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

Abstract

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 wildtype 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.

Memory T cells persisting in the brain following MCMV infection induce long-term microglial activation via interferon-γ

“…Using our previously described model of MCMV brain infection (Cheeran et al , 2004; Cheeran et al , 2007) we have shown that active viral infection could be detected up to 10 d p.i. Interestingly, in the present study CD8(+) T-cells isolated from the brains of infected animals at 30 d p.i.…”

“…Leukocytes were isolated from MCMV-infected murine brains using a previously described procedure with minor modifications (Cheeran et al , 2007; Ford et al , 1995; Marten et al , 2003; Mutnal et al ). In brief, brain tissues harvested from four to six animals were minced finely in RPMI 1640 (2 g/L D-glucose and 10 mM HEPES) and digested in 0.0625% trypsin (in Ca/Mg-free HBSS) at room temperature for 20 min.…”

Neuropathogenesis of Congenital Cytomegalovirus Infection: Disease Mechanisms and Prospects for Intervention

“…Although lack of IL-10 has little effect on viral clearance, the levels of IL-6, IFN-␥, CXCL10, and CCL2 are dramatically increased. However, not all the cytokines are dysregulated in the absence of IL-10; TNF-␣, IL-1␤, and CCL5 levels are relatively unaffected (52). Interestingly, human CMV carries its own IL-10 homolog that inhibits CXCL10 production in human microglial cells, which consequently inhibits lymphocyte migration (53).…”

“…hi CD11b Ϫ cells, a phenotype that characterizes infiltrating lymphocytes (52). The brain-infiltrating leukocyte profile in the absence of IL-10 and the mechanisms that regulate cytokine induction in brain cells are currently under investigation.…”

Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

“…37 This acute cytokine response is regulated by the anti-inflammatory cytokine IL-10. 80 Although lack of IL-10 has little effect on viral load, it leads to a severely dysregulated IFN-c response and renders CMV brain infection lethal. 80 Interestingly, HCMV carries its own IL-10 homolog that inhibits CXCL10 production in …”