Sentinels: Living-Tissue for Doppler Detection of Emerging Microbial Threats

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Antibiotic resistance may soon make common antibiotics ineffective, and there is a pressing need to find new-generation antimicrobial therapies. A novel approach to test antimicrobial drugs is to measure the effect of the drug on the microbes within living cells. Light reflected by small collections of living cells can sense when the cells are infected with microbes because the infection changes how the internal cellular machinery works. The use of natural intracellular motions in cell clusters that act as “sentinels” is an unprecedented new approach to detecting microbes. To further educational goals, the effect of cellular motion on reflected light will be easily demonstrated to high-school students using simple laser pointers and cell phone cameras.To improve the discovery of new antimicrobial compounds, a new physics-based optical screening technology will be developed to fill this need. Biodynamic Doppler profiling (BDP) performs Doppler spectroscopy of intracellular motions inside living tissue using low-coherence digital holography. It is a sensitive probe of the subtle changes of cellular dynamics caused by drugs or infections inside tissue. Biodynamic profiling has already been used to predict the response of cancer patients to chemotherapy by applying cancer drugs on living ex vivo biopsies. In this project the team will develop Doppler detection of bacterial infection of living-tissue sentinels. The premise of living-tissue sentinels is that the sentinel behavior is modified by early infection before the bacteria can be characterized directly themselves. In the proposed research, biodynamic profiling of microbial invasion will be extended along several lines by: 1) enhancing the sensitivity of the sentinels to detect lower-level bacterial infections; 2) assembling a library of sentinel response functions to microbial infection; 3) performing quantitative assays of antibiotic resistance; 4) demonstrating the first detection of viral infections of tissue sentinels, and 5) developing new deep-learning algorithms to classify pathogenicity and predict therapeutic efficacy. The outreach objective is to enlist undergraduates in the research experience, including under-represented groups in research, and developing hands-on intracellular motility imaging experiments for grades 7-12.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.