Multi-omics analysis of host responses in tracheal tissues of pigs after infection with a human- and swine-adapted influenza A viruses

Influenza is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. During the past century, four global IAV pandemics have claimed millions of human lives. The emergence of IAV pandemics is attributed to zoonotic transmission from avian or swine sources, followed by reassortment events. To understand the underlying molecular mechanisms behind infection, we need more knowledge in how the host reacts to different types of influenza strains, which can be both host-adapted and non-adapted. Even though most infections are assumed to be recognized and controlled by the innate immune system, viral recognition and immune responses in the respiratory tract are poorly understood.

To study the molecular landscape of infection and host response, we inoculated two groups of 12 pigs with 10^7 TCID50/ml of swine- (swH1N1) or human-adapted (huH1N1) influenza A virus, and one control group of 6 pigs with culture medium. We collected tracheal tissues three days post infection and investigated the host response by global proteomics, RNA-seq, high-throughput microfluidic qPCR, and immunohistochemistry.

With our results, we describe a classical antiviral immune response with induction of IFNs and ISGs in tracheal tissues after infection with both swH1N1 and huH1N1, though with differences in dynamics and expression levels after infection with the two strains. We find that infection with the swine-adapted strain results in necrotizing tracheitis and regulation of other host metabolic factors in the trachea, such as cytoskeleton elements, the pyrimidine metabolism, apoptosis, and factors involved in the JAK-STAT pathway.

We conclude that host factors centrally involved in the early orchestration of the antiviral immune response are tightly regulated in the trachea post infection. Expression levels, dynamics, histological findings, and regulation of metabolic host factors were altered depending on adaptation level of the virus, highlighting that host adaptation and the risk of cross-species infection might be connected to modulation of host factors by the virus.