Evasion by stealth: inefficient immune activation underlies poor T cell response and severe disease in SARS-CoV-infected mice.
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.
Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
Jincun
J
Zhao
Jingxian
J
Zhao
Nico
N
Van Rooijen
Stanley
S
Perlman
D000818:Animals; D004002:Clodronic Acid / Q000008:administration & dosage; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology; D018450:Disease Progression; D057131:Immune Evasion / Q000276:immunology / Q000502:physiology*; D008081:Liposomes / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019653:Myeloablative Agonists / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D017735:Virus Latency / Q000187:drug effects / Q000276:immunology / Q000502:physiology
D008081:Liposomes; D019653:Myeloablative Agonists; D004002:Clodronic Acid