Pathology and pathogenesis of severe acute respiratory syndrome

Abstract

Severe acute respiratory syndrome (SARS) is an emerging infectious viral disease characterized by severe clinical manifestations of the lower respiratory tract. The pathogenesis of SARS is highly complex, with multiple factors leading to severe injury in the lungs and dissemination of the virus to several other organs. The SARS coronavirus targets the epithelial cells of the respiratory tract, resulting in diffuse alveolar damage. Several organs/cell types may be infected in the course of the illness, including mucosal cells of the intestines, tubular epithelial cells of the kidneys, neurons of the brain, and several types of immune cells, and certain organs may suffer from indirect injury. Extensive studies have provided a basic understanding of the pathogenesis of this disease. In this review we describe the most significant pathological features of SARS, explore the etiological factors causing these pathological changes, and discuss the major pathogenetic mechanisms. The latter include dysregulation of cytokines/chemokines, deficiencies in the innate immune response, direct infection of immune cells, direct viral cytopathic effects, down-regulation of lung protective angiotensin converting enzyme 2, autoimmunity, and genetic factors. It seems that both abnormal immune responses and injury to immune cells may be key factors in the pathogenesis of this new disease.

Figure 1

Pathology in the lungs, brain, and spleen. A: Lung tissue of a SARS autopsy showing severe damage, hyaline membrane formation, edema, fibrin exudation, and some inflammatory cells (H&E staining). Sample from a 50-year-old male SARS patient who died 33 days after disease onset. B: Multinucleated cells (arrows) in the lungs of a SARS patient (H&E staining). Sample from a 51-year-old male SARS patient who died on day 45. C: Double labeling combining in situ hybridization (ISH) of SARS viral genomic sequence and IHC with antibodies to cytokeratin (AE1/AE3) showing both brownish red (cytokeratin) and purplish blue signals for viral genome in the same cells, identifying the infected cells as pneumocytes (arrow 1). Arrow 2 points to an ISH-positive and cytokeratin-negative cell (purplish blue signal only), representing an inflammatory cell that is infected by SARS virus. Arrow 3 points to an in situ hybridization-negative pneumocyte (cytokeratin-positive, brownish red signal only) that is not infected by SARS virus. Sample from a 58-year-old male patient with SARS who died 58 days after disease onset. D: SARS-CoV genomic sequence in various cells in the lungs. Both a dark blue in situ hybridization signal and a brownish red IHC (CD3) signal are present in the same cell (arrow 1), suggesting the infection of T lymphocytes. There are also some uninfected CD3-positive cells (arrow 2, brownish red signal only). Arrow 3 points to in situ hybridization-positive mononuclear cell (purplish blue signal only). A spindle-shaped pneumocyte with a positive in situ hybridization signal is also shown (arrow 4, purplish blue signal only). Arrow 5 points to an in situ hybridization-positive cell morphologically resembling a vascular endothelial cell (purplish blue signal only). Sample from a 24-year-old male SARS patient who died on day 21. E: Spleen tissue showing depletion of lymphocytes. Sample from same patient as in C. F: Positive in situ hybridization signals in the cytoplasm of many neurons (arrows) in brain tissue of a SARS patient. Sample from a 49-year-old female SARS patient who died on day 32. In C, D, and F, in situ hybridization was performed with a 154-nucleotide cRNA probe directed against fragments of the polymerase gene (R1ab) of SARS-CoV. The probe was labeled with digoxigenin, and a NBT/BCIP substrate chromogen kit (Promega Corp., Madison, WI) was used to visualize in situ hybridization signals, resulting in a purplish blue color. In C and D, IHC with antibodies to cytokeratin (AE1/AE3) and CD3 was performed. IHC signals were detected with the HRP reaction kit AEC, which gives a brownish red color. Scale bars: 50 μm (A); 25 μm (B, C, E, F); 20 μm (D).

Figure 2

Major mechanisms contributing to the pathogenesis of SARS. These pathological events and cascade of changes form the basis for clinical symptoms and pathological findings at different stages of SARS. Correct understanding of the pathogenesis will provide guidance to prevention, diagnosis, and treatment of this new disease. MIP-1α, macrophage inflammatory protein-1α; RANTES, regulated on activation normal T cell expressed and secreted; TNF-α, tumor necrosis factor-α; TGF-β1, transforming growth factor-β1; MCP-1, monocyte chemoattractant protein-1.