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Infection and Immunity, November 2009, p. 5059-5070, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00403-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Critical Role of the Interleukin-17/Interleukin-17 Receptor Axis in Regulating Host Susceptibility to Respiratory Infection with Chlamydia Species{triangledown}

Xiaohui Zhou,1,2,{dagger} Qiangwei Chen,1,2,{dagger} Jessica Moore,1,2 Jay K. Kolls,5 Scott Halperin,1,2,3,4 and Jun Wang1,2,3,4*

Canadian Center for Vaccinology,1 Department of Microbiology and Immunology,2 Department of Pediatrics, Dalhousie University,3 IWK Health Centre, Halifax, Nova Scotia, Canada,4 Department of Genetics, Louisiana State University Health Science Center, New Orleans, Louisiana5

Received 10 April 2009/ Returned for modification 9 June 2009/ Accepted 26 August 2009

The specific contribution of interleukin-17/interleukin-17 receptor (IL-17/IL-17R)-mediated responses in regulating host susceptibility against obligatory intracellular Chlamydia infection was investigated in C57BL/6 and C3H/HeN mice during Chlamydia muridarum respiratory infection. We demonstrated that Chlamydia stimulated IL-17/IL-17R-associated responses in both Chlamydia-resistant C57BL/6 and Chlamydia-susceptible C3H/HeN mice. However, C3H/HeN mice developed a significantly greater IL-17/IL-17R-associated response than C57BL/6 mice did. This was reflected by an increase in IL-17 mRNA expression, a higher recall IL-17 production from splenocytes upon antigen restimulation, and higher production of Th17-related cytokines (IL-23 and IL-6) and chemokines (chemokine [C-X-C motif] ligand 2 [CXCL1]/keratinocyte-derived chemokine [KC] and CXCL2/macrophage inflammatory protein 1 [MIP2]) in C3H/HeN mice than in C57BL/6 mice. Furthermore, C3H/HeN mice displayed a massive accumulation of activated and preactivated neutrophils in the airway and lung parenchyma compared to their C57BL/6 counterparts. We further demonstrated that the skewed IL-17/Th17 profile in C3H/HeN mice was predisposed by a higher basal level of IL-17 receptor C (IL-17RC) expression and then further amplified by a higher inducible IL-17RA expression in lungs. Most importantly, in vivo delivery of IL-17RA antagonist that resulted in a 50% reduction in the neutrophilic infiltration in lungs was able to reverse the susceptible phenotype of C3H/HeN mice to respiratory Chlamydia infection. Thus, our data for the first time have demonstrated a critical role for the IL-17/IL-17R axis in regulating host susceptibility to Chlamydia infection in mice.

* Corresponding author. Mailing address: Canadian Center for Vaccinology, IWK Health Centre, Research & Clinical Care Pavilion, 3rd Floor West, 5850/5980 University Avenue, Halifax, Nova Scotia B3K 6R8, Canada. Phone: (902) 470-7505. Fax: (902) 470-7590. E-mail: jun.wang{at}dal.ca

{triangledown} Published ahead of print on 8 September 2009.

Editor: J. L. Flynn

{dagger} These authors made equal contributions to this study.

Infection and Immunity, November 2009, p. 5059-5070, Vol. 77, No. 11
0019-9567/09/$08.00+0     doi:10.1128/IAI.00403-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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