Activation of Terminally Differentiated Human Monocytes/Macrophages by Dengue Virus: Productive Infection, Hierarchical Production of Innate Cytokines and Chemokines, and the Synergistic Effect of Lipopolysaccharide

The Journal of Immunology

et al. 2006

128

111

We examined the extent to which CXCR3 mediates resistance to dengue infection. Following intracerebral infection with dengue virus, CXCR3-deficient (CXCR3−/−) mice showed significantly higher mortality rates than wild-type (WT) mice; moreover, surviving CXCR3−/− mice, but not WT mice, often developed severe hind-limb paralysis. The brains of CXCR3−/− mice showed higher viral loads than those of WT mice, and quantitative analysis using real-time PCR, flow cytometry, and immunohistochemistry revealed fewer T cells, CD8+ T cells in particular, in the brains of CXCR3−/− mice. This suggests that recruitment of effector T cells to sites of dengue infection was diminished in CXCR3−/− mice, which impaired elimination of the virus from the brain and thus increased the likelihood of paralysis and/or death. These results indicate that CXCR3 plays a protective rather than an immunopathological role in dengue virus infection. In studies to identify critical CXCR3 ligands, CXCL10/IFN-inducible protein 10-deficient (CXCL10/IP-10−/−) mice infected with dengue virus showed a higher mortality rate than that of the CXCR3−/− mice. Although CXCL10/IP-10, CXCL9/monokine induced by IFN-γ, and CXCL11/IFN-inducible T cell α chemoattractant share a single receptor and all three of these chemokines are induced by dengue virus infection, the latter two could not compensate for the absence of CXCL10/IP-10 in this in vivo model. Our results suggest that both CXCR3 and CXCL10/IP-10 contribute to resistance against primary dengue virus infection and that chemokines that are indistinguishable in in vitro assays differ in their activities in vivo.

Section: Discussionmentioning

confidence: 99%

Both CXCR3 and CXCL10/IFN-Inducible Protein 10 Are Required for Resistance to Primary Infection by Dengue Virus

Hsieh

Lai

The Journal of Immunology

et al. 2006

128

111

“…Macrophages (M ) are the major source of inflammatory cytokines, 12 as well as the major target cells for DV replication. 13,14 However, M are heterogeneous throughout the body, 15 and the phenotypic and functional diversities of M are influenced by cytokines, which regulate their differentiation, tissue distribution, and defense to invaded pathogens.…”

Section: Introductionmentioning

confidence: 99%

CLEC5A is critical for dengue virus–induced inflammasome activation in human macrophages

Wu¹,

Yang

et al. 2013

Blood

184

174

“…Consistent with that idea, many viral infections induce expression of chemokines, which are most likely involved in orchestrating recruitment of effector leukocytes to the sites of infection (24 -26). DV is known to induce expression of a number of chemokines, including CXCL1/IL-8 (27)(28)(29)(30), CCL3/MIP-1␣ (27,31,32), CCL5/RANTES (27,30,33), and CCL4/MIP-1␤ (31,32) in various human cell lines, but to date there have been no studies of DV-induced chemokine expression in vivo. We therefore conducted an in vivo study using mice as an animal model to investigate the induction of chemokines and their functions following DV infection.…”

mentioning

confidence: 99%

Dengue Virus Induces Expression of CXC Chemokine Ligand 10/IFN-γ-Inducible Protein 10, Which Competitively Inhibits Viral Binding to Cell Surface Heparan Sulfate

The Journal of Immunology

Lai

et al. 2006

Dengue virus is an arthropod-borne flavivirus that causes a mild febrile illness, dengue fever, or a potentially fatal syndrome, dengue hemorrhagic fever/dengue shock syndrome. Chemokines primarily orchestrate leukocyte recruitment to the areas of viral infection, which makes them critical mediators of immune and inflammatory responses. In the present study, we investigated the induction and function of chemokines in mice early after infection with dengue virus in vivo. We found that CXCL10/IFN-γ-inducible protein 10 (IP-10) expression was rapidly and transiently induced in liver following infection. The expressed CXCL10/IP-10 likely mediates the recruitment of activated NK cells, given that anti-CXCL10/IP-10-treated mice showed diminished NK cell infiltration and reduced hepatic expression of effector molecules in activated NK cells after dengue virus infection. Of particular interest, we found that CXCL10/IP-10 also was able to inhibit viral binding to target cells in vitro. Further investigation revealed that various CXCL10/IP-10 mutants, in which the residues that mediate the interaction between the chemokine and heparan sulfate were substituted, failed to exert the inhibitory effect on dengue binding, which suggests that CXCL10/IP-10 competes with dengue virus for binding to heparan sulfate on the cell surface. Moreover, subsequent plaque assays showed that this inhibition of dengue binding blocked viral uptake and replication. The inhibitory effect of CXCL10/IP-10 on the binding of dengue virus to cells may represent a novel contribution of this chemokine to the host defense against viral infection.