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Vaccination is the most effective method for preventing infectious diseases. Oral vaccinations have attracted much attention due to the ability to boost intestinal and systemic immunity. The focus of this study was to develop a poly (lactide-co-glycolide) acid (PLGA)-based ternary polyelectrolyte complex (PEC) with chitosan, sodium alginate, and transmembrane peptides R8 for the delivery of antigen proteins. In this study, the antigen protein (HBf), consisting of the Mycobacterium avium subspecies paratuberculosis (MAP) antigens HBHA, Ag85B, and Bfra, was combined with R8 to generate self-assembled conjugates. The results showed that PEC presented a cross-linked reticular structure to protect the encapsulated proteins in the simulated gastric fluid. Then, the nanocomposite separated into individual nanoparticles after entering the simulated intestinal fluid. The ternary PEC with R8 promoted the in vivo uptake of antigens by intestinal lymphoid tissue. Moreover, the ternary PEC administered orally to mice promoted the secretion of specific antibodies and intestinal mucosal IgA. In addition, in the mouse models of MAP infection, the ternary PEC enhanced splenic T cell responses, thus reducing bacterial load and liver pathology score. These results suggested that this ternary electrolyte complex could be a promising delivery platform for oral subunit vaccine candidates, not limited to MAP infection.
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Alginatos , Quitosano , Inmunidad Mucosa , Quitosano/química , Alginatos/química , Animales , Inmunidad Mucosa/efectos de los fármacos , Ratones , Administración Oral , Polielectrolitos/química , Femenino , Ratones Endogámicos BALB C , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/química , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/químicaRESUMEN
Selenium nanoparticles (SeNPs) enhance the immune response as adjuvants, increasing the efficacy of viral vaccines, including those for COVID-19. However, the efficiency of mucosal SeNPs in boosting vaccine-induced protective immunity against tuberculosis remains unclear. Therefore, this study aims to investigate whether the combination of SeNPs with the AH antigen (Ag85A-HspX) can boost respiratory mucosal immunity and thereby enhance the protective effects against tuberculosis. We synthesized SeNPs and assessed their impact on the immune response and protection against Mycobacterium bovis (M. bovis) as a mucosal adjuvant in mice, administered intranasally at a dose of 20 µg. SeNPs outperformed polyinosinic-polycytidylic acid (Poly IC) in stimulating the maturation of bone marrow-derived dendritic cells (BMDCs), which enhanced antigen presentation. SeNPs significantly activated and proliferated tissue-resident memory T cells (TRMs) and effector CD4+ T cells in the lungs. The vaccines elicited specific antibody responses in the respiratory tract and stimulated systemic Th1 and Th17 immune responses. Immunization with AH and SeNPs led to higher levels of mucosal secretory IgA in bronchoalveolar lavage fluid (BALF) and secretory IL-17 in splenocytes. Moreover, SeNPs immunized mice showed reduced M. bovis infection loads and inflammatory lesions in the lungs post-challenge. Notably, immunization with AH and SeNPs significantly reduced bacterial load in the lungs, achieving the lowest levels compared to all other tested groups. This study calls for pre-clinical investigation of AHB-SeNPs as an anti-bovine tuberculosis vaccine and for exploring its human vaccine potential, which is anticipated to aid in the development of innovative vaccines or adjuvants.
