Dysregulated interferon-gamma responses during lethal cytomegalovirus brain infection of IL-10-deficient mice

• Published in: Virus research Vol. 130; no. 1; pp. 96 - 102
• Main Authors: Cheeran, Maxim C.-J., Hu, Shuxian, Palmquist, Joseph M., Bakken, Thomas, Gekker, Genya, Lokensgard, James R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2007
• Subjects: Animals; Brain - immunology; Brain - virology; Brain Chemistry; Chemokines; Cytokines - analysis; Cytomegalovirus; Encephalitis; Encephalitis - immunology; Encephalitis - virology; Female; Herpesviridae Infections - immunology; IFN-γ; IL-10; Interferon-gamma - biosynthesis; Interferon-gamma - immunology; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-4 - deficiency; MCMV; Mice; Mice, Inbred BALB C; Mice, Knockout; Murine cytomegalovirus; Muromegalovirus - immunology; RNA, Viral - analysis; Encephalitis; IFN-γ; MCMV; IL-10; Chemokines
• ISSN: 0168-1702; 1872-7492
• DOI: 10.1016/j.virusres.2007.05.022

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)-γ, and the IFN-γ-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-γ-mediated neuroimmune response.