Gene expression profiling of dengue infected human primary cells identifies secreted mediators in vivo

Abstract

We used gene expression profiling of human primary cells infected in vitro with dengue virus (DENV) as a tool to identify secreted mediators induced in response to the acute infection. Affymetrix Genechip analysis of human primary monocytes, B cells and dendritic cells infected with DENV in vitro revealed a strong induction of monocyte chemotactic protein 2 (MCP-2/CCL8), interferon gamma-induced protein 10 (IP-10/CXCL10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10). The expression of these genes was confirmed in dendritic cells infected with DENV in vitro at mRNA and protein levels. A prospectively enrolled cohort of DENV-infected Venezuelan patients was used to measure the levels of these proteins in serum during three different periods of the disease. Results showed significant increase of MCP-2, IP-10 and TRAIL levels in DENV-infected patients during the febrile period, when compared to healthy donors and patients with other febrile illnesses. MCP-2 and IP-10 levels were still elevated during the post-febrile period while TRAIL levels dropped close to normal after defervescense. Patients with primary infections had higher TRAIL levels than patients with secondary infections during the febrile period of the disease. Increased levels of IP-10, TRAIL and MCP-2 in acute DENV infections suggest a role for these mediators in the immune response to the infection.

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.…”

“…Our data suggest that CXCL10 participates in antiviral response independent of CXCL10-mediated leukocyte recruitment following DENV infection. Because CXCL10 is the predominant CXCR3 ligand induced by DENV infection (17,26,28) but was not critical for recruitment of effector cells, we examined other potential antiviral mechanisms. Previously, we demonstrated that CXCL10 inhibits DENV entry into hepatocytes by competing with DENV for binding to the cell surface heparan sulfate (31), a coreceptor for DENV entry (44)(45)(46).…”

“…There may be limitations of this intracerebral challenge model for reflecting human dengue infection, which may argue the importance of CXCL10 in DENV infection in humans. However, of particulate interest, recent human studies have demonstrated that CXCL10 expression is substantially induced upon DENV infection in a variety of human primary cells (28) and that serum levels of CXCL10 are significantly increased in patients with early DENV infection (26), indicating the importance of CXCL10 in human DENV infection. Altogether, it is possible that CXCL10 may play a critical role in DENV infection independent of the route of infection.…”

Dengue Virus Type 3 Isolated from a Fatal Case with Visceral Complications Induces Enhanced Proinflammatory Responses and Apoptosis of Human Dendritic Cells

“…Several studies in recent years have evaluated the host response to dengue virus infections by the use of high-throughput technologies such as microarrays (3,14,33,45). These studies generally demonstrated substantial activation of the innate immune response, mainly mediated through the presence of type I IFN.…”

Biomarcadores pronósticos de severidad del dengue

“…Cabe la hipótesis de que el incremento de la respuesta de citocinas en niños con dengue se origine a partir de células del sistema inmunitario innato (dianas para la replicación inicial de dengue) y no de las células T; por ejemplo, los experimentos in vitro muestran que los monocitos y las células dendríticas pueden actuar como una fuente importante de citocinas durante la infección por dengue (30,31). Chen, et al, (32) propusieron un modelo de patogénesis de dengue en el cual la producción de citocinas por monocitos durante la fase temprana de la infección desencadena una cascada de sucesos que eventualmente conducen a un incremento de la respuesta de citocinas y aumentan la permeabilidad vascular.…”