Human Rhinovirus Proteinase 2A Induces Th1 and Th2 Immunity in COPD

Singh, Manisha; Lee, Seung-Hyo; Porter, Paul; Xu, Chuang; Ohno, Ayako; Atmar, Robert L.; Greenberg, Stephen B.; Bandi, Venkata; Gern, Jim; Amineva, Svetlana; Aminev, Alex; Skern, Tim; Smithwick, Pamela; Perusich, Sarah; Barrow, Nadia; Roberts, Luz; Corry, David B.; Kheradmand, Farrah

BACKGROUND: Tobacco related lung diseases including chronic obstructive pulmonary disease (COPD), are major causes of lung-related disability and death worldwide. Acute exacerbation of COPD (AE-COPD) is commonly associated with upper and lower respiratory viral infections and may result in respiratory failure in those with advanced lung disease. OBJECTIVE: We sought to determine the mechanism underlying COPD exacerbation, and host response to pathogen-derived factors. METHODS: Over a 24 months period, we assessed the viral causes for upper and lower respiratory infections in COPD (n=155) and control (n=103) subjects. We collected nasal and bronchoalveolar lavage (BAL) fluid and peripheral blood under baseline and exacerbated condition. We determined the effect of human rhinovirus (HRV) proteinases on T cell activation in humans, and in mice. RESULTS: HRVs are isolated from nasal and lung fluid from subjects with AE-COPD. BAL fluid, and CD4 T cells from COPD patients exhibited a type 1 T helper (Th1), and Th2 cell cytokine phenotype during acute infection. HRV-encoded proteinase 2A activated monocyte-derived dendritic cells in vitro, and induced strong Th1, and Th2 immune responses from CD4 T cells. Intranasal administration of recombinant rhinovirus proteinase 2A in mice resulted in an increase in airway hyperreactivity, lung inflammation, and IL-4 and IFN-γ production from CD4 T cells. CONCLUSION: Our findings suggest that patients with severe COPD show Th1 and Th2 bias responses during AE-COPD. HRV-encoded proteinase 2A, like other microbial proteinases, could provide a Th1 and Th2-biasing adjuvant factor during upper and lower respiratory infection in patients with severe COPD. Alteration of the immune response to secreted viral proteinases may contribute to worsening of dyspnea and respiratory failure in COPD.