Martin Gengenbacher, Ph.D., is an Associate Member at the Center for Discovery and Innovation (CDI).
Dr. Gengenbacher has worked for more than 14 years in mycobacterial research, focusing on the optimization of existing therapies and the discovery of novel approaches to address the global crisis associated with the human pathogen Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB). He has developed several new vaccine candidates with superior efficacy or improved safety over Bacille Calmette-Guérin, the only TB vaccine in clinical use which only protects during childhood. Dr. Gengenbacher has also contributed to the discovery and preclinical characterization of novel drugs against M. tuberculosis and the emerging pathogen M. abscessus, that can cause a TB-like difficult-to-treat lung disease.
Novel mouse model of M. abscessus lung infection
Development of new antimicrobials requires testing drug candidates in animal models of infection. While M. abscessus animal infection models do exist, they have several significant limitations. For instance, they rely on immunodeficient mouse strains because standard immunocompetent research mouse strains are resistant to M. abscessus infection and spontaneously clear the pathogen. Dr. Gengenbacher received support from the National Institutes of Health to develop a novel mouse model of M. abscessus lung infection that can overcome the drawbacks of existing models (Figure 1).
The role of B cells during TB infection
Upon inhalation of aerosolized M. tuberculosis, the immune system of healthy individuals usually contains the infection by activating both innate and adaptive immune responses. While T cells have been intensively studied in the context of TB infection and were found to be critical for containment or the pathogen, the role of B cells is still open to debate and remains largely unclear. This lack of understanding is partly due to their versatile character and ability to transition between phenotypes, which necessitates simultaneous detection of multiple marker proteins to discriminate among defined B cell subsets. Dr. Gengenbacher has established a cutting-edge high dimensional flow cytometry platform at CDI (Figure 2) capable of measuring up to 30 parameters simultaneously to analyze B cells in animal models of M. tuberculosis and TB patients in great detail.
Figure 2. Data acquisition on the high dimensional flow cyotometer platform at CDI.
The combination of sophisticated high dimensional flow cytometry with state-of-the-art single cell analysis techniques and machine learning (Figure 3) enables him to study the dynamics of B cell immunology during TB infection and harness this knowledge for vaccine development.
- Nutrient-starved, non-replicating Mycobacterium tuberculosis requires respiration, ATP synthase and isocitrate lyase for maintenance of ATP homeostasis and viability. Gengenbacher M, Rao SP, Pethe K, Dick T. Microbiology. 2010 Jan;156(Pt 1):81-7.
- Vitamin B6 biosynthesis is essential for survival and virulence of Mycobacterium tuberculosis. Dick T, Manjunatha U, Kappes B, Gengenbacher M. Mol Microbiol. 2010 Nov;78(4):980-8.
- Mycobacterium tuberculosis: success through dormancy. Gengenbacher M, Kaufmann SH. FEMS Microbiol Rev. 2012 May;36(3):514-32.
- Reduced drug uptake in phenotypically resistant nutrient-starved nonreplicating Mycobacterium tuberculosis. Sarathy J, Dartois V, Dick T, Gengenbacher M. Antimicrob Agents Chemother. 2013 Apr;57(4):1648-53.
- The tuberculosis vaccine candidate Bacillus Calmette-Guérin ΔureC::hly coexpressing human interleukin-7 or -18 enhances antigen-specific T cell responses in mice. Rao M, Kaiser P, Schuerer S, Kaufmann SH, Gengenbacher M. PLoS One. 2013 Nov 13;8(11):e78966.
- Dietary pyridoxine controls efficacy of vitamin B6-auxotrophic tuberculosis vaccine bacillus Calmette-Guérin ΔureC::hly Δpdx1 in mice. Gengenbacher M, Vogelzang A, Schuerer S, Lazar D, Kaiser P, Kaufmann SH. mBio. 2014 Jun 3;5(3):e01262-14.
- Antibacterial drug discovery: doing it right. Gengenbacher M, Dick T. Chem Biol. 2015 Jan 22;22(1):5-6.
- Comprehensive insights into transcriptional adaptation of intracellular mycobacteria by microbe-enriched dual RNA sequencing. Rienksma RA, Suarez-Diez M, Mollenkopf HJ, Dolganov GM, Dorhoi A, Schoolnik GK, Martins Dos Santos VA, Kaufmann SH, Schaap PJ, Gengenbacher M. BMC Genomics. 2015 Feb 5;16:34.
- Absolute Proteome Composition and Dynamics during Dormancy and Resuscitation of Mycobacterium tuberculosis. Schubert OT, Ludwig C, Kogadeeva M, Zimmermann M, Rosenberger G, Gengenbacher M, Gillet LC, Collins BC, Röst HL, Kaufmann SH, Sauer U, Aebersold R. Cell Host Microbe. 2015 Jul 8;18(1):96-108.
- Post exposure vaccination with the vaccine candidate Bacillus Calmette-Guérin ΔureC::hly induces superior protection in a mouse model of subclinical tuberculosis. Gengenbacher M, Kaiser P, Schuerer S, Lazar D, Kaufmann SH. Microbes Infect. 2016 May;18(5):364-8.
- Deletion of nuoG from the vaccine candidate BCG ΔureC::hly improves protection against tuberculosis. Gengenbacher M, Nieuwenhuizen N, Vogelzang A, Liu H, Kaiser P, Schuerer S, Lazar D, Wagner I, Mollenkopf HJ, Kaufmann SH. mBio. 2016 May 24;7(3):e00679-16.
- Rifabutin is active against Mycobacterium abscessus complex. Aziz DB, Low JL, Wu ML, Gengenbacher M, Teo JWP, Dartois V, Dick T. Antimicrob Agents Chemother. 2017 May; 24;61(6). Pii: e00155-17.
- BCG – old workhorse, new skills. Gengenbacher M, Nieuwenhuizen NE, Kaufmann S. Curr Opin Immunol. 2017 Jul 15;47:8-16.
- NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans. Gengenbacher M, Duque-Correa MA, Kaiser P, Schuerer S, Lazar D, Zedler U, Reece ST, Nayyar A, Cole ST, Makarov V, Barry Iii CE, Dartois V, Kaufmann SHE. Sci Rep. 2017 Aug 18;7(1):8853.
- Novel acetamide indirectly targets mycobacterial transporter MmpL3 by proton motive force disruption. Shetty A, Xu Z, Lakshmanan U, Hill J, Choong ML, Chng SS, Yamada Y, Poulsen A, Dick T, Gengenbacher M. Front Microbiol. 2018 Dec 4;9:2960.
- Humanized mouse model mimicking pathology of human tuberculosis for in vivo evaluation of drug regimens. Arrey F, Löwe D, Kuhlmann S, Kaiser P, Moura-Alves P, Krishnamoorthy G, Lozza L, Maertzdorf J, Skrahina T, Skrahina A, Gengenbacher M, Nouailles G, Kaufmann SHE. Front Immunol. 2019 Jan 31;10:89.
- Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in Mycobacterium tuberculosis. Negatu DA, Yamada Y, Xi Y, Go ML, Zimmerman M, Ganapathy U, Dartois V, Gengenbacher M, Dick T. MBio. 2019 Mar 26;10(2). pii: e02781-18.
- Mycobacterium tuberculosis in the proteomics era. Gengenbacher M, Mouritsen J, Schubert OT, Aebersold R, Kaufmann SH. Molecular Genetics of Mycobacteria, 2nd edition. Edited by Hartful G, Jacobs WR. American Society for Microbiology, 2013.