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Adyuvantes Inmunológicos , Antígenos Bacterianos , Inmunidad Mucosa , Mycobacterium bovis , Nanopartículas , Selenio , Animales , Mycobacterium bovis/inmunología , Inmunidad Mucosa/efectos de los fármacos , Nanopartículas/administración & dosificación , Ratones , Adyuvantes Inmunológicos/administración & dosificación , Femenino , Antígenos Bacterianos/inmunología , Ratones Endogámicos C57BL , Tuberculosis/inmunología , Tuberculosis/prevención & control , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Vacunas contra la Tuberculosis/inmunología , Vacunas contra la Tuberculosis/administración & dosificación , Pulmón/inmunología , Pulmón/microbiología , Proteínas Bacterianas/inmunologíaRESUMEN
HIF-1α is a pivotal regulator of metabolic and inflammatory responses. This study investigated the role of HIF-1α in M. bovis infection and its effects on host immune metabolism and tissue damage. We evaluated the expression of immunometabolism markers and MMPs infected with M. bovis, and following HIF-1α inhibition in vitro. To understand the implications of HIF-1α inhibition on disease progression, mice at different infection stages were treated with the HIF-1α inhibitor, YC-1. Our results revealed an upregulation of the HIF-1α in macrophages post-M. bovis infection, facilitating enhanced M1 macrophage polarization. The blockade of HIF-1α moderated these responses but escalated MMP activity, hindering bacterial control. Consistent with our in vitro results, early-stage treatment of mice with YC-1 aggravated pathological alterations and tissue damage, while late-stage HIF-1α inhibition proved beneficial in managing the disease. Overall, our findings underscored the nuanced role of HIF-1α across varying phases of M. bovis infection.
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Given the worldwide problem posed by enteric pathogens, the discovery of safe and efficient intestinal adjuvants combined with novel antigen delivery techniques is essential to the design of mucosal vaccines. In this work, we designed poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) to codeliver all-trans retinoic acid (atRA), novel antigens, and CpG. To address the insolubility of the intestinal adjuvant atRA, we utilized PLGA to encapsulate atRA and form a "nanocapsid" with polydopamine. By leveraging polydopamine, we adsorbed the water-soluble antigens and the TLR9 agonist CpG onto the NPs' surface, resulting in the pathogen-mimicking PLPCa NPs. In this study, the novel fusion protein (HBf), consisting of the Mycobacterium avium subspecies paratuberculosis antigens HBHA, Ag85B, and Bfra, was coloaded onto the NPs. In vitro, PLPCa NPs were shown to promote the activation and maturation of bone marrow-derived dendritic cells. Additionally, we found that PLPCa NPs created an immune-rich microenvironment at the injection site following intramuscular administration. From the results, the PLPCa NPs induced strong IgA levels in the gut in addition to enhancing powerful systemic immune responses. Consequently, significant declines in the bacterial burden and inflammatory score were noted in PLPCa NPs-treated mice. In summary, PLPCa can serve as a novel and safe vaccine delivery platform against gut pathogens, such as paratuberculosis, capable of activating both systemic and intestinal immunity.
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Nanopartículas , Paratuberculosis , Animales , Nanopartículas/química , Paratuberculosis/inmunología , Paratuberculosis/prevención & control , Ratones , Tretinoina/química , Tretinoina/farmacología , Mycobacterium avium subsp. paratuberculosis/inmunología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/química , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Intestinos/inmunología , Intestinos/microbiología , Ratones Endogámicos C57BL , Femenino , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/administración & dosificación , Vacunas Bacterianas/inmunología , Ratones Endogámicos BALB CRESUMEN
Accumulating evidence indicates that antibodies can protect against some intracellular pathogens. Mycobacterium bovis is an intracellular bacterium, and its cell wall (CW) is essential for its virulence and survival. However, the questions of whether antibodies play a protective role in immunity against M. bovis infection and what effects antibodies specific to the CW of M. bovis have still remain unclear. Here, we report that antibodies targeting the CW of an isolated pathogenic M. bovis strain and that of an attenuated bacillus Calmette-Guérin (BCG) strain could induce protection against virulent M. bovis infection in vitro and in vivo. Further research found that the antibody-induced protection was mainly achieved by promoting Fc gamma receptor (FcγR)-mediated phagocytosis, inhibiting bacterial intracellular growth, and enhancing the fusion of phagosomes and lysosomes, and it also depended on T cells for its efficacy. Additionally, we analyzed and characterized the B-cell receptor (BCR) repertoires of CW-immunized mice via next-generation sequencing. CW immunization stimulated BCR changes in the complementarity determining region 3 (CDR3) isotype distribution, gene usage, and somatic hypermutation. Overall, our study validates the idea that antibodies targeting the CW induce protection against virulent M. bovis infection. This study highlights the importance of antibodies targeting the CW in the defense against tuberculosis. IMPORTANCE M. bovis is the causative agent of animal tuberculosis (TB) and human TB. Research on M. bovis is of great public health significance. Currently, TB vaccines are mainly aimed at eliciting protection by enhancement of cell-mediated immunity, and there are few studies on protective antibodies. This is the first report of protective antibodies against M. bovis infection, and the antibodies had both preventive and even therapeutic effects in an M. bovis infection mouse model. Additionally, we reveal the relationship between CDR3 gene diversity and the immune characteristics of the antibodies. These results will provide valuable advice for the rational development of TB vaccines.
