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

PLoS Pathogens

Jingxian Zhao¹  Jincun Zhao¹  Stanley Perlman²  Nico Van Rooijen³ 

[1] Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America;Department of Molecular Cell Biology, Vrije Universiteit Medisch Centrum, Amsterdam, The Netherlands;Institute for Tissue Transplantation and Immunology, Jinan University, Guangzhou, China

关键词: T cells;    Cytotoxic T cells;    SARS coronavirus;    Flow cytometry;    Respiratory infections;    Immune response;    Cell staining;    Toll-like receptors;   

DOI  :  10.1371/journal.ppat.1000636

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY