Efficient dengue virus (DENV) infection of human muscle satellite cells upregulates type I interferon response genes and differentially modulates MHC I expression on bystander and DENV-infected cells

Abstract

Dengue virus (DENV) is a mosquito-borne flavivirus that causes an acute febrile disease in humans, characterized by musculoskeletal pain, headache, rash and leukopenia. The cause of myalgia during DENV infection is still unknown. To determine whether DENV can infect primary muscle cells, human muscle satellite cells were exposed to DENV in vitro. The results demonstrated for the first time high-efficiency infection and replication of DENV in human primary muscle satellite cells. Changes in global gene expression were also examined in these cells following DENV infection using Affymetrix GeneChip analysis. The differentially regulated genes belonged to two main functional categories: cell growth and development, and antiviral type I interferon (IFN) response genes. Increased expression of the type I IFN response genes for tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), melanoma-derived antigen 5 (MDA-5), IFN-c-inducible protein 10 (IP-10), galectin 3 soluble binding protein (LGals3BP) and IFN response factor 7 (IRF7) was confirmed by quantitative RT-PCR. Furthermore, higher levels of cell-surface-bound intracellular adhesion molecule-1 (ICAM-1) and soluble ICAM-1 in the cellculture medium were detected following DENV infection. However, DENV infection impaired the ability of the infected cells in the culture medium to upregulate cell-surface expression of MHC I molecules, suggesting a possible mechanism of immune evasion by DENV. The findings of this study warrant further clinical research to identify whether muscle cells are targets for DENV infection during the acute stage of the disease in vivo. INTRODUCTIONDengue is an increasingly troublesome, mosquito-borne viral disease that is highly prevalent in both tropical and subtropical regions of the world. Annually, 50-100 million cases of dengue fever (DF) and 250 000 cases of dengue haemorrhagic fever (DHF) occur worldwide, as determined by the World Health Organization (Nathan & DayalDrager, 2006;Petersen & Marfin, 2005). Infection with any one of the four serotypes of DENV (DENV1-4) can cause DF or DHF. The general mechanisms that control virus replication and are involved in disease pathogenesis are not well understood in this complex, acute illness.Monocytes, dendritic cells and B cells are known to be susceptible to DENV in vivo (Halstead, 1989;King et al., 1999;Lin et al., 2002;Marovich et al., 2001;Wu et al., 2000), whilst DENV antigen has been detected in sinusoidal endothelial cells (Jessie et al., 2004) and hepatocytes (de Macedo et al., 2006;Rosen et al., 1999) in autopsy studies. In addition, a variety of primary human cells, including mast cells (King et al., 2002), endothelial et al., 2007) and hepatocytes (Suksanpaisan et al., 2007), can serve as hosts for DENV in vitro.Symptomatically, patients with dengue often present with general muscle affection as well as severe, persisting myalgia, headache and rash (Chaturvedi et al., 1970;Halstead, 1966). Higher serum levels of creatine phosphokinase (CPK), which is specifically produ...

Resistance to Dengue Virus Infection in Mice Is Potentiated by CXCL10 and Is Independent of CXCL10-Mediated Leukocyte Recruitment

“…However, CXCL10 function specific to DENV infection has not been examined in vivo. Recent studies have shown that CXCL10 is the most highly upregulated gene in dengue patient blood samples (26), in muscle satellite cells exposed to DENV in vitro (27), and in primary human dendritic cells infected by DENV (28), supporting the suggestion that CXCL10 is critical for defense against DENV infection. In this study, we investigated the antiviral activity of CXCL10 in DENV infection.…”

HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production

“…Its induction in the absence of IFNs suggests a parallel with dengue virus, which also induces IRF-7 in the absence of type 1 IFNs. 51 IRF-3 and -7 are the 2 most important inducers of type I IFNs in most cell types and are activated by interactions of viral RNA with Toll-like receptors in the endosome or by cytosolic retinoic acid-inducible gene I-like receptor pathways, resulting in their phosphorylation, homodimerization, or heterodimerization with IRF-3 and translocation to the nucleus. In myeloid DCs IRF-7 concentrations are constitutively low, perhaps explaining the need for up-regulation by HIV-1.…”

Neurological complications in dengue infection: a review for clinical practice

“…Cranial palsy may also occur, mostly with oculomotor and facial nerves involvement 9 . Benign acute myositis in dengue infection could be consequent of direct viral invasion and/or immune-mediated damage of muscle fibers 18 . In some areas, up to 50% of benign acute childhood myositis cases occur in dengue infection.…”

“…The clinical manifestations of GBS result from cell-mediated immunological reactions. Dengue virus would initiate the immunological event and myelin or axons could be the target of this immune response 18 . In endemic areas, dengue infection should be investigated in cases of GBS 7 .…”