In patients with chronic obstructive pulmonary disease (COPD), which is characterized by bacterial colonization of the airways, co-infection with respiratory viruses further impairs host defenses, leading to bacterial overgrowth and infection, as well as disease exacerbation. Our pilot studies indicate that pre-infection of well-differentiated airway epithelial cell cultures with rhinovirus (RV), the virus responsible for most respiratory tract infections, increases binding of both non- typeable Hemophilus influenzae (NTHI) and Pseudomonas aeruginosa (PA), as well as bacteria-induced chemokine expression. Further, we have found that RV infection of polarized airway epithelial cells induces the expression of new receptors for PA. Finally, we have developed two new mouse models which will allow us to test whether pre-infection with RV increases the susceptibility to bacterial infection in vivo. First, inoculation with RV1B, a minor group RV which binds to the low-density lipoprotein receptor, induces neutrophilic airway inflammation and hyperresponsiveness in C57/BL6 mice. Second, we have developed a murine model of COPD by sequential intranasal treatment with elastase and lipopolysaccharide. Our pilot studies indicate that elastase/LPS-treated """"""""COPD mice"""""""" pre-infected with RV are more susceptible to infection with NTHI. In this application, we propose the general hypothesis that RV increases airway epithelial cell expression of bacterial receptors, thereby predisposing the epithelium to bacterial infection. To address this, we propose the following Specific Aims: 1. Determine RV-induced changes in the airway epithelial cell membrane that potentiate bacterial adherence and/or internalization. We hypothesize that RV infection of airway epithelial cells increases the expression of new bacterial receptors. 2. Determine the effects of co-infection with RV and bacteria in vivo. We hypothesize that: (i) pre- infection of mouse airways with RV1B increases persistence of bacteria in infected mice;(ii) RV infection potentiates bacteria-induced inflammation in normal and elastase/LPS-treated """"""""COPD mice;"""""""" and (iii) RV increases the abundance of receptors for bacteria in vivo. Understanding the basic mechanisms by which viruses predispose the airways to secondary bacterial infection in COPD will improve existing preventive and therapeutic strategies for this disease.

Public Health Relevance

. Co-infections with virus and bacteria are common but poorly understood phenomena in patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Understanding how viral infections promote bacterial colonization and infection may lead to improved treatments that prevent progression of chronic lung disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Banks-Schlegel, Susan P
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Faris, Andrea N; Ganesan, Shyamala; Chattoraj, Asamanja et al. (2016) Rhinovirus Delays Cell Repolarization in a Model of Injured/Regenerating Human Airway Epithelium. Am J Respir Cell Mol Biol 55:487-499
Ganesan, Shyamala; Pham, Duc; Jing, Yaxun et al. (2016) TLR2 Activation Limits Rhinovirus-Stimulated CXCL-10 by Attenuating IRAK-1-Dependent IL-33 Receptor Signaling in Human Bronchial Epithelial Cells. J Immunol 197:2409-20
Ganesan, Shyamala; Comstock, Adam T; Kinker, Brenton et al. (2014) Combined exposure to cigarette smoke and nontypeable Haemophilus influenzae drives development of a COPD phenotype in mice. Respir Res 15:11
Unger, Benjamin L; Ganesan, Shyamala; Comstock, Adam T et al. (2014) Nod-like receptor X-1 is required for rhinovirus-induced barrier dysfunction in airway epithelial cells. J Virol 88:3705-18
Sajjan, Uma S (2013) Susceptibility to viral infections in chronic obstructive pulmonary disease: role of epithelial cells. Curr Opin Pulm Med 19:125-32
Ganesan, Shyamala; Unger, Benjamin L; Comstock, Adam T et al. (2013) Aberrantly activated EGFR contributes to enhanced IL-8 expression in COPD airways epithelial cells via regulation of nuclear FoxO3A. Thorax 68:131-41
Ganesan, Shyamala; Sajjan, Uma S (2013) Repair and Remodeling of airway epithelium after injury in Chronic Obstructive Pulmonary Disease. Curr Respir Care Rep 2:
Ganesan, Shyamala; Faris, Andrea N; Comstock, Adam T et al. (2012) Quercetin inhibits rhinovirus replication in vitro and in vivo. Antiviral Res 94:258-71
Chattoraj, Sangbrita S; Ganesan, Shyamala; Jones, Andrew M et al. (2011) Rhinovirus infection liberates planktonic bacteria from biofilm and increases chemokine responses in cystic fibrosis airway epithelial cells. Thorax 66:333-9
Chattoraj, Sangbrita S; Murthy, Rachana; Ganesan, Shyamala et al. (2010) Pseudomonas aeruginosa alginate promotes Burkholderia cenocepacia persistence in cystic fibrosis transmembrane conductance regulator knockout mice. Infect Immun 78:984-93

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