Fungal dysbiosis regulation of post-influenza bacterial pneumonia

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Project summary The discovery of antibiotics in the early 20th century opened up a new era of medical treatment. Indeed, many present-day infections that are easily treated could have had deadly consequences in the absence of antibiotics. The overuse of these medicines has been a concern in the recent years due to the selection pressures that have allowed resistant bacterial species to emerge. However, another untoward consequence of antibiotics is that treatment can alter the commensal organisms of the body, which we now understand has important homeostatic functions. Indeed, many bacterial, fungal, and viral organisms that live within tissues of the body can condition the immunologic system, and an altered microbiome, such as with antibiotic use, can contribute to the development of many acute and chronic pathologies. As such, our studies demonstrate that giving prophylactic antibiotics during influenza infection (a common clinical practice) increases the risk for development of a secondary bacterial pneumonia, which is major reason for the morbidity and mortality from the initial viral illness. Although antibiotics have direct effects on decreasing the abundance and diversity of the bacterial microbiome, the newly available niche with reduced nutritional competition provides an opportunity for expansion of fungal communities. Our data demonstrates that fungal dysbiosis is a driver of worsened secondary bacteria pneumonia after influenza infection. Moreover, we find that antibiotic-induced fungal dysbiosis increases lung inflammation including augmented interferon-γ levels, a cytokine that can clear detrimental effects that contribute to post- influenza bacterial pneumonia. Finally, we find that eosinophils partially modulate the augmented lung injury, and increased gut S. cerevisiae correlates with the phenotype induced by fungal dysbiosis. Altogether, these findings support our central hypothesis that antibiotic treatment during influenza infection causes fungal dysbiosis that has lung immunomodulatory effects, which in turn increases the host susceptibility to bacterial superinfection. We will test this hypothesis in the following aims: Aim 1. Determine if fungal dysbiosis alters innate immune functions in post-influenza pneumonia. Aim 2. Evaluate how fungal dysbiosis causes lung eosinophilia to augment lung inflammation. Aim 3. Investigate the role of S. cerevisiae in mediating lung injury from post-influenza MRSA pneumonia.