ORCID

http://orcid.org/0000-0002-8744-8136

Date of Award

Winter 12-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Bacteria live in, on, and around us. These bacteria affect human health through beneficial commensal interactions that promote normal development and through harmful infections or perturbations leading to disease. Understanding the prevalence, spread, and resilience of these bacteria in humans and human environments is critical to clinical medicine and epidemiology. I investigated environmental and human resident bacteria to understand dynamics in bacterial communities and how these dynamics may impact human health.Hospitals are one critical location of human-bacterial interactions. Bacteria can contaminate hospital surfaces from patients or environmental sources and subsequently transmit from surfaces to vulnerable patients. I analyzed bacteria from intensive care unit surfaces to understand the scope of hospital contamination. These bacteria included common nosocomial pathogens, rare opportunistic pathogens, and novel taxa. My genotypic and phenotypic analysis revealed high resistance to therapeutic antimicrobials and widespread resistance gene exchange across disparate taxa. I also discovered significant spatial and temporal associations both for highly related and for unrelated bacteria. The association between related “clonal” bacteria narrows potential contamination sources while the association between unrelated bacteria suggests a cooperative survival strategy. I validated this cooperative interaction in these bacterial species and found synergistic biofilm growth interactions. The human gut is another critical location of human-microbe interaction. Disturbance of microbial communities in the human gut (the gut microbiota) can lead to disease. I investigated gut microbiota disturbances in a pediatric cohort treated with antibiotics and in an adult cohort venturing on international travel. HIV exposed, uninfected (HEU) infants receive prophylactic cotrimoxazole antibiotics, but this treatment's effects on developing HEU infant gut microbiotas and resistance genes were unknown. I analyzed metagenomes longitudinally collected from HEU infants randomized to receive prophylactic cotrimoxazole treatment or placebo. Cotrimoxazole treatment did not significantly impact taxonomic or functional pathway alpha-diversity, but it did increase resistance gene prevalence and alpha-diversity. In contrast, cotrimoxazole treatment decreased inter-individual gut microbiome taxonomic, functional taxonomic, and resistance gene beta-diversity. These results are consistent with persistent antibiotic selection pressure. Travel may perturb the gut microbiota and its resistance genes through exchange between environmental and gut resident bacteria. To understand travel's effects on resistance genes in the gut microbiota I analyzed metagenomes from Nederlanders before and after they visited Africa or Asia. With markers for resistance genes from established databases and functional selections, I found that travel increased resistance gene acquisition and abundance. Some acquired resistance genes like blaCTX-M (an extended spectrum beta-lactamase) confer resistance to common therapeutic antimicrobials, and others like mcr-1 neutralize antibiotics of last resort. Destination was a major determinant in shaping these resistance gene dynamics; individuals traveling to similar regions acquired similar resistance genes. Microbiota taxonomic changes did not explain resistance gene increases, but increased detection of mobilizable elements in the highest risk destinations suggest possible gene transfer. In this dissertation, I examined the distribution of bacteria in a critical human environment, the impact of antimicrobial perturbation on vulnerable HEU infants, and the impact of environment change on resistance gene carriage. Each project demonstrates the ubiquity of bacteria in and around humans. Future studies will continue to detail the impacts of bacteria and resistance genes on human health and lead to intervention opportunities.

Language

English (en)

Chair and Committee

Gautam Dantas

Committee Members

Megan T. Baldridge

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