Measles Virus Infection Induces Chemokine Synthesis by Neurons

Abstract

The role that neurons play in the induction of the immune response following CNS viral infection is poorly understood, largely owing to the belief that these cells are immunologically quiescent. In this report, we show that virus infection of neurons results in the synthesis of proinflammatory chemokines, which are early and important mediators of leukocyte recruitment to sites of viral infection. For these studies, a transgenic mouse model of neuron-restricted measles virus (MV) infection was used. Inoculation of immunocompetent and immunodeficient transgenic adult mice resulted in CNS induction of the mRNAs encoding IFN-γ inducible protein of 10 kD, monokine inducible by γ and RANTES. Colocalization of chemokine proteins with MV-infected neurons was detected by immunofluorescence in infected brain sections. Both IFN-γ inducible protein 10 kD and RANTES were also induced in MV-infected primary hippocampal neurons cultured from transgenic embryos, as shown by RNase protection assay, confocal microscopy, and ELISA. Interestingly, neuronal infection with another RNA virus (lymphocytic choriomeningitis virus) was not associated with induction of these chemokines. In immunocompetent mice, chemokine synthesis preceded the infiltration of T lymphocytes, and chemokine ablation by neutralizing Abs resulted in a 20–50% reduction in the number of infiltrating lymphocytes. Collectively, these data indicate that neurons play an important role in the recruitment of a protective antiviral response to the CNS following viral infection, although such a role may be virus type-dependent.

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

“…CXCL10 is an inflammatory chemokine that mainly recruits activated T cells and NK cells to sites of infection and/or inflammation. Using mouse animal models, it has been shown that CXCL10 expression is significantly induced and plays a critical role in a variety of viral infections, including infection with measles virus (20), West Nile virus (21), lymphocytic choriomeningitis virus (42), murine hepatitis virus (19,22), and herpes simples virus (24,43). The primary function of CXCL10 in these viral diseases is to recruit effector cells to the sites of infection.…”

“…CXCL10 has been reported to play an important role in host defense following a variety of viral infections. Using CXCL10 2/2 mice, the major function for CXCL10 in host defense against viral infection has been shown to be recruitment of effector T cells and NK cells to sites of infection/inflammation (19)(20)(21)(22)(23)(24)(25). However, CXCL10 function specific to DENV infection has not been examined in vivo.…”

T Cell-, Interleukin-12-, and Gamma Interferon-Driven Viral Clearance in Measles Virus-Infected Brain Tissue

“…Therefore, we investigated the role of chemokines in lymphocyte migration within MV-infected brain slices. As T cells contribute to MV immune protection in brain explants, we focused our study on the T cell-tropic chemokines CCL5 and CXCL10 (16,25,57) as possible stimuli for migration within brain tissue. Neutralizing antibodies to each chemokine alone or in combination were added to infected brain slices before coculturing with antiviral leukocytes.…”

“…Antiviral leukocytes at 7 dpi were isolated from the adult mice and added to MV-infected organotypic brain slices at 3 dpi. To inhibit the chemokines CCL5 and CXCL10, previously identified as targets for T cell infiltration (57), infected slices were treated with neutralizing anti-CCL5 and anti-CXCL10 antibodies (0.05 mg MAB466 and 5 mg MAB478, in accordance with the manufacturer's neutralization assay instructions; R&D Systems, Minneapolis, MN) or the matched isotype control (MAB006; R&D Systems) in PBS. Antibodies were preincubated for 20 min in a humidified 37°C incubator with 5% CO 2 .…”

High CRMP2 expression in peripheral T lymphocytes is associated with recruitment to the brain during virus-induced neuroinflammation

“…Thus, immune cells control the spread of viruses and participate in viral clearance. However, T-lymphocytes can mediate inappropriate inflammatory responses, producing multiple cytokines, chemokines, and reactive oxygen species that contribute to severe neural tissue injury and CNS dysfunction (Carlson et al, 2006) (Peterson and Fujinami, 2007;Galelli et al, 2000;Giraudon et al, 2004;Lane et al, 2000;Patterson et al, 2003). Considering the importance of viral encephalitis in humans, the homing behavior and functional status of immune cells that infiltrate the virus-infected brain need to be clarified.…”