Reto Guler

Monday, 8 January 2018 | 12:00 noon

Division of Immunology, IDM, University of Cape Town & International Centre for Genetic Engineering and Biotechnology (ICGEB) Cape Town Component, SOUTH AFRICA 

Host transcriptomics of tuberculosis to statins and minor groove binders as host/pathogen-directed drug therapy for tuberculosis

(Host: A. Marcello)

Using CAGE transcriptomics we redefined the transcriptional regulatorydynamics of differentially activated classical (M1) or alternative (M2)macrophages and identified new genes and noncoding RNA species.We uncovered a novel transcription factor Batf2 in macrophages anddemonstrated that Batf2, together with Irf1, induces inflammatoryresponses in classically activated macrophages, lipopolysaccharides, aswell as mycobacterial infection. Subsequent experimental Mycobacteriumtuberculosis (Mtb) infection in Batf2 deficient mice resulted in reducedpulmonary inflammation with increased survival compared to infectedwild type mice. Mechanistically, we identified Batf2 as a transcriptionalinducer of inflammatory responses during Mtb infection in mice andshowed that BATF2 is a predictive biomarker for TB disease in humansin a prospective cohort study in adolescents.

We further demonstratedthat Mtb exploits the host cholesterol pathway for its survival and wewere able to increase host protection against tuberculosis by reducingcholesterol by statins. Isolated human monocytes and macrophagesfrom statin-treated patients show significantly reduced bacterialburden compared to the cells of healthy donors. Mechanistically, statinsincreased phagosomal maturation and autophagy as host-protectivefunctions to contain and reduce Mtb growth within macrophages. Newclasses of drugs are constantly being evaluated for anti-mycobacterialactivity with currently a very limited number of new drugs approvedfor TB treatment.

We show minor groove binders (MGB) with novel anti-mycobacterial activities against intracellular clinical Beijing strain HN878in macrophages. We further employed non-ionic surfactant vesiclesas a drug delivery system to deliver entrapped MGB with increasedintracellular drug activity against a clinical strain of Mtb. Taken togetherwe report that minor groove binders constitute an important newclass of drug/chemical entity, which holds promise in future pathogen-directed therapy for tuberculosis.

In addition, targeting Batf2 and itstranscriptional pathway together with repurposed drugs such as statinsoffers possible adjunctive host-directed drug therapy that may reducethe burden and pathological inflammation of tuberculosis.