The role of PMNs and CD73 in host-resistance against S. pneumoniae / influenza A virus co-infection - ABSTRACT Following influenza A virus (IAV) infection, the risk for subsequent pneumococcal pneumonia caused by Streptococcus pneumoniae is enhanced 100-fold. Host aging is associated with more severe outcomes, thus novel approaches that boost resistance to infections are needed. Our goal is to elucidate how IAV infection alters the responses of polymorphonuclear leukocytes (PMN) and the extracellular adenosine (EAD) pathway across host age, during pneumococcal pneumonia. Background: Following primary S. pneumoniae infection, PMNs, which are innate immune cells whose function declines with age, are required for controlling bacterial numbers. EAD, which is produced from breakdown of ATP leaking from injured cells by CD73, controls PMN responses during infection. We found that CD73 was crucial for host resistance and PMN pulmonary influx as well as anti-microbial function during primary pneumococcal pneumonia. Importantly, old mice had significant changes in expression of EAD enzymes and receptors and targeting this pathway reversed the age-driven susceptibility to primary pneumococcal infection. In humans, pneumococcal carriage in the nasopharynx is a prerequisite to invasive diseases. Further, IAV infection of the respiratory tract where it triggers epithelial damage and impairs host antibacterial responses is key for the lethal synergy of co-infection. However, animal models incorporating the evolution of S. pneumoniae from colonizer to pathogen during IAV co-infection while mimicking the severe disease seen in humans, are lacking. Therefore, we established an optimized model where mice are intra-nasally colonized with pneumococci followed by IAV infection of the nasopharynx and lungs. This model resulted in obvious signs of illness and lethality in half of the young mice and importantly, reproduced the susceptibility of aging, where significantly more old mice displayed severe clinical signs and succumbed to lethality compared to young controls. Using this model, we strikingly found that the role of CD73 was reversed, where CD73 became detrimental to resistance of young hosts to co-infection. This highlighted that IAV infection triggers profound changes in the interaction of the host with pneumococci. However, the effect of polymicrobial infections on host responses and the mechanisms behind that remain a gap in the field. Here we will use our improved model to test the Hypothesis that IAV infection alters CD73-mediated control of PMN responses to pneumococcal infection across host age using two specific Aims: 1) Test the effect of age and IAV infection on PMN responses during secondary pneumococcal pneumonia; 2) Test the role of CD73 in PMN responses and host resistance to S. pneumoniae/IAV co-infection. Significance/innovation/ relevance: Using this physiologically relevant model that mimics aspects of human disease to elucidate how PMN responses change in mono vs polymicrobial infections across host age and the role of CD73 in that, has the potential to uncover novel pathways that drive host susceptibly to infection. This work can lead to highly innovative approaches incorporating adenosine-based drugs to combat this serious lung disease.
