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Immunopathogenesis of coronavirus infections: implications for SARS - PubMed

Review

Immunopathogenesis of coronavirus infections: implications for SARS

Stanley Perlman et al. Nat Rev Immunol. 2005 Dec.

Abstract

At the end of 2002, the first cases of severe acute respiratory syndrome (SARS) were reported, and in the following year, SARS resulted in considerable mortality and morbidity worldwide. SARS is caused by a novel species of coronavirus (SARS-CoV) and is the most severe coronavirus-mediated human disease that has been described so far. On the basis of similarities with other coronavirus infections, SARS might, in part, be immune mediated. As discussed in this Review, studies of animals that are infected with other coronaviruses indicate that excessive and sometimes dysregulated responses by macrophages and other pro-inflammatory cells might be particularly important in the pathogenesis of disease that is caused by infection with these viruses. It is hoped that lessons from such studies will help us to understand more about the pathogenesis of SARS in humans and to prevent or control outbreaks of SARS in the future.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. The severe-acute-respiratory-syndrome coronavirus genome and virion.

a | The severe-acute-respiratory-syndrome coronavirus (SARS-CoV) genome consists of 28 putative open reading frames (ORFs) in 9 mRNA transcripts. ORF1a and ORF1b, which account for about two-thirds of the genome, both encode large polyproteins. ORF1b protein is produced by a –1-base-pair ribosomal frameshift from the reading frame of ORF1a. The SARS-CoV genome encodes four structural proteins: spike (S), envelope (E), matrix (M) and nucleocapsid (N). In non-human isolates, transcription of ORF8a and ORF8b produces a single protein. b | A schematic representation of a SARS-CoV virion is shown. ssRNA, single-stranded RNA.

Figure 2
Figure 2. Macrophage infection and antibody-dependent enhancement of virus entry in infection with feline infectious peritonitis virus.

a | Infection of macrophages and possibly dendritic cells (DCs) results in both dissemination of feline infectious peritonitis virus (FIPV) infection and dysregulation of these cells, leading to lymphocyte apoptosis. b | FIPV usually infects cells through the binding of the spike protein to its cellular receptor, CD13. The virus is then internalized and released into the cytoplasm. c | In antibody-dependent entry, specific antibodies bind the spike protein. The antibody-opsonized FIPV virions then interact with FcγRs (receptors for IgG). Some evidence indicates that this process augments the normal spike–CD13 interaction. After binding of the opsonized virions to FcγRs, the virus is internalized and released into the cytoplasm. Antigen–antibody complexes are also deposited in the vasculature, resulting in complement activation. Activation of complement contributes to the development of vasculitis and oedema, with death of the animal occurring soon after. C3, complement component 3; IL-10, interleukin-10; TH2 cell, T helper 2 cell; TNF, tumour-necrosis factor.

Figure 3
Figure 3. Mechanisms of immune-mediated demyelination in infection with murine hepatitis virus.

In immunocompetent mice, infection of glial cells (that is, astrocytes, microglia and oligodendrocytes) results in migration of T cells into the central nervous system (a). Myelin destruction is mediated by CD4+ and CD8+ T cells, and these cells activate macrophages by the production of cytokines (b) or kill infected cells directly (c), both of which result in demyelination. In recombination-activating gene 1 (Rag1−/−) mice, which lack T and B cells, two additional mechanisms of demyelination have been elucidated. Rag1−/− mice do not develop demyelination when infected with the JHM strain of murine hepatitis virus (MHV-JHM); as occurs in immunocompetent mice, demyelination develops after the adoptive transfer of MHV-JHM-specific T cells. However, demyelination also results if infected Rag1−/− mice are infected with a recombinant MHV-JHM expressing the macrophage attractant CC-chemokine ligand 2 (CCL2) (d), presumably by direct activation of macrophages. Similarly, exogenous delivery of neutralizing MHV-JHM-specific antibody (e) results in macrophage activation and demyelination; this process depends on activation through complement and activating Fcg receptors (receptors for IgG). TCR, T-cell receptor.

Figure 4
Figure 4. Infection with murine hepatitis virus strain 3 results in upregulation of expression of fibrinogen-like protein 2.

Murine hepatitis virus strain 3 (MHV-3) becomes internalized after binding macrophages through its receptor, CD66 (a). Subsequent to internalization, virions are uncoated and begin to replicate. As part of the replication process (b), the nucleocapsid protein is synthesized. Subsequently, a signalling pathway involving p38 mitogen-activated protein kinase (p38MAPK) activation, as well as the nucleocapsid protein and other unknown host factors, is initiated (c), resulting, ultimately, in binding of the transcription factor hepatocyte nuclear factor 4α (HNF4α) to the gene that encodes fibrinogen-like protein 2 (FGL2) (d), which is a prothrombinase. The FGL2 protein that is produced then translocates to the cell surface (e), where it induces fibrin deposition and, consequently, acute liver necrosis.

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