RESUMO
Research suggests that both tuberculosis (TB) and type 2 diabetes mellitus (T2DM) have an immuno-endocrine imbalance characterized by dysregulated proinflammatory molecules and hormone levels (high cortisol/DHEA ratio), impeding an effective immune response against Mycobacterium tuberculosis (Mtb) driven by cytokines, antimicrobial peptides (AMPs), and androgens like DHEA. Insulin, sulfonylurea derivatives, and metformin are commonly used glucose-lowering drugs in patients suffering from TB and T2DM. For this comorbidity, metformin is an attractive target to restore the immunoendocrine mechanisms dysregulated against Mtb. This study aimed to assess whether metformin influences cortisol and DHEA synthesis in adrenal cells and if these hormones influence the expression of proinflammatory cytokines and AMPs in Mtb-infected macrophages. Our results suggest that metformin may enhance DHEA synthesis while maintaining cortisol homeostasis. In addition, supernatants from metformin-treated adrenal cells decreased mycobacterial loads in macrophages, which related to rising proinflammatory cytokines and AMP expression (HBD-2 and 3). Intriguingly, we find that HBD-3 and LL-37 can modulate steroid synthesis in adrenal cells with diminished levels of cortisol and DHEA, highlighting the importance of crosstalk communication between adrenal hormones and these effectors of innate immunity. We suggest that metformin's effects can promote innate immunity against Mtb straight or through modulation of corticosteroid hormones.
RESUMO
Non-tuberculosis infections in immunocompromised patients represent a cause for concern, given the increased risks of infection, and limited treatments available. Herein, we report that molecules for binding to the catalytic site of histone deacetylase (HDAC) inhibit its activity, thus increasing the innate immune response against environmental mycobacteria. The action of HDAC inhibitors (iHDACs) was explored in a model of type II pneumocytes and macrophages infection by Mycobacterium aurum. The results show that the use of 1,3-diphenylurea increases the expression of the TLR-4 in M. aurum infected MDMs, as well as the production of defb4, IL-1ß, IL-12, and IL-6. Moreover, we observed that aminoacetanilide upregulates the expression of TLR-4 together with TLR-9, defb4, CAMP, RNase 6, RNase 7, IL-1ß, IL-12, and IL-6 in T2P. Results conclude that the tested iHDACs selectively modulate the expression of cytokines and antimicrobial peptides that are associated with reduction of non-tuberculous mycobacteria infection.
Assuntos
Citocinas , Reposicionamento de Medicamentos , Inibidores de Histona Desacetilases , Imunidade Inata , Infecções por Mycobacterium não Tuberculosas , Imunidade Inata/efeitos dos fármacos , Humanos , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Inibidores de Histona Desacetilases/farmacologia , Citocinas/metabolismo , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Micobactérias não Tuberculosas/efeitos dos fármacos , Micobactérias não Tuberculosas/imunologia , Mycobacterium/imunologia , Mycobacterium/efeitos dos fármacosRESUMO
Over the past few decades, there has been extensive research on the use of vitamin D as an adjunctive therapy in the treatment and prevention of tuberculosis. In vitro studies have provided valuable insights into the mechanisms by which vitamin D activates the immune response to combat Mycobacterium tuberculosis. These encouraging findings have spurred clinical investigations globally to assess the effectiveness of vitamin D as a preventive measure and as an adjunctive treatment for tuberculosis. However, the results from these clinical studies have been contradictory, with some demonstrating clear efficacy while others report only modest or no activity. In this review, we aim to analyze the clinical studies on vitamin D and examine the possible discrepancies observed in their outcomes.
Assuntos
Mycobacterium tuberculosis , Tuberculose , Vitamina D , Humanos , Vitamina D/uso terapêutico , Vitamina D/administração & dosagem , Tuberculose/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Ensaios Clínicos como Assunto , Animais , Antituberculosos/uso terapêutico , Antituberculosos/administração & dosagem , Vitaminas/uso terapêutico , Vitaminas/administração & dosagemRESUMO
Mycobacterium tuberculosis (Mtb) is one of the most important infectious agents worldwide and causes more than 1.5 million deaths annually. To make matters worse, the drug resistance among Mtb strains has risen substantially in the last few decades. Nowadays, it is not uncommon to find patients infected with Mtb strains that are virtually resistant to all antibiotics, which has led to the urgent search for new molecules and therapies. Over previous decades, several studies have demonstrated the efficiency of antimicrobial peptides to eliminate even multidrug-resistant bacteria, making them outstanding candidates to counterattack this growing health problem. Nevertheless, the complexity of the Mtb cell wall makes us wonder whether antimicrobial peptides can effectively kill this persistent Mycobacterium. In the present review, we explore the complexity of the Mtb cell wall and analyze the effectiveness of antimicrobial peptides to eliminate the bacilli.
