How the SARS coronavirus causes disease: host or organism?

Abstract

The previous epidemic of severe acute respiratory syndrome (SARS) has ended. However, many questions concerning how the aetiological agent, the novel SARS coronavirus (CoV), causes illness in humans remain unanswered. The pathology of fatal cases of SARS is dominated by diffuse alveolar damage. Specific histological changes are not detected in other organs. These contrast remarkably with the clinical picture, in which there are apparent manifestations in multiple organs. Both pathogen and host factors are important in the pathogenesis of SARS. The choice of specific receptors and the unique genome of the SARS-CoV are important elements in understanding the biology of the pathogen. For the host cells, the outcome of SARS-CoV infection, whether there are cytopathic effects or not, depends on the cell types that are infected. At the whole-body level, immune-mediated damage, due to activation of cytokines and/or chemokines and, perhaps, autoimmunity, may play key roles in the clinical and pathological features of SARS. Continued research is still required to determine the pathogenetic mechanisms involved and to combat this new emerging human infectious disease.

Figure 1

SARS‐CoV replicates in cultured Vero E6 cells and is produced in large numbers inside cytoplasmic vesicles (A). Virus particles can also be seen budding through the cytoplasmic membrane (B). Each virion particle is 60–90 nm in size by transmission electron microscopy and is characterized by the numerous club‐shaped projections on the outside, a ring beneath the envelope, and an electron‐lucent centre. Scale bars = 200 nm (A) and 50 nm (B)

Figure 2

Diffuse alveolar damage is the most consistent finding in the terminal stages of SARS. The lung may appear grossly consolidated (A) or have a honeycomb appearance (B). Although the latter finding may be related to pre‐morbid lung pathology, a correlation with interstitial fibrosis and disease duration has been demonstrated 21. Diffuse alveolar damage at different stages of organization, from fibrin deposition (C, H&E, original magnification ×200), to interstitial fibrosis (D, H&E, original magnification ×100) and cellular organization (E and F, H&E, original magnification ×400), can be detected. Atypical pneumocytes with enlarged nuclei and prominent nucleoli are often seen and some pneumocytes coalesce into syncytial multi‐nucleated cells (G, H&E, original magnification ×600). Multi‐nucleated histiocytes may also be found (H, H&E, original magnification ×600). SARS‐CoV can be detected in pneumocytes by in situ hybridization (I, using a DNA probe against the M gene, original magnification ×600 22). A large array of antibodies against the viral proteins including nucleocapsid N, spike S, membrane M, and SARS‐3a 23, has been developed for the detection of SARS‐CoV in formalin‐fixed, paraffin‐embedded tissue sections (J, showing immunohistochemical staining with an anti‐peptide antibody against N, original magnification ×600)

Figure 3

The small intestine shows no gross or microscopic pathology in terminal cases of SARS. Apart from autolytic changes, light microscopy reveals no specific abnormalities in the small bowel muocsa (A, original magnification ×400). However, SARS‐CoV can be detected on the surface enterocytes using in situ hybridization (B, with a DNA probe against the M gene, original magnification ×600 22) or immunohistochemical staining (C, using anti‐peptide antibody against SARS‐3a, original magnification ×600 23)

Figure 4

Serum taken from SARS patients during the acute phase of the disease contains IgG against cytoplasmic antigens of pneumocytes. Application of acute phase serum as a primary antibody lights up the cytoplasm of pneumocytes of autopsy adult lung sections (A, original magnification ×1000) as well as fetal lung sections (B, original magnification ×1000)

Figure 5

Chemokines are aberrantly expressed in terminal cases of SARS. Immunohistochemical staining using a monoclonal antibody against CXCL10 (IP‐10) demonstrated overexpression of CXCL10 in the pneumocytes of SARS patients (A, original magnification ×600) but not in control autopsy lung (B, original magnification ×600)