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Blood, 1 September 2008, Vol. 112, No. 5, pp. 2028-2034.
Prepublished online as a Blood First Edition Paper on June 10, 2008; DOI 10.1182/blood-2008-01-132860.
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Submitted January 8, 2008
Accepted May 29, 2008
Toll-like receptor-mediated activation of neutrophils by influenza A virus
Jennifer P. Wang*, Glennice N. Bowen, Carolyn Padden, Anna Cerny, Robert W. Finberg, Peter E Newburger, and Evelyn A. Kurt-Jones
Medicine, University of Massachusetts, Worcester, MA, United States
Pediatrics, University of Massachusetts, Worcester, MA, United States
* Corresponding author; email: jennifer.wang{at}umassmed.edu.
Influenza virus infection of the respiratory tract is characterized by a neutrophil infiltrate accompanied by inflammatory cytokine and chemokine production. We and others have reported that Toll-like receptor (TLR) proteins are present on human neutrophils and that GM-CSF treatment enhances IL-8 (CXCL8) secretion in response to stimulation with TLR ligands. We demonstrate that influenza virus can induce IL-8 and other inflammatory cytokines from GM-CSF-primed human neutrophils. Using heat inactivation of influenza virus, we show that viral entry but not replication is required for cytokine induction. Furthermore, endosomal acidification and viral uncoating is necessary. Finally, using single cell analysis of intracellular cytokine accumulation in neutrophils from knockout mice, we prove that TLR7 is essential for influenza viral recognition and inflammatory cytokine production by murine neutrophils. These studies demonstrate neutrophil activation by influenza virus and highlight the importance of TLR7 and TLR8 in that response.
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