Advisory Committee Chair
W Edward Swords
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Stenotrophomonas maltophilia is a Gram-negative bacillus that can act as an opportunistic pathogen in patients with respiratory diseases, including cystic fibrosis (CF) and ventilator-associated pneumonia. Infection with S. maltophilia is associated with worse lung function, but it remains unclear if this organism contributes directly to lung function decline. Lung infections are often polymicrobial, and S. maltophilia can be isolated from the lung with the key pulmonary pathogen Pseudomonas aeruginosa. In the first half of this work, we investigated the pathogenicity of S. maltophilia alone and during polymicrobial infection with P. aeruginosa. We used respiratory infections in mice to assess persistence and virulence and found that S. maltophilia transiently colonizes the lung accompanied by modest immune cell infiltration, and the expression of early inflammatory markers. Importantly, polymicrobial infection with P. aeruginosa resulted in a more virulent infection, with a higher burden of S. maltophilia in the lung, a longer time to clearance, and increased mortality. In the second half of this work, we focused on identifying the mechanisms underlying cooperativity between S. maltophilia and P. aeruginosa. We performed host and bacterial RNA sequencing from whole lung during murine pulmonary infection, using pathogen hybrid capture (PatH-Cap) to enrich for pathogen-specific transcripts. We found that the type IV pilus (T4P) was upregulated in S. maltophilia during polymicrobial infection. Further, we found that pre-treatment of cystic fibrosis bronchial epithelial cells iv (CFBEs) with P. aeruginosa significantly increases adherence of S. maltophilia. Deletion of a T4P-associated regulator in S. maltophilia prevented cooperativity on epithelial cells. Deletion of the elastase-encoding gene lasB in P. aeruginosa, a protease that contributes to loss of lung barrier integrity, similarly prevented dual-species cooperativity in cell and mouse models of infection. Taken together, these data suggest that the presence of P. aeruginosa promotes infection with S. maltophilia indirectly, by disrupting lung tissue integrity and increasing binding of S. maltophilia to the lung epithelium in a T4P-dependent manner. While previous work has demonstrated in vitro mechanisms of synergy between these two organisms, this is the first demonstration and mechanistic understanding of cooperative behavior between S. maltophilia and P. aeruginosa in vivo.
McDaniel, Melissa Skye, "Synergy Between Stenotrophomonas Maltophilia and Pseudomonas Aeruginosa During Polymicrobial Airway Infections" (2022). All ETDs from UAB. 180.