Article
Dysregulation of the CXCL10-CXCR3 (chemokine-chemokine receptor) loop in SARS-infected individuals
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Published: | May 26, 2004 |
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Severe acute respiratory syndrome (SARS) infected thousands as it spread globally in 2003. It has been suggested that the natural course of SARS is determined by proinflammatory cytokines; however the linkage between dysregulation of the immune system and the severity of the disease is not understood. With the hypothesis that lung injury progresses in SARS patients as a result of unabated adaptive immune responses initiated by the virus, we profiled proinflammatory cytokine and chemokine/chemokine receptor interactions in mild and critical care SARS patients from the onset of symptoms through convalescence or, in some cases, death.
We found that plasma levels of interferon (IFN)-gamma were significantly elevated in SARS patients at onset of symptoms. Levels of the IFN-gamma-induced chemokine CXCL10 were also significantly increased in SARS patients at onset, but remained specifically elevated in critical patients and were highest in dying SARS patients. Furthermore, we found that CXCL10 and its receptor, CXCR3, were elevated locally in lung specimens from deceased patients. Indeed, SARS coronavirus (CoV) infection of VERO E6 cells induced CXCL10 expression in vitro within 12 hours indicating that SARS CoV can regulate CXCL10 expression directly. In addition, SARS antigen-specific T cells from convalescent SARS patients expressed high levels of CXCR3.
We contend that IFN-gamma and the lung tropism of SARS CoV stimulates early expression of CXCL10 in the lungs that in turn regulates infiltration of SARS antigen-specific T cells and potentially uncontrollable immune responses against SARS CoV.
Funding for this work was provided by the Canadian Institutes of Health Research, the Canadian Network for Vaccines and Immunotherapies (CANVAC) and Genome Canada.