Projects
Development of novel live attenuated vaccine (LAV) strains for Tuberculosis prevention
The Mtb genome encodes numerous genes that regulate production and expression of lipid virulence factors. The Martinot lab leverages screens using transposon mutagenized Mtb libraries (TnSeq) to develop attenuated Mtb strains for use as live attenuated vaccines. Dr. Martinot’s former work in the Rubin lab (Harvard School of Public Health) identified the virulence operon LprG-Rv1410 as critical for bacterial survival in the host. We showed this operon regulated triglyceride export in Mtb using lipidomics. After further characterization and testing of this strain as a vaccine in the Barouch Lab (Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center) we proposed to create second generation vaccine constructs eligible for testing in people. The lab is now working to further improve the safety profile of this vaccine and we have generated new LAV strains based on rationale deletion of Mtb virulence factors on the backbone of the LprG-Rv1410 mutation while also determining mechanisms of enhanced immunogenicity, and the role of IL-17, in protection. Using genetic tools such as TnSeq, we are also investigating bacterial vulnerabilities in the face of LAV vaccine protection.
Comparative pathology of COVID-19 infection for vaccine and drug efficacy testing
At the height of the COVID-19 pandemic, animal models for SARS-CoV-2 infection were needed to understand the basic biology of infection, potential therapeutic targets, and vaccine efficacy. The lab was fortunate to contribute to some of the earliest reports on key features of pathogenicity and immunological responses in hamsters and non-human primates. We currently work with the mouse-adapted SARS-CoV-2 model to investigate memory immune cell phenotypes developed during natural infection and vaccination. We are also working to establish mouse models of long COVID to establish risk factors and mechanisms of co-morbidities associated with severe disease. The lab is employing novel spatial biology, image analysis, and AI tools aiming to improve reproducibility and efficiency of pathological assessments in research models and to interrogate the spatial contribution of cell networks to regional tissue resident immune responses and pathology.
Spatial profiling in animal models of Mycobacterium tuberculosis infection to establish mechanisms of granuloma formation during natural infection, drug treatment, and following vaccination and challenge
Animal models of tuberculosis disease vary in their ability to model key features of tuberculosis granuloma formation. Our lab assesses tissue pathology in both drug-treated and vaccinated non-human primates and mice receiving novel drug and vaccine regimens to better establish predictive therapeutic endpoints. We utilize multimodal models of tissue response including highly multiplexed immune cell phenotyping coupled with spatial protein and transcriptional profiling to understand granuloma microenvironments. We aim to develop bacteriologic genetic tools to better understand how bacterial virulence factors contribute to granuloma microenvironments in the context of drug treatment and vaccination.
Animal models of human disease
As a board-certified veterinary pathologist, Dr. Martinot works closely with other investigators to evaluate tissue pathology to develop novel animal models to better understand the pathogenesis of diseases of global animal and human health importance. Currently, the lab works with investigators evaluating models of Clostridial disease, Lyme disease, avian influenza, and mpox, in addition to tuberculosis and SARS-CoV-2.
Tuberculosis Granuloma Atlas
The Tuberculosis Granuloma Atlas is an endeavor spear-headed by the Laboratory of Systems Pharmacology (Professor Peter Sorger) at Harvard Medical School and Tufts School of Medicine (Bree Aldridge). The project aims to understand the biology of granulomas, sites of chronic lung inflammation shaped by the biology Mycobacterium tuberculosis (Mtb) and host immune responses. Within a granuloma, Mtb growth is often limited, but this provides a niche from which bacteria can subsequently disseminate. The project also aims to build capacity for digital pathology in low and middle income countries (LIMC). As part of the Atlas, LSP investigators are assembling a cloud-based Tuberculosis Data Resource that will consolidate a rich collection of imaging and genomic data on TB granulomas and make the data publicly available. Dr. Martinot’s laboratory has contributed to annotations and investigations of human derived granulomas profiled as part of this project using spatial pathology tools.