title: The chemokine receptor CCR5, a therapeutic target for HIV/AIDS antagonists, is critical for recovery in a mouse model of Japanese encephalitis.
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.
authors.affiliation: Department of Emerging Pathogens and Vaccines, John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Larena
authors.forename: Matthias
authors.initials: M
authors.lastname: Regner
authors.forename: Mario
authors.initials: M
authors.lastname: Lobigs
mesh_terms: D000818:Animals; D065100:CCR5 Receptor Antagonists; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004672:Encephalitis, Japanese / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D056724:Immunity, Humoral / Q000187:drug effects; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D058990:Molecular Targeted Therapy; D019713:Receptors, CCR5 / Q000172:deficiency / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D016019:Survival Analysis; D014709:Vero Cells
chemical_list: D065100:CCR5 Receptor Antagonists; D019713:Receptors, CCR5