All ETDs from UAB

Advisory Committee Chair

W Edward Swords

Advisory Committee Members

William Benjamin

Susan Birket

Megan R Kiedrowski

Jessica A Scoffield

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) School of Medicine

Abstract

Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative commensal of the healthy nasopharynx; however, this organism can function as an opportunistic pathogen as a result of disruptions to the microbiome, as is the case in cystic fibrosis (CF) disease. People with CF experience changes in microbial residents of the respiratory tract over the course of their lifespan, seen in shifts from early-life pathogens, such as NTHi, to late-stage pathogens, such as Pseudomonas aeruginosa, that accompany a decrease in organismal diversity of the microbiome. In this work, we characterized the pathogenicity of NTHi alone and in polymicrobial respiratory infections. Using CF specific isolates of NTHi, we compared genomic and phenotypic factors of these strains to a well-characterized laboratory strain of NTHi. Through mouse respiratory infections, we identified one NTHi isolate that persists in the airways longer than other tested strains. As lung infections are polymicrobial in nature, we investigated the inter-species interaction between NTHi and P. aeruginosa in a mouse model. We sequentially introduced these organisms, representing the way they would be temporally acquired in the CF lungs. We found that preceding NTHi infection leads to decreases in bacterial burden, inflammatory cytokine response, and severity lung tissue damage caused by P. aeruginosa compared to a singlespecies P. aeruginosa infection. iv Finally, we evaluated polymicrobial infections in CF mouse models, testing bacterial inter-species interactions within this disease specific environment. We saw that sequentially introduced NTHi followed by P. aeruginosa reduced the infection consequences of P. aeruginosa similarly to that of non-CF mice. We also saw that dualinfection with Stenotrophomonas maltophilia, another late-stage pathogen, and P. aeruginosa led to a more virulent infection than either organism alone, a previously established cooperative phenotype. For polymicrobial infection experiments, we saw that the genetic background of mice may influence the response to infection more than the specific underlying CF mutation. Herein, we characterize an example of immune priming against P. aeruginosa, where consequences following dual-infection are reduced, as well as inter-species cooperativity with P. aeruginosa, where consequences of dual-infection are more severe. Overall, these data suggest that polymicrobial relationships within the lungs likely influence CF disease progression.

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