Evasion by Stealth: Inefficient Immune Activation Underlies Poor T Cell Response and Severe Disease in SARS-CoV-Infected Mice

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Abstract
Severe Acute Respiratory Syndrome caused substantial morbidity and mortality during the 2002–2003 epidemic. Many of the features of the human disease are duplicated in BALB/c mice infected with a mouse-adapted version of the virus (MA15), which develop respiratory disease with high morbidity and mortality. Here, we show that severe disease is correlated with slow kinetics of virus clearance and delayed activation and transit of respiratory dendritic cells (rDC) to the draining lymph nodes (DLN) with a consequent deficient virus-specific T cell response. All of these defects are corrected when mice are treated with liposomes containing clodronate, which deplete alveolar macrophages (AM). Inhibitory AMs are believed to prevent the development of immune responses to environmental antigens and allergic responses by interacting with lung dendritic cells and T cells. The inhibitory effects of AM can also be nullified if mice or AMs are pretreated with poly I:C, which directly activate AMs and rDCs through toll-like receptors 3 (TLR3). Further, adoptive transfer of activated but not resting bone marrow–derived dendritic cells (BMDC) protect mice from lethal MA15 infection. These results may be relevant for SARS in humans, which is also characterized by prolonged virus persistence and delayed development of a SARS-CoV-specific immune response in individuals with severe disease. Severe Acute Respiratory Syndrome (SARS) occurred in human populations in 2002–2003 and was caused by a novel coronavirus (CoV). Human SARS was characterized by prolonged virus excretion, lymphopenia and delayed adaptive immune responses in patients with severe disease. Recently, small animal models have been developed that mimic some of the features of the human disease. Specifically, BALB/c mice infected with mouse-adapted SARS-CoV develop severe respiratory disease. Here, we show that the T cell response is defective in these mice and that this results from inefficient activation of the initial immune response to the virus. This defect can be corrected by several treatments, including depletion of inhibitory macrophages from the lungs and direct activation of respiratory dendritic cells, important in initiating the immune response or transfer of activated dendritic cells prior to infection. All of these modalities result in improved initiation of the immune response and an enhanced anti-virus T cell response. Inefficient activation of the immune response may play a role in human SARS, and our results suggest possible strategies that might be used to develop novel anti-viral therapies.