Dysregulated interferon-gamma responses during lethal cytomegalovirus brain infection of IL-10-deficient mice.
Murine cytomegalovirus (MCMV) brain infection induces a transient increase in chemokine production, which precedes the infiltration of CD3(+) lymphocytes. In this study, we hypothesized that an absence of anti-inflammatory cytokines would result in sustained proinflammatory neuroimmune responses. Direct intracerebroventricular injection of MCMV into IL-10 knockout (KO) mice produced an unexpected result: while wild-type animals controlled MCMV, the infection was lethal in IL-10 KO animals. Identical infection of IL-4 KO animals did not produce lethal disease. To further characterize the role of IL-10, infected brain tissue from both wild-type and IL-10 KO animals was assessed for cytokine and chemokine levels, as well as viral gene expression. These data show vastly elevated levels of interferon (IFN)-gamma, and the IFN-gamma-inducible chemokines CXCL9 and CXCL10, as well as IL-6 in brain homogenates obtained from IL-10 KO animals. However, MCMV viral load, glycoprotein B mRNA levels, and titers of infectious virus were similar in both IL-10 KO and wild-type animals. Separation of cells isolated from murine brain tissue into distinct populations using FACS, along with subsequent quantitative RT real-time PCR, showed that brain-infiltrating CD45(hi)/CD11b(-) and CD45(hi)/CD11b(int) were the cellular source of IL-10 in the brain. Taken together, these data demonstrate that MCMV brain infection of IL-10-deficient mice causes lethal disease, which occurs in the presence of a dysregulated IFN-gamma-mediated neuroimmune response.
Cheeran
Maxim C-J
MC
Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, MN, United States.
Hu
Shuxian
S
Palmquist
Joseph M
JM
Bakken
Thomas
T
Gekker
Genya
G
Lokensgard
James R
JR
D000818:Animals; D001921:Brain / Q000276:immunology / Q000821:virology; D001923:Brain Chemistry; D016207:Cytokines / Q000032:analysis; D004660:Encephalitis / Q000276:immunology* / Q000821:virology; D005260:Female; D006566:Herpesviridae Infections / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology*; D012367:RNA, Viral / Q000032:analysis
D016207:Cytokines; D012367:RNA, Viral; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma