Sabine Ehrt
Weill Medical College of Cornell University, NY·Microbiology & Immunology
Tuberculosis still sickens and kills large numbers of people worldwide, and the bacterium that causes it, Mycobacterium tuberculosis (Mtb), keeps changing in response to antibiotics and to the human immune system. Work here asks how Mtb survives these pressures: which of its genes are essential inside a living host, how it rewires its metabolism when nutrients are scarce, how it tolerates damaged proteins and RNAs, and which mutations found in patient samples actually change disease or drug response.
- Fields
Microbiology & Immunology
Genetics
Medicine & Clinical Research
- Topics
tuberculosis
Mtb
antibiotic resistance
- Grants
- 8 known grants, through Apr 2031
What they work on
- Test whether mutations found repeatedly in patient strains in the metabolic enzymes PPGK, PEPCK and LDH change M. tuberculosis disease progression and antibiotic susceptibility, and identify the clinical pressures and interacting mutations that select them.
- Determine how naturally occurring variants in the ESX-1 type VII secretion system — both in the export machinery itself and in an RNA-based cascade controlling its genes — alter virulence and drug sensitivity, using mouse infection and associations with patient outcomes.
- Identify post-transcriptional systems that let M. tuberculosis tolerate aberrant RNAs, and find the adapter proteins that deliver misfolded proteins to Clp proteases, using genetic screens and candidate-based approaches.
- Test whether these protein- and RNA-handling systems offset the fitness costs of mutations that are common in clinical M. tuberculosis strains.
- Map genes and local codon clusters under diversifying selection across thousands of global M. tuberculosis genomes, using local dN/dS analysis plus phylodynamics and association testing to find lineage-specific selection and epistasis.
- Validate candidate drug targets and genetic and chemical-genetic interactions in acute, chronic and low-burden relapse mouse infections, and identify genes whose inactivation rapidly kills M. tuberculosis in vivo.
- Test whether conditional knockdown of thioredoxin reductase (TrxB2) and biotin protein ligase (BPL) blocks infection in C3HeB/FeJ mice, which form human-like caseating granulomas, and whether such lesions more often harbor latent bacilli that relapse.
- Determine whether the glycolytic enzyme phosphofructokinase (PFK) and the gluconeogenic enzyme PEPCK are required for M. tuberculosis to establish and sustain infection in nonhuman primates, using deletion and conditional knockdown mutants across lesion types.
More about the research
A second thread is methodological: building mouse infection models that reproduce the varied, damaged lung tissue seen in people, so that candidate drug targets can be tested under realistic conditions.
Why it matters
New tuberculosis drugs are badly needed, and candidate targets often fail because they were validated in animals whose lung lesions do not resemble human disease. By testing bacterial enzymes and genes in mice with human-like granulomas and in nonhuman primates, this work could identify targets whose inhibition shortens treatment. Mapping the mutations that patients' strains are actually acquiring could also help flag more transmissible or drug-resistant variants and inform diagnostics, vaccines and treatment choices.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Patricia A Champion
University of Notre Dame, IN·Microbiology & Immunology
Identify how Mycobacterium marinum senses the detergent tyloxapol, combining unbiased genetic screens with hemolysis assays, and test whether tyloxapol suppresses ESX-1 membrane-breaking activity during macrophage infection.
Bree Aldridge
Weill Medical College of Cornell University, NY·Microbiology & Immunology
Generate single-cell profiles of Mycobacterium tuberculosis responding to drug treatment and to gene knockdown, working with the four program projects on the treatments and genes each one studies.
Karl Schmitz
University of Delaware, DE·Biochemistry
Use phosphoproteomics to identify stress conditions that raise phosphoarginine (pArg) levels in mycobacteria, test whether pArg is needed for stress tolerance, and find the arginine kinases and phosphatases that add and remove it.
The school
Weill Medical College of Cornell University: 35 labs on PI Pages, $1.6B a year on research, 59 research doctorates a year.
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