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. Finally, molecular assays using blood, sputum, and urine samples are being investigated with the goal of developing rapid, sensitive, and specific point-of-care tests for TB diagnosis and detection of drug resistance.

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.

The role of cell wall lipids in pathogenesis of rifampin-resistant TB

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

October 17, 2019

Harley Parker passes her Graduate Program in Pathobiology Oral Exam​.

May 22, 2019

Petros gives a talk on "Statins: Good for the Heart and Good for TB?" at the Scientific Symposium on "Host-Directed Therapy for Tuberculosis: Theory and Current Evidence", American Thoracic Society International Conference, Dallas, TX.

May 8, 2019

Will Matern gave his Thesis Defense for his PhD in Biomedical Engineering.

January 30, 2019

Farewell breakfast for Vicky Campodónico, MD, PhD, who accepted a Research Associate position in the Departments of Medicine and Oncology, JHUSOM.

January 25, 2019

Petros gives a talk on targeting Mtb persisters at the Memorial Sloan Kettering/Weil Cornell Medical College Advanced Topics seminar series, New York, NY.​

November 15, 2018:

Petros gives a talk on “Inhibiting the Mtb Stringent Response: The Krotalon for Rousing Persisters?”, at the Johns Hopkins Bloomberg School of Public Health Department of Molecular Microbiology and Immunology Seminar series.

 

November 6, 2018:

Will Matern is awarded a Potts Foundation postdoctoral fellowship for his proposal entitled: “Identifying the mechanism of caeA/Hip1/Rv2224c mediated tolerance to rifampin in Mycobacterium tuberculosis”.

October 25, 2018:

Petros hosts a scientific session on “Advancing Host-Directed Therapies for TB” at the 49th Union World Conference on Lung Health at the Hague, the Netherlands.

October 19, 2018:

After winning the first prize two years in a row, the Karakousis Lab settles for second place at the Annual JHU TB Center Pumpkin Carving Contest.

October 11, 2018:

Division of Infectious Diseases reception for Petros’s promotion to Professor of Medicine.

August 30, 2018:

Farewell lunch for MMI Master student, Alysha Ellison, who has joined the PhD Graduate Program of the W. Harry Feinstone Department of Molecular Microbiology and Immunology at Johns Hopkins Bloomberg School of Public Health.

July 2, 2018:

Petros gives a talk on “What can ‘omics tell us about TB reactivation risk in HIV-infected and uninfected adults and children?” at the NIH/NIAID-sponsored meeting on ‘Understanding the Resources and Gaps in DAIDS funded TB Research’.

July 1, 2018:

Petros becomes a standing member of the NIH Bacterial Pathogenesis (BACP) Study section.

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Artwork by Monika Looney - Inquiries welcome