Abstract
The functional role of ELR-positive CXC chemokines in host defense during acute viral-induced encephalomyelitis was determined. Inoculation of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice resulted in the rapid mobilization of PMNs expressing the chemokine receptor CXCR2 into the blood. Migration of PMNs to the CNS coincided with increased expression of transcripts specific for the CXCR2 ELR-positive chemokine ligands CXCL1, CXCL2, and CXCL5 within the brain. Treatment of JHMV-infected mice with anti-CXCR2 blocking antibody reduced PMN trafficking into the CNS by >95%, dampened MMP-9 activity, and abrogated blood-brain-barrier (BBB) breakdown. Correspondingly, CXCR2 neutralization resulted in diminished infiltration of virus-specific T cells, an inability to control viral replication within the brain, and 100% mortality. Blocking CXCR2 signaling did not impair the generation of virus-specific T cells, indicating that CXCR2 is not required to tailor anti-JHMV T cell responses. Evaluation of mice in which CXCR2 is genetically silenced (CXCR2−/− mice) confirmed that PMNs neither expressed CXCR2 nor migrated in response to ligands CXCL1, CXCL2, or CXCL5 in an in vitro chemotaxis assay. Moreover, JHMV infection of CXCR2−/− mice resulted in an approximate 60% reduction of PMN migration into the CNS, yet these mice survived infection and controlled viral replication within the brain. Treatment of JHMV-infected CXCR2−/− mice with anti-CXCR2 antibody did not modulate PMN migration nor alter viral clearance or mortality, indicating the existence of compensatory mechanisms that facilitate sufficient migration of PMNs into the CNS in the absence of CXCR2. Collectively, these findings highlight a previously unappreciated role for ELR-positive chemokines in enhancing host defense during acute viral infections of the CNS.
Highlights
Inoculation of the neurotropic JHM strain of mouse hepatitis virus (JHMV) strain of mouse hepatitis virus into the central nervous system (CNS) of susceptible strains of mice results in an acute encephalomyelitis, characterized by wide spread infection and replication within astrocytes, microglia, and oligodendrocytes, while relatively sparing neurons [1]
The localized expression of proinflammatory chemokines within the CNS in response to viral infection has been shown to be important in host defense by attracting antigen-specific lymphocytes from the microvasculature into the parenchyma that control and eventually eliminate the replicating pathogen
Emerging evidence has indicated that the mobilization of neutrophils into the blood and recruitment to the CNS following microbial infection or injury contributes to permeabilization of the blood-brain-barrier that subsequently allows entry of inflammatory leukocytes
Summary
Inoculation of the neurotropic JHMV strain of mouse hepatitis virus (a positive-strand RNA virus and member of the Coronaviridae family) into the CNS of susceptible strains of mice results in an acute encephalomyelitis, characterized by wide spread infection and replication within astrocytes, microglia, and oligodendrocytes, while relatively sparing neurons [1]. Mechanisms associated with control of viral growth are dictated by the infected host cell. Astrocytes and microglia are susceptible to perforin-mediated lysis by cytotoxic T lymphocytes [2], whereas IFN-c suppresses viral replication within oligodendrocytes [3]. While virus-specific CD8+ T cells are retained within the CNS of persistently infected mice and lytic activity is muted, these cells retain the capacity to secrete IFN-c that limits viral replication in oligodendrocytes [3,5,6,7]. Histological features associated with viral persistence include the development of an immunemediated demyelinating disease similar to the human demyelinating disease multiple sclerosis (MS), with both T cells and macrophages being important in amplifying disease severity by contributing to myelin damage [8,9]
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