Cellular Immune Responses to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection in Senescent BALB/c Mice: CD4+ T Cells Are Important in Control of SARS-CoV Infection

被引:318
作者
Chen, Jun [1 ]
Lau, Yuk Fai [1 ]
Lamirande, Elaine W. [1 ]
Paddock, Christopher D. [2 ]
Bartlett, Jeanine H. [2 ]
Zaki, Sherif R. [2 ]
Subbarao, Kanta [1 ]
机构
[1] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA
[2] Ctr Dis Control & Prevent, Atlanta, GA 30333 USA
关键词
INFLUENZA-VIRUS INFECTION; CYTOKINE/CHEMOKINE PROFILES; PULMONARY INFECTION; INTERFERON-GAMMA; A VIRUS; CLEARANCE; PATHOGENESIS; NEUTROPHILS; MECHANISMS; CHEMOKINES;
D O I
10.1128/JVI.01281-09
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
We characterized the cellular immune response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in 12- to 14-month-old BALB/c mice, a model that mimics features of the human disease. Following intranasal administration, the virus replicated in the lungs, with peak titers on day 2 postinfection. Enhanced production of cytokines (tumor necrosis factor alpha [TNF-alpha] and interleukin-6 [IL-6]) and chemokines (CXCL10, CCL2, CCL3, and CCL5) correlated with migration of NK cells, macrophages, and plasmacytoid dendritic cells (pDC) into the lungs. By day 7, histopathologic evidence of pneumonitis was seen in the lungs when viral clearance occurred. At this time, a second wave of enhanced production of cytokines (TNF-alpha, IL-6, gamma interferon [IFN-gamma], IL-2, and IL-5), chemokines (CXCL9, CXCL10, CCL2, CCL3, and CCL5), and receptors (CXCR3, CCR2, and CCR5), was detected in the lungs, associated with an influx of T lymphocytes. Depletion of CD8(+) T cells at the time of infection did not affect viral replication or clearance. However, depletion of CD4(+) T cells resulted in an enhanced immune-mediated interstitial pneumonitis and delayed clearance of SARS-CoV from the lungs, which was associated with reduced neutralizing antibody and cytokine production and reduced pulmonary recruitment of lymphocytes. Innate defense mechanisms are able to control SARS-CoV infection in the absence of CD4(+) and CD8(+) T cells and antibodies. Our findings provide new insights into the pathogenesis of SARS, demonstrating the important role of CD4(+) but not CD8(+) T cells in primary SARS-CoV infection in this model.
引用
收藏
页码:1289 / 1301
页数:13
相关论文
共 59 条
[51]  
WHO, 2004, SUMM PROB SARS CAS O
[52]   Production of interferon-γ by influenza hemagglutinin-specific CD8 effector T cells influences the development of pulmonary immunopathology [J].
Wiley, JA ;
Cerwenka, A ;
Harkema, JR ;
Dutton, RW ;
Harmsen, AG .
AMERICAN JOURNAL OF PATHOLOGY, 2001, 158 (01) :119-130
[53]   Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome [J].
Wong, CK ;
Lam, CWK ;
Wu, AKL ;
Ip, WK ;
Lee, NLS ;
Chan, IHS ;
Lit, LCW ;
Hui, DSC ;
Chan, MHM ;
Chung, SSC ;
Sung, JJY .
CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2004, 136 (01) :95-103
[54]   Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis [J].
Wong, RSM ;
Wu, A ;
To, KF ;
Lee, N ;
Lam, CWK ;
Wong, CK ;
Chan, PKS ;
Ng, MHL ;
Yu, LM ;
Hui, DS ;
Tam, JS ;
Cheng, G ;
Sung, JJY .
BRITISH MEDICAL JOURNAL, 2003, 326 (7403) :1358-1362
[55]   Persistent memory CD4+ (and CD8+ T-cell responses in recovered severe acute respiratory syndrome (SARS) patients to SARS coronavirus M antigen [J].
Yang, Litao ;
Peng, Hui ;
Zhu, Zhaoling ;
Li, Gang ;
Huang, Zitong ;
Zhao, Zhixin ;
Koup, Richard A. ;
Bailer, Robert T. ;
Wu, Changyou .
JOURNAL OF GENERAL VIROLOGY, 2007, 88 :2740-2748
[56]   Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro [J].
Yen, YT ;
Liao, F ;
Hsiao, CH ;
Kao, CL ;
Chen, YC ;
Wu-Hsieh, BA .
JOURNAL OF VIROLOGY, 2006, 80 (06) :2684-2693
[57]   CXCR3 mediates region-specific antiviral T cell trafficking within the central nervous system during west nile virus encephalitis [J].
Zhang, Bo ;
Chan, Ying Kai ;
Lu, Bao ;
Diamond, Michael S. ;
Klein, Robyn S. .
JOURNAL OF IMMUNOLOGY, 2008, 180 (04) :2641-2649
[58]   Functional characterization of BK virus-specific CD4+ T cells with cytotoxic potential in seropositive adults [J].
Zhou, Wendi ;
Sharma, Madeva ;
Martinez, Joy ;
Srivastava, Tumul ;
Diamond, Don J. ;
Knowles, Wendy ;
Lacey, Simon F. .
VIRAL IMMUNOLOGY, 2007, 20 (03) :379-388
[59]   Severe acute respiratory syndrome coronavirus fails to activate cytokine-mediated innate immune responses in cultured human monocyte-derived dendritic cells [J].
Ziegler, T ;
Matikainen, S ;
Rönkkö, E ;
Österlund, P ;
Sillanpää, M ;
Sirén, J ;
Fagerlund, R ;
Immonen, M ;
Melén, K ;
Julkunen, L .
JOURNAL OF VIROLOGY, 2005, 79 (21) :13800-13805