A major focus of the laboratory has been defining the mechanisms by which mycobacterial populations diversify and the functional consequences of this heterogeneity. We have demonstrated that Mtb is relatively genetically stable yet we, and others, have shown that there is dramatic phenotypic heterogeneity at a single cell level. We have found that this phenotypic variation arises through many mechanisms, including asymmetric growth and division and DNA methylation-based regulation of gene expression and…
The COVID-19 pandemic has challenged the US healthcare system in unprecedented ways, highlighting the importance of data-informed public health policymaking and healthcare management within and across states. Under Dr. Fortune’s leadership, HSPH is working together with Siemens Healthineers to explore how diagnostic data collected routinely at high temporal and spatial resolution across the US might be used to better understand how the COVID-19 pandemic has affected healthcare systems nationwide. Furthermore, the team…
Immune Response: Mechanisms of Host Protection Against TB We need new and effective vaccines to control the ongoing TB epidemic, but we lack the deeper understanding of the mechanisms by which the human immune response can kill TB and prevent disease needed to design these life-saving therapeutics. (I/Dr. Fortune) serves as the Principal Investigator for a 7-year NIH-funded contract called Immune Mechanisms of Protection against Tuberculosis (IMPAcTB), which aims to…
It takes months to treat even drug susceptible TB. Even in culture, most TB cells die quickly in the face of drug but some TB bacteria are persistently tolerant of drug. Here we seek to understand why genetically identical TB bacilli are very difficult to eliminate with antibiotics while others are quite susceptible. In addition, we seek to identify genetic mutations that put some TB strains at risk of acquiring drug resistance and thus…
One of the hallmarks of TB infection is the variability in infection outcome. We see this recapitulated at a lesional level within an individual host and at a single cell level. We are using single cell approaches including dynamic imaging and single cell RNAseq to identify correlates and drivers of these differences in infection outcome.
We seek to identify novel mechanisms by which the bacterium establishes and maintains phenotypically distinct subpopulations. Specifically, we are interested in DNA methylation and post-translational modification of bacterial nucleoid associated proteins as bases of epigenetic inheritance. Other work focuses on the regulatory roles of ncRNAs and housekeeping proteases.
Pulse-chase labeling of the cell wall in mycobacteria We use this protocol to pulse chase label the cell wall in mycobacteria. This experiment allows us to establish the sites of new growth in the chase portion of the experiment. For examples, please see above and Aldridge et al. Science 2012. Make up and aliquot the dye (Alexa Fluor® 488 Carboxylic Acid, Succinimidyl Ester, mixed isomers (1 mg) 1.Add 250 uL…
Harvard University School of Public Health Environmental & Health Services Tuberculist NCBI Old Mtb Whole Genome Sequences New BLAST Tuberculosis Database (TbDb) MIRU/VNTR plus PFAM – protein domain search site CMR (Comprehensive Microbial Resources) Homepage CRISPR – Jeremy sRNA sequencing aind identification-Eli Barcode sequencing-Forrest Live cell imaging-Jemila
