Biochemical Study of Certain Enzymes and Metabolites of the Carbohydrate Metabolism in the Skeletal Muscle of the Dengue Virus-Infected Mice

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...

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Warke

Becerra

Zawadzka³

et al. 2008

“…It has been reported that infective DV was detected not only in the brain but also in the heart, liver, spleen and skeletal muscle (Agrawal et al, 1978) of infected mice. However, the target cells in these organs were not completely investigated.…”

Section: Discussionmentioning

confidence: 99%

Inoculation of Dengue Virus into Nude Mice

Hotta

Murakami

Miyasaki

et al. 1981

SUMMARYWhen athymic nude (nu/nu) and heterozygous littermate (nu/+) mice were injected intraperitoneally (i.p.) with a mouse-adapted strain of dengue virus (DV), the following differences were noted in the course of infection. (i) The average survival time of nu/nu mice was longer than that of nu/+ mice, although the mortality ratios were not significantly different. (ii) DV persisted in some of the nu/nu mice for long periods of time without exhibiting any symptoms but they died after prolonged incubation periods. These aspects were not observed in the nu/+ mice. (iii) Infected nu/nu mice produced IgM antibody only transiently in the early stage of infection but they did not subsequently show regular IgG antibody production which normally occurred in nu/+ mice. (iv) Piamatral and perivascular mononuclear cell infiltration in the infected brain was more intense in nu/+ than in nu/nu mice. It is suggested from these data that the course of DV infection in mice is affected by the availability of thymus-derived lymphocytes (T-cells).Infectious virus was detected in various organs and tissues of infected mice. The hearts of nu/nu mice tended to show higher virus titres than those of nu/+ mice, whereas the virus concentrations in the brain, skeletal muscle and lymph node were the same in both groups of mice. Specific DV antigen was revealed by the fluorescent antibody (FA) technique in cells located in the infected tissues.

“…The virus also produces a severe syndrome, dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS), which is characterized by increased vascular permeability and abnormal haemostasis (Halstead, 1980(Halstead, , 1988. Extensive biochemical changes occur in the enzymes and metabolites of skeletal muscles during DEN infection of mice which may explain the origin of myalgia (Agrawal et al, 1978). Halstead (1980) put forward a hypothesis that a vascular permeability factor is produced in cases of DHF/DSS.…”

Section: Introductionmentioning

confidence: 99%

Breakdown of the blood-brain barrier during dengue virus infection of mice

Chaturvedi

Dhawan

Khanna

et al. 1991

Self Cite

127

108

A breakdown of the blood-brain barrier occurred in mice inoculated intracerebrally (i.c.) or intraperitoneally (i.p.) with dengue virus type 2 (DEN2). This resulted in leakage of protein-bound Evans blue dye and 51Cr-labelled erythrocytes into the brain tissue. The leakage increased with time after infection and coincided with an increase of a DEN2-induced cytokine, the cytotoxic factor (CF), in the spleens of such mice. The titres of virus in the brain increased exponentially in i.c. inoculated mice but the virus was not detected in brains of mice given DEN2 by the i.p. route. Similar breakdown of the blood-brain barrier also occurred in mice inoculated intravenously with CF; the damage was dose-dependent and the vascular integrity was restored during the 3 h period after inoculation. Treatment of mice with antihistamine drugs, blocking H1 or H2 receptors, decreased the DEN2-induced protein leakage by up to 50% in i.c. inoculated mice and up to 92 % in those inoculated i.p. Indomethacin, a prostaglandin synthetase inhibitor, had no effect. In i.c. inoculated mice protein leakage was inhibited by about 60% by treatment with CFspecific (CFA) or DEN2-specific antisera (DEN2A) whereas protection was complete with the combined treatment with both antisera. On the other hand, in i.p. inoculated mice the inhibition of protein leakage was 80 to 89% with CFA. These findings show a breakdown of the blood-brain barrier leading to cerebral oedema during DEN2 infection which is mediated via the release of histamine by a virus-induced cytokine.