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Mycolic acids constitute pivotal constituents within the cell wall structure of Mycobacterium tuberculosis. Due to their structural diversity, the composition of mycolic acids exhibits substantial variations among different strains, endowing them with the distinctive label of being the 'signature' feature of mycobacterial species. Within Mycobacterium tuberculosis, the primary classes of mycolic acids include α-, keto-, and methoxy-mycolic acids. While these mycolic acids are predominantly esterified to the cell wall components (such as arabinogalactan, alginate, or glucose) of Mycobacterium tuberculosis, a fraction of free mycolic acids are secreted during in vitro growth of the bacterium. Remarkably, different types of mycolic acids possess varying capabilities to induce foamy macro-phages and trigger immune responses. Additionally, mycolic acids play a regulatory role in the lipid metabolism of host cells, thereby exerting influence over the progression of tuberculosis. Consequently, the multifaceted properties of mycolic acids shape the immune evasion strategy employed by Mycobacterium tuberculosis. A comprehensive understanding of mycolic acids is of paramount significance in the pursuit of developing tuberculosis therapeutics and unraveling the intricacies of its pathogenic mechanisms.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Metabolismo de los Lípidos , Ácidos Micólicos , Alginatos , Tuberculosis/tratamiento farmacológicoRESUMEN
Introduction: The limited efficacy of BCG (bacillus Calmette-Guérin) urgently requires new effective vaccination approaches for the control of tuberculosis. Poly lactic-co-glycolic acid (PLGA) is a prevalent drug delivery system. However, the effect of PLGA-based nanoparticles (NPs) against tuberculosis for the induction of mucosal immune response is no fully elucidated. In this study, we hypothesized that intranasal immunization with culture filtrate protein-10 (CFP10)-loaded PLGA NPs (CFP10-NPs) could boost the protective immunity of BCG against Mycobacterium bovis in mice. Methods: The recombinant protein CFP10 was encapsulated with PLGA NPs to prepare CFP10-NPs by the classical water-oil-water solvent-evaporation method. Then, the immunoregulatory effects of CFP10-NPs on macrophages in vitro and on BCG-immunized mice in vivo were investigated. Results: We used spherical CFP10-NPs with a negatively charged surface (zeta-potential -28.5 ± 1.7 mV) having a particle size of 281.7 ± 28.5 nm in diameter. Notably, CFP10-NPs significantly enhanced the secretion of tumor necrosis factor α (TNF-α) and interleukin (IL)-1ß in J774A.1 macrophages. Moreover, mucosal immunization with CFP10-NPs significantly increased TNF-α and IL-1ß production in serum, and immunoglobulin A (IgA) secretion in bronchoalveolar lavage fluid (BALF), and promoted the secretion of CFP10-specific interferon-γ (IFN-γ) in splenocytes of mice. Furthermore, CFP10-NPs immunization significantly reduced the inflammatory area and bacterial load in lung tissues at 3-week post-M. bovis challenge. Conclusion: CFP10-NPs markedly improve the immunogenicity and protective efficacy of BCG. Our findings explore the potential of the airway mucosal vaccine based on PLGA NPs as a vehicle for targeted lung delivery.
