Project 452361

In 2009, influenza A H1N1 re-emerged as a global pandemic, but now this deadly virus has become endemic and despite 11 years of annual vaccinations against H1N1 this subtype continues to be a major cause of severe lung failure and mortality. For example, the 2018/19 flu watch (Public Health Agency of Canada) reported that 69% of the 6,602 influenza A virus infections and 68% and of 3,525 hospital admissions, were H1N1, including 613 ICU admissions and 224 deaths. Moreover, 80% of the 402 pediatric hospital admissions were H1N1. Thus, H1N1 represents a severe and dominant seasonal infectious pneumonia which remains a threat to global health. Although H1N1 re-emerged over a decade ago, the pathophysiology of this deadly infection remains under investigated in relation to connections between neutrophils and negative outcomes following H1N1 pneumonia in vivo. Three important factors related to negative outcomes following H1N1 are the development of acute respiratory distress syndrome (ARDS), acquiring a secondary infection, and biological sex. Importantly, ARDS is commonly caused by H1N1. Additionally, H1N1 is more associated with secondary Aspergillus fungal pneumonias (60% H1N1-associated vs other influenzas) for which 30% of co-infection occurred in previously healthy individuals and only 8% had COPD and 9% used chronic steroids. The role of sex as a variable in H1N1 infections remains unclear, but in 2009, more females in the US, Canada, and Japan had severe H1N1 infections and worse outcomes. We believe that neutrophils are a major cellular culprit driving negative outcomes during H1N1 pneumonia. In this grant we will study how neutrophils, the major innate immune cells, contribute to important severe outcomes of H1N1 influenza pneumonia.