Long-term survival of influenza virus infected club cells drives immunopathology

Nicholas S. Heaton, Ryan A. Langlois, David Sachs, Jean K. Lim, Peter Palese, and Benjamin R. tenOever

 Journal of Experimental Medicine 211, 9, 1707-1714, 2014

Speaker: Ming-Yang Wu (吳明陽)                                     Time: 13:00~14:00, Dec 10, 2014

Commentator: Dr. Guey-Chuen, Perng (彭貴春 老師)       Place: Room 601

Abstract:

Influenza A virus (IAV) is well-known to cause devastating pandemics. Several kinds of cells, such as cilated epithelial cells and type I and II alveolar cells, within respiratory tract (RT) are infected with IAV. Infected cells are removed by two major ways. One is cell apoptosis/necrosis, the other is innate and adaptive arms of the immune system that can clear virus. Clearance of IAV infection can come at the price of abnormal immune-mediated disease that cause tissue damage [1]. Accordingly, the degree of RT pathology is expected to reflect both the extent of virus replication and the magnitude of the host immune response. In this study, the author uses IAV expressing Cre recombinase (IAV-Cre) and transgenic reporter mice that harbor red fluorescent protein (RFP), tdTomato [2], to find out the long-term surviving cells within the lung. When transgenic mice infected with IAV-Cre, IAV-infected cells will express RFP, called tdTomato⁺ cells. Surprisingly, tdTomato⁺ cells can be detected in the RT up to day 21 post-infection (p.i.), long after viral replication is stalled and virus-infected cells are cleared. They identify these residualtdTomato⁺ cells are located at bronchi (small airway), the same physiological location where club cells  exist. Remarkably, no virus was detected at day 10 p.i., that is, club cells were “cured.” Theyobserved an increase in magnitude of  interferon stimulated genes (ISGs) in club cells, and production of inflammatory chemokines, suggesting that these cells may contribute to RT pathology. Supporting this idea, selective depletion of club cells reduce the RT damage. However, severe RT injury is associated with infection of alveolar cells, which are not “cured” in this model, so the contribution of club cells in IAV pathogenesis remains to be determined.

Reference:

1.    Damjanovic, Daniela, et al. "Immunopathology in influenza virus infection: uncoupling the friend from foe." Clinical Immunology 144.1 (2012): 57-69.

2.   Kasparek, Petr, et al. "Transgenic mouse model expressing tdTomato under involucrin promoter as a tool for analysis of epidermal differentiation and wound healing." Transgenic research 21.3 (2012): 683-689.