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It has been established that kallikrein12 (KLK12) expression is closely related to bovine tuberculosis (bTB) development. Herein, we sought to clarify the regulatory mechanism of KLK12 and its application in tuberculosis diagnosis. KLK12 knockdown macrophages were produced by siRNA transfection. Bradykinin receptors (BR, including B1R and B2R) were blocked with specific inhibitors. Mannose-capped lipoarabinomannan (ManLAM) was extracted from Mycobacterium bovis (M. bovis) and used to study the mechanism of KLK12 activation. In addition, we constructed different mouse models representing the latent and active stages of M. bovis infection. Mouse models and clinical serum samples were used to assess the diagnostic value of biomarkers. Through the above methods, we confirmed that KLK12 regulates MMP-1 and MMP-9 via BR. KLK12 upregulation is mediated by the M. bovis-specific antigen ManLAM. KLK12, MMP-1, and MMP-9 harbor significant value as serological markers for differentiating between latent and active bTB, especially KLK12. In conclusion, we identified a novel signaling pathway, KLK12/BR/ERK/MMPs, in M. bovis-infected macrophages, which is activated by ManLAM. From this signaling pathway, KLK12 can be used as a serological marker to differentiate between latent and active bTB. Importantly, KLK12 also has enormous potential for the clinical diagnosis of human tuberculosis (TB).
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Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculosis Bovina , Tuberculosis , Ratones , Animales , Bovinos , Humanos , Tuberculosis Bovina/diagnóstico , Tuberculosis Bovina/metabolismo , Mycobacterium tuberculosis/metabolismo , Manosa/metabolismo , Metaloproteinasa 1 de la Matriz , Receptores de Bradiquinina , Metaloproteinasa 9 de la Matriz , ARN Interferente Pequeño , Antígenos Bacterianos , Biomarcadores , CalicreínasRESUMEN
Mycobacterium bovis is the cause of bovine tuberculosis, and it can also cause disease in humans, with symptoms similar to those caused by M. tuberculosis. However, our understanding of its genomic diversity, biogeography, and drug resistance remains incomplete. We performed a comparative and phylogenetic analysis of 3228 M. bovis genomes from 24 countries. Following drug susceptibility testing, we applied a bacterial genome-wide association study to capture associations between genomic variation and drug resistance in 74 newly isolated strains from China. The data show that the cattle-adapted M. bovis were divided into six lineages with a strong phylogeographical population structure. Lineages 1 and 6 are the most widespread globally, while others show a strong geographical restriction. Note that 17.39% of M. bovis isolates were resistant to at least one drug in China. Furthermore, we identify genomic variations associated with an increased risk of resistance acquisition. This study furthers our knowledge of M. bovis diversity, biogeography, and drug resistance and will facilitate more deeply informed genomic tracking and surveillance to minimize its threat to human health, as a cause of zoonotic tuberculosis.
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Enfermedades de los Bovinos , Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculosis Bovina , Tuberculosis , Animales , Bovinos , Resistencia a Medicamentos , Estudio de Asociación del Genoma Completo/veterinaria , Genómica , Humanos , Pruebas de Sensibilidad Microbiana/veterinaria , Mycobacterium tuberculosis/genética , Filogenia , Tuberculosis/epidemiología , Tuberculosis/veterinaria , Tuberculosis Bovina/epidemiologíaRESUMEN
The role of gut microbiota has been described as an important influencer of the immune system. Gut-lung axis is critical in the prevention of mycobacterium infection, but the specific mechanism, by which dysbiosis affects tuberculosis, has not been reported. In this study, we attempted to provide more information on how the gut-lung axis contributes to Mycobacterium bovis (M. bovis) infection. Mice are pre-treated with broad-spectrum antibiotics cocktail (Abx) to induce gut dysbiosis. Interestingly, dysbiosis of microbes showed a significant increase in the bacterial burden in the lungs and inhibited the level of COX-2. After faecal transplantation, cyclooxygenase 2 (COX-2) expression was restored and the inflammatory lesion in the lungs was reduced. Further research found that the deficiency of COX-2 inhibited endoplasmic reticulum stress (ER stress). This mechanism was completed by COX-2 interaction with BIP. Moreover, we found a positive feedback mechanism by which blocking ER stress could reduce COX-2 levels by the NF-κB pathway. Taken together, we reveal for the first time gut dysbacteriosis exacerbates M. bovis disease by limiting the COX-2/ER stress pathway. The finding strengthens the foundation of gut microbiota-targeted therapy for tuberculosis treatment.
