Early apoptosis of porcine alveolar macrophages limits avian influenza virus replication and pro-inflammatory dysregulation.

Pengxiang Chang,Suresh V Kuchipudi,Kin-Chow Chang,Kenneth H Mellits,Sujith Sebastian,Holly Shelton,Joe James,Jinhua Liu

doi:10.1038/srep17999

Abstract

Pigs are evidently more resistant to avian than swine influenza A viruses, mediated in part through frontline epithelial cells and alveolar macrophages (AM). Although porcine AM (PAM) are crucial in influenza virus control, their mode of control is unclear. To gain insight into the possible role of PAM in the mediation of avian influenza virus resistance, we compared the host effects and replication of two avian (H2N3 and H6N1) and three mammalian (swine H1N1, human H1N1 and pandemic H1N1) influenza viruses in PAM. We found that PAM were readily susceptible to initial infection with all five avian and mammalian influenza viruses but only avian viruses caused early and extensive apoptosis (by 6 h of infection) resulting in reduced virus progeny and moderated pro-inflammation. Full length viral PB1-F2 present only in avian influenza viruses is a virulence factor that targets AM for mitochondrial-associated apoptotic cell death. With the use of reverse genetics on an avian H5N1 virus, we found that full length PB1-F2 contributed to increased apoptosis and pro-inflammation but not to reduced virus replication. Taken together, we propose that early apoptosis of PAM limits the spread of avian influenza viruses and that PB1-F2 could play a contributory role in the process.

Highlights

Pigs are more resistant to avian than swine influenza A viruses, mediated in part through frontline epithelial cells and alveolar macrophages (AM)
Given the ability of pigs to effectively resist low pathogenicity avian influenza (LPAI) and highly pathogenic avian influenza (HPAI) virus infections, and the functional importance of AM in the control of influenza virus infection we determined the relative resistance of porcine AM (PAM) to infections with avian and mammalian influenza viruses in connection with their permissiveness to virus replication and host pro-inflammatory response
PAM were infected with two avian, and three mammalian (A/swine/England/117316/1986 [swine H1N1], human A/USSR/77 [USSR H1N1] and human A/California/07/2009 [pandemic H1N1 2009]) influenza viruses for 5h at multiplicity of infection (MOI) of 1.0, based on virus titrations on Madin Darby canine kidney (MDCK) cells

Summary

Introduction

Pigs are more resistant to avian than swine influenza A viruses, mediated in part through frontline epithelial cells and alveolar macrophages (AM). Avian influenza virus infections in pigs, on the other hand, appear to be clinically mild compared with swine influenza virus infections. Depletion of AM (with the use of dichloromethylene diphosphonate as liposome encapsulated clodronate) in lungs of pigs resulted in severe clinical signs and 40% mortality from human H1N1 virus infection[9]. Depletion of murine AM in lungs of C57BL/6 mice resulted in severe pneumonia with dysregulated cytokine and chemokine production, and in 100% mortality from BJx-109 virus infection which was an engineered H3N2 virus (with PR8 [A/PR/8/34, H1N1] core proteins)[11]. Given the ability of pigs to effectively resist LPAI and HPAI virus infections, and the functional importance of AM in the control of influenza virus infection we determined the relative resistance of PAM to infections with avian and mammalian influenza viruses in connection with their permissiveness to virus replication and host pro-inflammatory response

Methods

Results

Conclusion