Abstract
Japanese encephalitis is a severe central nervous system (CNS) inflammatory disease caused by the mosquito-borne flavivirus, Japanese encephalitis virus (JEV). In the current study we have investigated the immune responses against JEV in mice lacking expression of the chemokine receptor CCR5, which functions in activation and chemotaxis of leukocytes during infection. We show that CCR5 serves as a host antiviral factor against Japanese encephalitis, with CCR5 deficiency markedly increasing mortality, and viral burden in the CNS. Humoral immune responses, which are essential in recovery from JEV infection, were of similar magnitude in CCR5 sufficient and deficient mice. However, absence of CCR5 resulted in a multifaceted deficiency of cellular immune responses characterized by reduced natural killer and CD8+ T cell activity, low splenic cellularity, and impaired trafficking of leukocytes to the brain. Interestingly, adoptive transfer of immune spleen cells, depleted of B lymphocytes, increased resistance of CCR5-deficient recipient mice against JEV regardless of whether the cells were obtained from CCR5-deficient or wild-type donor mice, and only when transferred at one but not at three days post-challenge. This result is consistent with a mechanism by which CCR5 expression enhances lymphocyte activation and thereby promotes host survival in Japanese encephalitis.
Highlights
The migration of leukocytes in lymphoid organs and to sites of inflammation is coordinated by an array of chemokines that bind to specific receptors on immune cells
To assess the impact of CCR5 on the pathogenesis of Japanese encephalitis, mortality was recorded in 8-week-old congenic CCR52/2 and CCR5+/+ wild-type mice after i.v. challenge with 103 PFU of Japanese encephalitis virus (JEV)
An important disease-ameliorating contribution of CCR5 has been documented in settings of trypanosomiasis [28], toxoplasmosis [29], influenza [30,31], parainfluenza [32], West are presented, and data are representative of 2 independent experiments. (B) natural killer (NK) cell cytotoxicity at indicated time points with an e/t cell ratio of 120:1
Summary
The migration of leukocytes in lymphoid organs and to sites of inflammation is coordinated by an array of chemokines that bind to specific receptors on immune cells (reviewed in [1]). The chemokine receptor, CCR5, is expressed on natural killer (NK) cells, macrophages, and CD4+ and CD8+ T cells. In these cell types, it regulates chemotaxis and cell activation through interaction with the chemokine ligands CCL3, CCL4 and CCL5, which are up-regulated at the site of infection (reviewed in [2]). The chemokine receptor is an important target for therapeutic intervention against HIV/AIDS, and recent clinical trials investigating the efficacy of CCR5 antagonists in patients with HIV/AIDS have provided promising results (reviewed in [4]). It has been argued that if CCR5 had a protective role against another group of pathogens, for instance in flaviviral encephalitis, it follows that a therapeutic treatment, which aims to block the receptor, could exacerbate the diseases caused by these pathogens [5,6]
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