors (IL-6, IL-1β, TNF-β and CCL2) in comparison to RRV-infected healthy hOBs.ConclusionsDelayed activation of type I IFN-signalling pathway may have contributed to enhanced susceptibility to RRV infection in hOBs from OA patients. RRV-induced increases in RANKL/OPG ratio and expression of osteotropic factors that favour bone resorption, which may be exacerbated during osteoarthritis. This study provides the novel insight that osteoarthritis may be a risk factor for exacerbated arthritogenic alphaviral infection.

Highlights

Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) have caused widespread outbreaks of chronic polyarthritis
Enhanced RRV infectivity in primary human osteoblasts (hOBs) of OA patients, modulated through delayed type IFN signalling pathway To investigate if underlying OA has any effect on viral replication during RRV infection, primary hOBs cultured from trabecular bones of healthy donors and OA patients were used
We showed that IL-6, IL-1β, tumor necrosis factor-α (TNF-α) and CCL2 are highly expressed in RRV-infected hOBs of healthy donors and that these infected cells are crucial in mediating RRV-induced bone loss through the up-regulation of RANKL/OPG ratio [17]

Summary

Introduction

Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) have caused widespread outbreaks of chronic polyarthritis. Infection rates of arthropod-borne alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) are currently rising in different geographic regions of the world [1]. Pro-inflammatory immune mediators, including interleukin (IL)-6, IL-1, tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1; or CCL2) have been shown to contribute to the progression of alphaviral disease [7,8,9]. These pro-inflammatory cytokines are known as osteotropic factors that modulate the bone remodelling system

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