Assuntos
Mycobacterium tuberculosis , Humanos , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Antituberculosos/química , Peptídeos Antimicrobianos , Farmacorresistência Bacteriana Múltipla , Parede Celular/químicaRESUMO
Tobacco consumption is related to an increased risk to develop tuberculosis. Antimicrobial peptides are essential molecules in the response to Mycobacterium tuberculosis (Mtb) because of their direct antimicrobial activity. The aim of this study was to demonstrate that nicotine enters into Mtb infected epithelial cells and associates with the mycobacteria inducing genes related to antimicrobial peptides resistance. Epithelial cells were infected with virulent Mtb, afterwards cells were stimulated with nicotine. The internalization of nicotine was followed using electron and confocal microscopy. The lysX expression was evaluated isolating mycobacterial RNA and submitted to RT-PCR analysis. Our results indicated that nicotine promotes Mtb growth in a dose-dependent manner in infected cells. We also reported that nicotine induces lysX expression. In conclusion, nicotine associates to intracellular mycobacteria promoting intracellular survival.
Assuntos
Mycobacterium tuberculosis , Tuberculose , Peptídeos Antimicrobianos , Humanos , Macrófagos , Mycobacterium tuberculosis/genética , Nicotina/farmacologiaRESUMO
Tuberculosis (TB) is the leading cause of death by a single infectious agent, Mycobacterium tuberculosis (Mtb). Alveolar macrophages and respiratory epithelial cells are the first cells exposed to Mtb during the primary infection, once these cells are activated, secrete cytokines and antimicrobial peptides that are associated with the Mtb contention and elimination. Vitamins are micronutrients that function as boosters on the innate immune system, however, is unclear whether they have any protective activity during Mtb infection. Thus, we investigated the role of vitamin A (retinoic acid), vitamin C (ascorbic acid), vitamin D (calcitriol), and vitamin E (alfa-tocopherol) as inductors of molecules related to mycobacterial infection in macrophages and epithelial cells. Our results showed that retinoic acid promotes the expression of pro- and anti-inflammatory molecules such as Thymic stromal lymphopoietin (TSLP), ß-defensin-2, IL-1ß, CCL20, ß-defensin-3, Cathelicidin LL-37, TGF-ß, and RNase 7, whereas calcitriol, ascorbic acid, and α-tocopherol lead to an anti-inflammatory response. Treatment of Mtb-infected epithelial cells and macrophage-like cells with the vitamins showed a differential response, where calcitriol reduced Mtb in macrophages, while retinoic acid reduced infection in epithelial cells. Thereby, we propose that a combination of calcitriol and retinoic acid supplementation can drive the immune response, and promotes the Mtb elimination by increasing the expression of antimicrobial peptides and cytokines, while simultaneously modulating inflammation.
Assuntos
Peptídeos Antimicrobianos/farmacologia , Brônquios/efeitos dos fármacos , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Tretinoína/farmacologia , Tuberculose/tratamento farmacológico , Antineoplásicos/farmacologia , Autofagia , Brônquios/metabolismo , Brônquios/microbiologia , Brônquios/patologia , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Tuberculose/metabolismo , Tuberculose/microbiologia , Tuberculose/patologiaRESUMO
Infectious diseases are an important growing public health problem, which perspective has worsened due to the increasing number of drug-resistant strains in the last few years. Although diverse solutions have been proposed, one viable solution could be the use of immune system modulators. The induction of the immune response can be increased by histone deacetylase inhibitors (iHDAC), which in turn modulate the chromatin and increase the activation of different cellular pathways and nuclear factors such as STAT3, HIF-1α NF-kB, C/EBPα and, AP-1. These pathways are capable to promote several immune response-related molecules including those with antimicrobial properties such as antimicrobial peptides (AMPs) that lead to the elimination of pathogens including multi drug-resistant strains.