Coronavirus infection of the central nervous system: host-virus stand-off

Abstract

Several viruses infect the mammalian central nervous system (CNS), some with devastating consequences, others resulting in chronic or persistent infections associated with little or no overt pathology. Coronavirus infection of the murine CNS illustrates the contributions of both the innate immune response and specific host effector mechanisms that control virus replication in distinct CNS cell types. Despite T-cell-mediated control of acute virus infection, host regulatory mechanisms, probably designed to protect CNS integrity, contribute to the failure to eliminate virus. Distinct from cytolytic effector mechanisms expressed during acute infection, non-lytic humoral immunity prevails in suppressing infectious virus during persistence.

Figure 1. Summary of mouse hepatitis virus (MHV) replication.

MHV binds to the host-cell receptor CEACAM-1 through interaction of the spike (S) glycoprotein. Virus entry into the host cell can occur through fusion with the surface of the host cell, with the subsequent release of the genomic RNA into the cytoplasm. Alternatively, MHV can enter the host cell through the formation of endocytic vesicles, and genomic RNA is released into the cytoplasm following fusion with the vesicle membrane (not shown). Translation of the positive-strand genomic RNA gives rise to a large polyprotein that undergoes proteolytic processing to generate an RNA-dependent RNA polymerase. Through the action of the RNA polymerase, a full-length, antisense negative-strand template is generated. Subgenomic mRNAs are synthesized, presumably from subgenomic negative-strand templates. Translation of subgenomic mRNAs gives rise to structural viral proteins. S glycoprotein is expressed on the surface of the host cell and this might contribute to fusion with neighbouring uninfected cells by binding to CEACAM-1. Virus assembly occurs within vesicles, followed by virus release by fusion of virion-containing vesicles with the plasma membrane. Released virus can infect other cells and can replicate within the parent cell through binding to CEACAM-1. E, envelope protein; ER, endoplasmic reticulum; M, membrane protein; N, nucleocapsid protein; ORF, open reading frame. Modified with permission from Ref. © (2003) Macmillan Publishers Ltd.

Figure 2. Kinetics of viral spread and central nervous system (CNS) tropism.

Overview of viral spread following intracranial inoculation of mouse hepatitis virus (MHV) into susceptible mice. Ependymal cells lining the lateral ventricles (LV) are the initial targets of replication, followed by spread of virus into the parenchyma and viral infection of resident glial cells of the CNS — astrocytes, oligodendrocytes and microglia. Early during acute infection, the inflammatory infiltrate consists primarily of innate components, that is, neutrophils, macrophages and natural killer (NK) cells, which presumably respond to proinflammatory signals such as TNF-α, IL-6 and CXCL10 released by glia. These proinflammatory signals enhance trafficking and accumulation of cells within the CNS. The adaptive stage of acute infection is characterized by rapid spread of virus throughout the parenchyma and increased infiltration of virus-specific CD4⁺ and CD8⁺ T cells that secrete IFN-γ, and subsequently increase expression of additional proinflammatory chemokines such as CXCL9, CXCL10 and CCL5 from astrocytes as well as inflammatory cells. Accumulation of virus-specific T cells, especially CD8⁺ T cells, ultimately results in a decrease in virus replication in glia. As virus replication is controlled, the number of inflammatory cells decreases, but viral persistence is associated with the retention of immune effectors in the CNS.

Figure 3. Host responses in the central nervous system (CNS) associated with neurotropic coronavirus replication.

a | John Howard Mueller (JHMV) strain replication is controlled by two weeks post infection (p.i.), but viral antigen (vAg) and viral RNA (vRNA) persist. Clearance of infectious virus is accompanied by primary demyelination, which is most severe between days 14 and 21 p.i. b | Overview of the relative levels of chemokine mRNA expressed within the CNS following JHMV infection of mice. A systematic analysis of the functional contributions reveals both redundant and non-redundant roles for these molecules in participating in host defence by linking innate and adaptive immune responses (CCL3), promoting T-cell infiltration (CXCL9, CXCL10 and CCL5) and macrophage accumulation (CCL2 and CCL5). c | Schematic of cytokine mRNA kinetics during acute JHMV infection.

Figure 4. Kinetics of the cellular and humoral inflammatory response to neurotropic coronavirus infection.

Infiltrating cells following infection of the central nervous system (CNS) with the John Howard Mueller (JHMV) strain are identified by flow cytometric analysis. Bone-marrow-derived infiltrates are distinguished from resident cells by their CD45^hi phenotype and other surface markers that characterize distinct myeloid and lymphoid populations. Symbols depict representative numbers of individual cell populations within total brain cells. a–b | Macrophages make up the vast majority of early infiltrates up to day 5 following infection, whereas T cells are most abundant during peak inflammation and thereafter. c | Humoral responses emerge after infectious virus is cleared. Neutralizing antibodies in serum emerge following clearance of infectious virus and stay elevated. d | Virus-specific antibody-secreting cells (ASCs) do not emerge in the CNS until after infectious virus is cleared, and ASCs peak ∼2 weeks after maximal T-cell inflammation. Virus-specific CD8⁺ T cells, measured by major histocompatibility complex (MHC) class I tetramer staining, decline rapidly as virus is cleared. Compared to virus-specific CD8⁺ T cells, virus-specific ASCs persist at high frequencies and decline slowly, supporting a role in preventing virus recrudescence.

Figure 5. Distinct immune effector mechanisms control acute and persistent infection.

a | CD8⁺ T cells are crucial for elimination of replicating virus during acute infection. The direct antiviral role of CD4⁺ T cells is unclear; however, they enhance CD8⁺ T-cell survival and function by an unknown mechanism. Whereas perforin-mediated mechanisms, in the absence of IFN-γ, control virus in astrocytes and microglia, IFN-γ is crucial for reducing infection in oligodendrocytes. Major histocompatibility complex (MHC) class I expression on astrocytes is postulated, as perforin-mediated cytolysis requires class I expression; however, this has not been demonstrated in vivo. Increased IFN-γ release by T cells during interaction with virus-infected targets enhances class I expression on all glial cells and induces class II expression on microglia, therefore further enhancing target–T-cell interactions. b | As viral antigen is cleared, CD8⁺ T cells lose cytolytic function and virus persists predominantly in oligodendrocytes. IFN-γ secretion decreases, MHC is downregulated and T cells decline but persist at low frequencies. Virus-specific antibody-secreting cells are crucial to prevent virus recrudescence. Ab, antibody; IFN-γR, IFN-γ receptor; MHV, mouse hepatitis virus; TCR, T-cell receptor.