RESEARCH FOCUS

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. A randomized clinical trial of Statins as Adjunctive Therapy for TB (StAT-TB trial) is investigating the potential adjunctive role of pravastatin in improving microbiological and lung-function outcomes in HIV-infected and uninfected individuals with drug-susceptible, pulmonary TB in South Africa. Recently, the Karakousis Lab has begun developing a novel DNA vaccine targeting conserved regions of SARS-CoV-2, as well as novel immune-modulating therapies for COVID-19.

CURRENT PROJECTS

Statins as Adjunctive, Host-Directed Therapy for TB

The goal of this study is to investigate the potential utility of pravastatin as an adjunctive, host-directed therapy for drug-susceptible pulmonary TB in a two-stage randomized control trial. The primary outcomes of the Stage 1 study are safety and toxicity, and will allow the selection of pravastatin dose for the Stage 2 efficacy study. In the latter, the primary outcomes will include median time to sputum culture conversion and the serial assessment of various subjective and objective measures of lung function. We are also investigating the anti-TB mechanism of action of statins using a variety of high-throughput and targeted molecular approaches.

A novel ‘shock and kill’ strategy for eliminating Mtb persisters in the CD4 T-cell-deficient host

The objective of this study is to determine if pharmacological inhibition of the Mtb stringent response leads to accelerated eradication of TB infection in CD4-deficient mice. The structure activity relationship of various RelMtb inhibitors is being explored.

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.

Targeting foam cells as adjunctive TB therapy

We are using a combination of transcriptional, lipidomic, genetic, and imaging techniques to investigate whether phthiocerol dimycocerosate (PDIM) accumulation compensates for the fitness cost associated with M. tuberculosis rpoB mutation during host infection.

Evaluation of a novel serum biosignature for detecting TB in HIV-infected individuals

This study will use multiple high-throughput modalities, including LC-MS/MS and RNA-seq, to detect a panel of host metabolites and miRNAs associated with active TB in HIV-infected individuals. Clinical samples are available through the Regional Prospective Observational Research in Tuberculosis (RePORT) International Consortium.

NEWS

UPCOMING EVENTS

July 3, 2020

Journal Club has been cancelled.

July 10, 2020

SGLM via Zoom by Dr. Noton Dutta.

July 17, 2020

The Karakousis Lab's bi-weekly Journal Club will be conducted via zoom at 3:00 pm by Marissa McDonald (B.S. Student in Biomedical Engineering)

© 2019 - All Rights Reserved - Karakousis Lab

P.C. Monika Looney & Anna Saorin - Inquiries welcome