ABSTRACT
Mycobacterium leprae and Mycobacterium tuberculosis antimicrobial resistance has been followed with great concern during the last years, while the need for new drugs able to control leprosy and tuberculosis, mainly due to extensively drug-resistant tuberculosis (XDR-TB), is pressing. Our group recently showed that M. leprae is able to induce lipid body biogenesis and cholesterol accumulation in macrophages and Schwann cells, facilitating its viability and replication. Considering these previous results, we investigated the efficacies of two statins on the intracellular viability of mycobacteria within the macrophage, as well as the effect of atorvastatin on M. leprae infections in BALB/c mice. We observed that intracellular mycobacteria viability decreased markedly after incubation with both statins, but atorvastatin showed the best inhibitory effect when combined with rifampin. Using Shepard's model, we observed with atorvastatin an efficacy in controlling M. leprae and inflammatory infiltrate in the BALB/c footpad, in a serum cholesterol level-dependent way. We conclude that statins contribute to macrophage-bactericidal activity against Mycobacterium bovis, M. leprae, and M. tuberculosis. It is likely that the association of statins with the actual multidrug therapy effectively reduces mycobacterial viability and tissue lesion in leprosy and tuberculosis patients, although epidemiological studies are still needed for confirmation.
Subject(s)
Antitubercular Agents/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Mycobacterium leprae/drug effects , Mycobacterium leprae/pathogenicity , Rifampin/therapeutic use , Animals , Atorvastatin , Cell Line , Drug Synergism , Heptanoic Acids/therapeutic use , Humans , Leprosy/drug therapy , Macrophages/microbiology , Mice , Mice, Inbred BALB C , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/pathogenicity , Pyrroles/therapeutic use , Simvastatin/therapeutic useABSTRACT
Mycobacterium leprae and Mycobacterium tuberculosis antimicrobial resistance has been followed with great concern during the last years, while the need for new drugs able to control leprosy and tuberculosis, mainly due to extensively drug-resistant tuberculosis (XDR-TB), is pressing. Our group recently showed that M. leprae is able to induce lipid body biogenesis and cholesterol accumulation in macrophages and Schwann cells, facilitating its viability and replication. Considering these previous results, we investigated the efficacies of two statins on the intracellular viability of mycobacteria within the macrophage, as well as the effect of atorvastatin on M. leprae infections in BALB/c mice. We observed that intracellular mycobacteria viability decreased markedly after incubation with both statins, but atorvastatin showed the best inhibitory effect when combined with rifampin. Using Shepard's model, we observed with atorvastatin an efficacy in controlling M. leprae and inflammatory infiltrate in the BALB/c footpad, in a serum cholesterol level-dependent way. We conclude that statins contribute to macrophage-bactericidal activity against Mycobacterium bovis, M. leprae, and M. tuberculosis. It is likely that the association of statins with the actual multidrug therapy effectively reduces mycobacterial viability and tissue lesion in leprosy and tuberculosis patients, although epidemiological studies are still needed for confirmation.
