This application is for an individual fellowship for an MD-PhD student, with a research training plan designed to aid his long-term goal of becoming an independent physician-scientist in the field of innate immunity and inflammation. The inflammatory response is particularly important and carefully regulated in the respiratory tract, which must respond to a wide range of microbial insults while also preserving the gas-exchange function of the lungs. Bacterial colonization is rapidly countered by an inflammatory response, which includes the rapid release of mucins. Secreted mucins are heavily decorated with sialic acid, a carbon source that some bacteria, including the important respiratory pathogen pneumococcus, can catabolize. Preliminary data show that inflammation promotes pneumococcal growth in mice, and that the inflammatory response to bacterial colonization includes mucin secretion. The central hypothesis of this application is that airway inflammation promotes bacterial growth by providing sialylated mucin as a nutrient source.
In Aim 1, a murine model of colonization will be used to determine the host and bacterial factors that contribute to inflammatory mucin secretion in the upper respiratory tract. Using a novel flow cytometric assay, we will determine whether this inflammatory response can promote bacterial growth in vivo, and whether that growth is dependent on sialylated mucin secretion.
In Aim 2, we will determine whether influenza infection promotes sialylated mucin secretion, and define the innate signaling pathways required for this inflammatory response. We will determine whether sialic acid generated by influenza-induced inflammation promotes bacterial growth. These experiments will determine how the innate inflammatory response to pneumococcal colonization (Aim 1) and viral infection (Aim 2) promotes bacterial growth by providing a nutrient source through mucin secretion.
Despite antibiotics and vaccines, acute respiratory infections remain a major source of morbidity and mortality worldwide. This application proposes to study how the inflammatory response in the airway may promote rather than inhibit bacterial growth. Understanding the interplay between host and pathogen better is an important basic step in designing new therapeutic strategies for acute respiratory infections.
|Siegel, Steven J; Weiser, Jeffrey N (2015) Mechanisms of Bacterial Colonization of the Respiratory Tract. Annu Rev Microbiol 69:425-44|
|Siegel, Steven J; Tamashiro, Edwin; Weiser, Jeffrey N (2015) Clearance of Pneumococcal Colonization in Infants Is Delayed through Altered Macrophage Trafficking. PLoS Pathog 11:e1005004|
|Siegel, Steven J; Roche, Aoife M; Weiser, Jeffrey N (2014) Influenza promotes pneumococcal growth during coinfection by providing host sialylated substrates as a nutrient source. Cell Host Microbe 16:55-67|