The role of Krt5+p63+ lung progenitor cells in alveolar regeneration upon Influenza A/ H5N1 virus infection

Identification: Cheung, Man Chun



The role of Krt5+p63+ lung progenitor cells in alveolar regeneration upon Influenza A/ H5N1 virus infection
Cheung Man Chun1, Kenrie PY Hui1, Wa Xian2, Frank McKeon3, John M Nicholls4, JS Malik Peiris1, Michael CW Chan1
1School of Public Health, LKS Faculty of Medicine, HKU; 2Center for Stem Cell & Regenerative Medicine, The University of Texas Health Science Center at Houston; 3Department of Biology and Biochemistry, University of Houston; 4Department of Pathology, LKS Faculty of Medicine, Queen Mary Hospital, HKU
Influenza A/H5N1 virus infection damage alveolar epithelium and there is a special stem cell population, Krt5+ p63+ lung stem/ progenitor cell (LPC), responsible for the recovery process. This study is to investigate the possible mechanism involved in lung regeneration upon influenza A virus infection using in vitro and in vivo model. We showed that the LPC response to low pathogenic influenza virus infection eg. H1N1pdm which expand extensively upon infection at damaged site and convert to alveolar epithelial cells. This process was evidenced by some in vitro and in vivo studies which showed that the gene expression of Krt5 and p63 were up-regulated upon H1N1pdm virus infection. These two genes were also found highly expressed in DASC isolated from human lungs. However, we showed that the highly pathogenic influenza virus H5N1 inhibited the gene and protein expression of Krt5 and p63 upon infection. This inhibition cause the delay of recovery in infected mice which turns with higher mobility. Besides, in vitro study suggested that DASC can serve as the target of influenza virus and H5N1 virus replicate with higher rate than those found in H1N1pdm. DASC undergo cell death more extensively upon in vitro infection and therefore may cause an early deterioration of stem cell population for recovery. Furthermore, mice recovered from H5N1 infection showed an alternative pathway for recovery. Although Krt5 expression was inhibited, the regeneration of alveolus was observed at a later time point in the in vivo infection experiment. This suggested that H5N1 virus inhibit LPC population expansion, while on the other hand induce the recovery via another progenitor cells population. To conclude, H1N1 and H5N1 infection cause different fate of LPC: H1N1 induce the proliferation and differentiation of LPC; H5N1 deteriorate LPC population, but are able to employ another progenitor cell to proliferate and differentiate during the recovery of alveolus.



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