The primary focus of the Karakousis Lab is to understand the molecular basis of persistence and reactivation in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Major research activities include studying the adaptation of M. tuberculosis to stress conditions believed to be important in the infected human host, as well as the phenomenon of phenotypic tolerance to antibiotics. In particular, the regulatory cascade involved in the mycobacterial stringent response is under active investigation. A systems biology-based approach is being used to identify host defense mechanisms responsible for immunological control of M. tuberculosis growth, as well as M. tuberculosis regulatory and metabolic pathways required for bacterial persistence and antibiotic tolerance. The laboratory is also actively investigating the repurposing of various clinically available agents with immune-modulatory properties as adjunctive host-directed therapy, in order to shorten the duration of TB treatment and improve lung pathology.
Characterizing mechanisms of Mtb antibiotic tolerance
A transposon mutant library screen has identified multiple candidates of genes/pathways involved in Mtb tolerance to rifampin, including several virulence factors implicated in host-pathogen interactions and components of the phosphate-specific transport system. A combination of genetic, biochemical and phenotypic approaches is being used to elucidate their contribution to antibiotic tolerance.
Repurposing agents with host-directed activity against TB
These studies are investigating multiple agents targeting macrophage defense mechanisms, including the induction of autophagy, the mTOR signaling pathway, heme degradation and nitric oxide synthesis.
Immunotherapy Targeting Mtb Persisters in the DC-impaired Setting of HIV and TB
The goal of this research program is to determine whether enhanced immunity to critical components of the Mtb stringent response accelerates immune-based clearance of persistent bacteria and shortens the time required to achieve relapse-free cure in antibiotic-treated mice.
Evaluation of blood-based biomarkers for TB diagnosis and assessing treatment response
This study is using multiple high-throughput modalities, including LC-MS/MS and RNA-seq, to detect a panel of host metabolites and miRNAs associated with active TB, as well as their change in abundance in response to TB treatment, in the plasma of patients with and without HIV co-infection. Clinical samples are available through the Regional Prospective Observational Research in Tuberculosis (RePORT) International Consortium.
Targeting foam cells as adjunctive TB therapy
The goal of this study is to identify druggable targets in the pro-lipogenic and anti-lipogenic pathways of macrophages, with the long-term goal of shortening the duration of TB treatment and improving TB-related immunopathology.
September 14, 2022
Stela Karanika's paper, “An intranasal stringent response vaccine targeting dendritic cells as a novel adjunctive therapy against tuberculosis” was accepted for publication. Congratulations, Stela!!
July 5, 2022
Lab farewell party for Marissa McDonald, who will be enrolling in the Harvard-MIT HST graduate program in the fall. Congratulations, Marissa!!
July 1, 2022
Stela Karanika received a Clinician Scientist Career Development Award and will be joining the faculty of the Johns Hopkins Division of Infectious Diseases as an Assistant Professor of Medicine. Congratulations, Stela!!
June 10, 2022
Stela Karanika was awarded the Arthur M. Dannenberg, Jr. Award for the year 2022!
May 31, 2022
Hannah Bailey got engaged!
May 21, 2022
Darla Quijada got engaged!
February 24, 2022
Welcome Addis Yilma and Hannah Bailey to the Lab!
January 28, 2022
Monika Looney's last day in the Karakousis Lab, and she is off to start her new postdoc at SATVI, university of Cape Town. Good Luck, Monika!!