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H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression

Umadevi S. Sajjan^*, Yue Jia^*, Dawn C. Newcomb, J. Kelley Bentley^*, Nicholas W. Lukacs, John J. LiPuma^* and Marc B. Hershenson^*,,1

^* Department of Pediatrics and Communicable Diseases,

Department of Molecular and Integrative Physiology, and

Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

¹Correspondence: University of Michigan, 1150 W. Medical Center Dr., Rm. 3570, MSRBII, Box 0688, Ann Arbor, MI 48109-0688, USA. E-mail: mhershen{at}umich.edu

ABSTRACT

Rhinovirus (RV) is an important trigger of chronic obstructive pulmonary disease (COPD) exacerbations. In addition, respiratory viruses are more likely to be isolated in patients with a history of frequent exacerbations, suggesting that these patients are more susceptible to viral infection. To examine potential mechanisms for cooperative effects between bacterial and viral infection in COPD, we studied the responses of cultured human airway epithelial cells to nontypeable Hemophilus influenzae and RV. In both 16HBE14o- and primary mucociliary-differentiated cells, preincubation with H. influenzae enhanced RV serotype 39-induced protein expression of interleukin (IL)-8, epithelial-derived neutrophil attractant-78, and growth-related oncogene-. H. influenzae infection also increased the binding of RV39 to cultured cells, as well as expression of intercellular adhesion molecule (ICAM)-1 and Toll-like receptor (TLR)-3, receptors for RV and dsRNA, respectively. Neutralizing antibody against tumor necrosis factor- inhibited IL-8 expression induced by H. influenzae and RV39. Finally, siRNA against TLR3 attenuated RV-induced IL-8 expression. We conclude that H. influenzae infection increases airway epithelial cell ICAM-1 and TLR3 expression, leading to enhanced binding of RV and a potentiation of RV-induced chemokine release. These data provide a cellular mechanism by which H. influenzae infection may increase the susceptibility of COPD patients to RV-induced exacerbations.—Sajjan, U. S., Jia, Y., Newcomb, D. C., Bentley, J. K., Lukacs, N. W., LiPuma, J. J., Hershenson, M. B. H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression

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