Host-pathogen interactions as a new paradigm for infectious disease therapy

The spread of antibiotic resistance poses immense risks to human health on a global scale. And yet, the antibiotic pipeline appears to have slowed dramatically over the last several decades. At the same time, World Health Organization analyses suggest that current drug pipelines will likely be insufficient, by themselves, to overcome antimicrobial resistance seen across human pathogens. The development of whole new strategies and therapeutic tactics, rather than single drugs, has become a pressing need.

The project will apply to infectious disease some of the lessons learned in cancer immunotherapy where it has become apparent that patient microbiomes influence patient outcomes via a microbiome-immune system interface. This project aims to answer fundamental biological questions about how patient microbiomes influence antimicrobial drug efficiencies by modulating patient immune systems; by doing so, it will have the potential to create a new paradigm for how infectious diseases can be more effectively treated.

This project will leverage diverse expertise from across the UW–Madison to make revelatory discoveries about host-pathogen interactions by: 1) determining how minocycline treated macrophages exert antibacterial activity against the human pathogen Acinetobacter baumannii; 2) deciphering how small molecules produced by the human gut microbiota trigger and/or amplify the antibacterial capabilities of the immune system; and 3) identifying (via TnSeq and CRISPRi approaches) conditionally essential genes in the model pathogen Listeria monocytogenes that are especially vulnerable to innate immune responses.

Beyond its translational impact on infectious disease therapies, this work will also increase understanding of the molecular mechanisms governing innate immunity.

PRINCIPAL INVESTIGATOR

Timothy Bugni, professor of pharmacy

CO-PRINCIPAL INVESTIGATOR

Warren Rose, associate professor of pharmacy

Nasia Safdar, professor of medicine

JD Sauer, associate professor of medical microbiology and immunology

CO-INVESTIGATOR

Claire O’Leary, assistant professor of pediatrics

Jason Peters, assistant professor of pharmacy