HSDM Scholarly Articles

Leveraging systems biology approaches, we illustrate how metabolically distinct species of Clostridia protect against or worsen Clostridioides difficile infection in mice by modulating the pathogen's colonization, growth, and virulence to impact host survival. Gnotobiotic mice colonized with the amino acid fermenter Paraclostridium bifermentans survive infection with reduced disease severity, while mice colonized with the butyrate-producer, Clostridium sardiniense, succumb more rapidly. Systematic in vivo analyses revealed how each commensal alters the gut-nutrient environment to modulate the pathogen's metabolism, gene regulatory networks, and toxin production. Oral administration of P. bifermentans rescues conventional, clindamycin-treated mice from lethal C. difficile infection in a manner similar to that of monocolonized animals, thereby supporting the therapeutic potential of this commensal species. Our findings lay the foundation for mechanistically informed therapies to counter C. difficile disease using systems biology approaches to define host-commensal-pathogen interactions in vivo.

Multidrug-resistant (MDR) infections have been identified globally among men who have sex with men (MSM). The highly drug-resistant phenotype often confounds initial antimicrobial therapy, placing patients at risk for adverse outcomes, the development of more drug-resistant strains, and additional treatment failures. New macrolide-resistant strains complicate treatment further as azithromycin is a next-in-line antibiotic for MDR strains, and an antibiotic-strain combination confounded by gaps in validated clinical breakpoints for clinical laboratories to interpret macrolide resistance in We present the first high-resolution genomic analyses of 2,097 U.S. isolates, including those from MDR outbreaks. A sentinel shigellosis case in an MSM patient revealed a strain carrying 12 plasmids, of which two carried known resistance genes, the pKSR100-related plasmid pMHMC-004 and spA-related plasmid pMHMC-012. Genomic-epidemiologic analyses of isolates revealed high carriage rates of pMHMC-004 predominantly in U.S. isolates from men and not in other demographic groups. Isolates genetically related to the sentinel case further harbored elevated numbers of unique replicons, showing the receptivity of this lineage to plasmid acquisition. Findings from integrated genomic-epidemiologic analyses were leveraged to direct targeted clinical actions to improve rapid diagnosis and patient care and for public health efforts to further reduce spread. Multidrug-resistant isolates with resistance to macrolides are an emerging public health threat. We define a plasmid/pathogen complex behind infections seen in the United States and globally in vulnerable patient populations and identify multiple outbreaks in the United States and evidence of intercontinental transmission. Using new tools and sequence information, we experimentally identify the drivers of antibiotic resistance that complicate patient treatment to facilitate improvements to clinical microbiologic testing for their detection. We illustrate the use of these methods to support multiagency efforts to combat multidrug-resistant using publicly available tools, existing genomic data, and resources in clinical microbiology and public health laboratories to inform credible actions to reduce spread.