Subject(s)
Humans , Animals , Mice , Pyrroles/therapeutic use , Rifampin/therapeutic use , Cell Line , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Simvastatin/therapeutic use , Drug Synergism , Atorvastatin , Heptanoic Acids/therapeutic use , Leprosy/drug therapy , Macrophages/microbiology , Mice, Inbred BALB C , Mycobacterium leprae/drug effects , Mycobacterium leprae/pathogenicity , Mycobacterium tuberculosis/pathogenicity , Antitubercular Agents/therapeutic useABSTRACT
O Mycobacterium leprae, agente causador da hanseníase, e o M. tuberculosis, agente etiológico da tuberculose, são micobactérias que infectam e se multiplicam no interior das células do hospedeiro. O surgimento de cepas resistentes tem se tornado algo cada vez mais comum e preocupante, evidenciando a necessidade de um rápido desenvolvimento de estratégias capazes de controlar o avanço dessas doenças.Atualmente o envolvimento dos lipídeos derivados do hospedeiro e o seu papel nas doenças infecciosas tem sido alvo de vários estudos. Estes estudos apontam principalmente o colesterol como molécula chave na interação bactéria-célula durante infecções causadas por micobactérias e outros patógenos. Dados do nosso grupo demonstraram que o M. leprae é capaz de induzir a biogênese de corpúsculos lipídicos na célula hospedeira e que tais organelas são recrutadas para o fagossoma contendo a micobactéria, sendo a inibição deste recrutamento importante na redução da viabilidade intracelular do M. leprae. Também tem sido descrito que o colesterol está relacionado à persistência do M. tuberculosis nos pulmões e a resistência deste bacilo à rifampicina. No presente estudo, investigamos o efeito de duas estatinas usadas no controle da hipercolesterolemia, a atorvastatina e a sinvastatina, na viabilidade intracelular do M. bovis BCG, M. tuberculosis H37Rv e M. leprae Thai-53. Em nosso modelo de infecção in vitro utilizando macrófagos derivados de monócitos humanos de linhagem THP-1, foi possível observar uma diminuição da viabilidade intracelular micobacteriana após incubação com as estatinas individualmente, sem efeito citotóxico sobre a célula hospedeira. Quando as estatinas foram combinadas com a rifampicina, foi observado um efeito aditivo entre essas drogas, aumentando a morte bacteriana. Adicionalmente, quando utilizamos um modelo de infecção in vivo, foi possível confirmar o efeito da atorvastatina contra o M. leprae...
Mycobacterium leprae and M. tuberculosis, causative agents of leprosy andtuberculosis respectively, are mycobacteria that infect and multiply within the hostcell. The emergence of resistant strains has become increasingly common, and thereis need for development of novel strategies to control the progression of thesediseases. Currently the involvement of lipids in biological processes and their role ininfectious diseases has been the subject of several studies that demonstrate theimportance of host-derived lipids, particularly cholesterol, in the bacterium-cellinteraction during mycobacterial infections. Data from our group demonstrated thatM. leprae is able to induce the biogenesis of lipid droplets in the host cell, and thatthese organells are recruited to the mycobacterial phagosome. The inhibition of thisrecruitment is important for reduction of M. leprae viability. It has also been reportedthat cholesterol is related to the persistence of M. tuberculosis in the lungs andrifampin resistance of this bacillus. In the present study atorvastatin and simvastatin,two statins used in the control of hypercholesterolemia, were analyzed in terms oftheir effects on viability of intracellular M. bovis BCG, M. tuberculosis H37Rv andM. leprae Thai-53. In our in vitro model of infection using THP-1 human monocyticcells, we observed a decrease in bacterial viability after incubation with either statins,with no cytotoxic effects on the host cell. When statins were associated withrifampicin, an additive effect between these drugs was also observed...
Subject(s)
Mice , Leprosy/diagnosis , Neglected Diseases , Tuberculosis/diagnosis , Rifampin , SimvastatinABSTRACT
Peripheral nerve lesions are considered the most relevant symptoms of leprosy, a chronic infectious disease caused by Mycobacterium leprae. The strategies employed by M. leprae to infect and multiply inside Schwann cells (SCs), however, remain poorly understood. In this study, it is shown that treatment of SCs with M. leprae significantly decreased cell death induced by serum deprivation. Not displayed by Mycobacterium smegmatis or Mycobacterium bovis BCG, the M. leprae survival effect was both dose dependent and specific. The conditioned medium (CM) of M. leprae-treated cultures was seen to mimic the protective effect of the bacteria, suggesting that soluble factors secreted by SCs in response to M. leprae were involved in cell survival. Indeed, by quantitative RT-PCR and dot blot/ELISA, it was demonstrated that M. leprae induced the expression and secretion of the SC survival factor insulin-like growth factor-I. Finally, the involvement of this hormone in M. leprae-induced SC survival was confirmed in experiments with neutralizing antibodies. Taken together, the results of this study delineate an important strategy for the successful colonization of M. leprae in the nerve based on the survival maintenance of the host cell through induction of IGF-I production.
