Human immunopathogenesis of severe acute respiratory syndrome (SARS)

Abstract

Progressive immune-associated injury is a hallmark of severe acute respiratory syndrome (SARS). Viral evasion of innate immunity, hypercytokinemia and systemic immunopathology in the SARS coronavirus (SARS CoV) infected host have been suggested as possible mechanisms for the cause of severe pathology and morbidity in SARS patients. The molecular and cellular basis for how SARS CoV impacts the host immune system resulting in severe SARS, however, has not been elucidated. The variable clinical course of SARS may be the result of complex programs of host responses against the infectious agent. Therefore, the systematic analysis of innate and adaptive immune responses to SARS CoV is imperative in building as complete an immunological model as possible of host immunity and inflammatory responses during illness. Here we review recent advances in SARS immunopathogenesis research and present a summary of our findings regarding host responses in SARS patients. We contend that dysregulated type I and II interferon (IFN) responses during SARS may culminate in a failure of the switch from hyper-innate immunity to protective adaptive immune responses in the human host.

Fig. 1

Microarray analysis of host gene expression during SARS infection. Detailed microarray procedures are posted at the UHN Microarray Facility website (http://www.microarrays.ca) and described previously (Bosinger et al., 2004). 102 significantly deviated genes (P < 0.05) involved with IFN-responses (ISGs), adaptive immune responses, inflammation, antigen presentation (HLA/MHC class I and II) and immunoglobulin (IgL and IgH) gene clusters were chosen from larger gene lists identified by ANOVA (F-test) analysis of early (n = 15, 5369 genes) and late phase (n = 13, 3860 genes) SARS patients versus healthy controls (n = 10). GO annotation (http://www.geneontology.org) and the Interferon Stimulated Gene Database (de Veer et al., 2001) were used to classify genes by related function. SARS patient datasets were then normalized gene by gene against healthy control means. Agglomerative hierarchical clustering with Pearson correlation and average linkage distance metrics was used to organize datasets corresponding to multiple time points (at onset of symptoms and every 5–7 days) throughout SARS in three representative patients described in the text. Genes shown in red are upregulated and genes shown in blue are downregulated >1.5-fold relative to healthy controls.

Fig. 2

Model of immunopathological events associated with SARS clinical evolution. SARS patients mount robust IFN-mediated innate immune responses during early (acute) illness and peak symptomology. Following the median SO₂ nadir in surviving patients (late SARS), most SARS patients resolve inflammation and mount effective adaptive immunity against SARS CoV. Immune dysregulation in severe SARS patients is hallmarked by continued expression of inflammatory chemokines and ISGs and deficiencies in MHC and Ig gene expression. Immune-mediated pathology worsens in the minority of susceptible SARS patients and unresolved CXCL10 expression and viral burden is associated with poor outcome.