Husson Laboratory Research | Overview
The Husson laboratory is based in the Division of Infectious Diseases at Boston Children’s Hospital, affiliated with Harvard Medical School. We are located in the Enders Research building in the heart of the Longwood Medical Area of Boston.
Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide, with over 9 million new cases of active TB annually. Research in the Husson laboratory focuses on two adaptive mechanisms of Mycobacterium tuberculosis that are important for the pathogenesis of TB: transcription regulation and signal transduction. We use a range of genetic, microbiologic, biochemical and cell biology approaches to address questions of interest in these areas.
One major focus of the laboratory is the regulation of transcription by the alternative sigma factors of this slow-growing bacterial pathogen. We have defined the regulons of several of the alternative sigma factors of M. tuberculosis. These include SigE and SigH, which are important in the bacterial responses to oxidative, nitrosative and cell surface stresses, and SigL and SigM, which regulate secreted proteins and surface lipid synthesis. Several of these M. tuberculosis sigma factors are required for virulence in cellular and mouse models of infection. Ongoing work is focused on determining the biochemical functions and physiologic effects of specific genes regulated by these sigma factors, as well as investigation of as yet uncharacterized sigma factors.
Related to this work we have recently optimized a human in vitro granuloma infection model in the laboratory. We are using this system in several ways, including quantitative analysis of bacterial gene expression in the granuloma, examining the roles of sigma factors in bacterial survival in the granuloma, and the host gene expression following M. tuberculosis infection.
The second major research area in the Husson laboratory focuses on signal transduction pathways of M. tuberculosis. In addition to the more intensively studied bacterial two-component signal transduction systems, the M. tuberculosis genome encodes 11 eukaryotic-like serine/ threonine protein kinases. We have defined a role for the two essential kinases PknA and PknB in regulating cell shape and cell wall synthesis and we have determined the molecular requirements for ligand binding to the extracellular domains of PknB. In additional recent work we defined a large proportion of the M. tuberculosis phosphoproteome, identifying over 500 in vivo phosphorylation sites in over 300 M. tuberculosis proteins. Current research in this area seeks to characterize the in vivo targets of individual kinases, to determine the signals that activate these kinases, and to define the effects of Ser/Thr phosphorylation on specific pathways in M. tuberculosis physiology.
In addition to these primary areas of research, we collaborate with Dr. Nancy Woychik of UMDNJ on a project to investigate the function of MazF family toxins in M. tuberculosis. Pilot translational research projects are also underway to identify M. tuberculosis antigens that may be useful for diagnosis and to investigate a novel approach to identify inhibitors of M. tuberculosis.