This report describes how Drosophila are used to study species of bacteria in the Mycobacterium genus, which includes Mycobacterium tuberculosis, the causative agent of tuberculosis. The Mycobacterium species used most frequently in fly research is M. marinum, but M. tuberculosis, M. fortuitum, and M. abscessus have also been studied.
OMIM lists several genes associated with susceptibility to or protection against M. tuberculosis infections (MIM:607948). Two genes associated with M. tuberculosis susceptibility that have high-ranking orthologs in Drosophila are human SLC11A1 (Mvl) and TLR2 (Toll-9). Both Hsap\SLC11A1 and Hsap\TLR2 have been introduced into flies, but have not been studied in an immune context.
M. marinum's optimal growth temperature of 25-35 degrees C is suitable for Drosophila. Drosophila are highly susceptible to M. marinum infection, which is quickly fatal. M. marinum infects hemocytes (phagocytes) and replicates within them, and later spread to fill extracellular spaces and abcesses in the fat body. Before death, flies lose stored fat and glycogen, a "wasting" symptom associated with tuberculosis. Mutants of the Imd pathway and Toll pathway (FBgg0001059) are not more susceptible than wild-type flies, indicating that M. marinum can evade these two pathways central to the fly immune response.
S2 cells (FBtc0000999) are a hemocyte-derived line, used to study infection by Mycobacterium species. S2 cells containing live M. marinum were not acidified, indicating that the bacteria are restricting phagosome-lysosome fusion process. Knockdown of Hexo2 (β-hexosaminidase) promoted replication of M. marinus; it most likely exerts a bactericidal effect by breaking down peptidoglycan.
[updated June 2019 by FlyBase; FBrf0222196]
Tuberculosis is a communicable infectious disease, transmitted almost exclusively by cough aerosol, caused by the Mycobacterium tuberculosis complex, and characterised pathologically by necrotising granulomatous inflammation usually in the lung (about 85% of cases), although almost any extrapulmonary site can be involved. Tuberculosis, if untreated, has a mortality of about 70% in smear-positive people. Tuberculosis has killed roughly 1 billion people in the past two centuries, still ranks amongst the top ten causes of death worldwide, results in substantial chronic lung disability, and reduces gross domestic product (GDP) substantially in endemic countries. (Adapted from Dheda et al. 2016, pubmed:26377143.)
Mycobacterium marinum (Mm), a bacterial pathogen of fish and amphibians, is one of the closest relatives to the Mtb complex, measured both by similarity in 16S rRNA and by more complex estimates of the phylogenetic tree. The genetic relatedness, together with similarity in macroscopic and microscopic pathology of diseases caused by Mm and M. tuberculosis (Mtb), has resulted in wide acceptance of Mm infection as a model for pathogenesis of TB. Its fast growth rate (five times that of Mtb), and ease of genetic manipulation have facilitated studies of the organism. Additionally, Mm has a lower optimum growth temperature than Mtb, allowing it to cause disease in poikilotherms but remain innocuous to healthy humans. (Koo et al. 2008, FBrf0202775.)
Mycobacterium tuberculosis (Mtb), the pathogen responsible for TB, is unanimously recognized as one of the most successful human pathogens because of its ability to persist and survive in the macrophages of immunocompetent individuals. Macrophages are key components of the immune system that neutralize intracellular pathogens and initiate protective adaptive immune responses via antigen presentation to T cells. Recent advances in cellular mycobacteriology demonstrate that Mtb uses a plethora of complex strategies to evade the major antimicrobial mechanisms of macrophages, including phagosome-lysosome fusion, the recruitment of potent hydrolytic lysosomal enzymes, the production of reactive oxygen and nitrogen species, antigen presentation and major histocompatibility complex class II (MHC II) expression and trafficking, autophagy, and apoptosis. Disruption of these macrophage functions in turn disrupts innate and adaptive immune responses and impairs the macrophage's ability to properly recognize, respond, and react to infection. (Hmama et al. 2015, pubmed:25703562.)
