Arboviruses and Muscle Disorders: From Disease to Cell Biology

Abstract

Infections due to arboviruses (arthropod-borne viruses) have dramatically increased worldwide during the last few years. In humans, symptoms associated with acute infection of most arboviruses are often described as "dengue-like syndrome", including fever, rash, conjunctivitis, arthralgia, and muscular symptoms such as myalgia, myositis, or rhabdomyolysis. In some cases, muscular symptoms may persist over months, especially following flavivirus and alphavirus infections. However, in humans the cellular targets of infection in muscle have been rarely identified. Animal models provide insights to elucidate pathological mechanisms through studying viral tropism, viral-induced inflammation, or potential viral persistence in the muscle compartment. The tropism of arboviruses for muscle cells as well as the viral-induced cytopathic effect and cellular alterations can be confirmed in vitro using cellular models. This review describes the link between muscle alterations and arbovirus infection, and the underlying mechanisms.

Keywords: alphavirus; arbovirus; flavivirus; myoblasts; myopathy; myositis; pathophysiology.

Figure 1

Study model of human primary muscle cells. Human primary mononucleated myoblasts (left panel), cultured in vitro, are differentiated into multinucleated myotubes (right panel). Muscle cells are labeled by an anti-desmin mouse antibody, and a secondary goat anti-mouse monoclonal antibody (green staining), and nuclei by DAPI staining. Magnification: 200×.

Figure 2

In vitro infection of human myoblasts by Chikungunya virus (CHIKV). Human myoblasts in culture were inoculated with CHIKV (strain from La Reunion outbreak, 2006), at a multiplicity of infection of 1, as described in Ozden et al. (2007). Twenty-four hours later, infection was assessed by immunofluorescence using a mouse serum directed towards CHIKV, and a secondary goat anti-mouse monoclonal antibody coupled to FITC. Magnification: 400×.

Figure 3

Proposed model for arboviral-induced muscle cell alteration leading to muscle disorders. Muscle cell alteration may include infection of myoblasts and/or myotubes, according to different Arboviruses. Infection may induce the release of cytokines (e.g., TNF-α, MCP-1, IFN-γ, MIF, IL-6, Rantes…), macrophage recruitment and CD8+ T lymphocytes activation. These events may lead to cytopathic effect, dysregulation of myogenesis, and may inhibit the self-renewal of muscle progenitor cells. Alternatively, or in addition, cytotoxicity may send molecular signals to attract inflammatory cells. Abbreviations. CHIKV: Chikungunya virus; SINV: Sindbis virus; ZIKV: Zika virus; DENV: dengue virus; CTL: cytotoxic T lymphocyte.