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Mycobacterium bovis , Tuberculosis , Animales , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Disbiosis/microbiología , Estrés del Retículo Endoplásmico , Ratones , Tuberculosis/microbiologíaRESUMEN
Respiratory mucosal immunization is an effective immunization strategy against tuberculosis (TB), and effective mucosal vaccines require adjuvants that can promote protective immunity without deleterious inflammation. Mucosal BCG (Bacille Calmette-Guerin) is effective, but it causes a severe inflammatory response in the lung. A novel less cytotoxic mucosal vaccine AH-PB containing Mycobacterium tuberculosis (Mtb) cell surface antigens Ag85A and HspX (AH), as well as polyinosinic-polycytidylic acid (Poly IC) and bovine neutrophil ß-defensin-5 (B5) adjuvants were prepared, with the overarching goal of protecting against TB. Then, the immunogenicity and protective efficacy of these vaccines via the intranasal route were evaluated in a mouse model. Results showed that intranasal AH-PB promoted tissue-resident memory T cells (TRMs) development in the lung, induced antigen-specific antibody response in airway, provided protection against Mycobacterium bovis (M. bovis), conferred better protection than parenteral BCG in the later stage of infection, and boosted the protective immunity generated by BCG in mice. Moreover, both B5 and Poly IC were indispensable for the protection generated by AH-PB. Furthermore, intranasal immunization with AH-B5 fusion vaccines also provided similar protection against M. bovis compared to AH-PB. Collectively, B5-based TB vaccine via the intranasal route is a promising immunization strategy against bovine TB, and this kind of immunization strategy may be applied to human TB vaccine development. These findings highlight the potential importance of B5 as a mucosal adjuvant used in TB vaccines or other respiratory disease vaccines.
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Mycobacterium bovis , Mycobacterium tuberculosis , Vacunas contra la Tuberculosis , Tuberculosis , beta-Defensinas , Animales , Antígenos Bacterianos , Antituberculosos , Vacuna BCG , Bovinos , Modelos Animales de Enfermedad , Inmunidad Mucosa , Ratones , Tuberculosis/prevención & controlRESUMEN
Background: Escherichia coli remains a major pathogen of poultry. Most vaccines are inactivated and produced empirically. Although inactivated Salmonella vaccines have been produced by culture under conditions of Fe deprivation, no vaccines have been produced which are likely to express all the proteins expressed during infection of antigen-presenting cells. Aim: The aim was to produce a more protective inactivated vaccine by culturing the avian E. coli in a synthetic medium that resembled the environment of the phagolysosome. Methods: Global gene expression in a pathogenic avian O78:K80 strain of E. coli, harvested from infected avian macrophage-like HD11 cells, was compared by microarray with bacteria cultured in a tissue culture medium. A liquid synthetic medium was produced based on the environmental conditions identified to which the bacteria were exposed intracellularly. A bacterin was produced from this strain and its protective ability was assessed in chickens. Results: The changes in E. coli gene expression observed included the use of different electron acceptors and carbon sources such as ethanolamine, ß-glucosides, galactonate, dicarboxylic acids, and amino acids, up-regulation of genes associated with Fe and Mn uptake, and up-regulation of type-1 and curli fimbriae, other adhesion genes and down-regulation of sialic acid synthesis genes. The bacterin produced in the synthetic medium was statistically more protective than a bacterin prepared from bacteria cultured in the nutrient broth when tested in vaccinated chickens challenged with a different virulent E. coli O78:K80 strain. Conclusion: The approach of using gene expression to produce synthetic media for the generation of more effective bacterins could be used for a number of intracellular bacteria pathogens including Enteroinvasive E. coli, Salmonella, and the Pasteurella/Riemerella/Mannheimia group of organisms.
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Infecciones por Escherichia coli , Enfermedades de las Aves de Corral , Animales , Vacunas Bacterianas , Pollos , Escherichia coli/genética , Infecciones por Escherichia coli/prevención & control , Infecciones por Escherichia coli/veterinaria , Vacunas de Productos InactivadosRESUMEN
Background: Glycerol kinase (glpK) is essential for the first step of glycerol catabolism in Mycobacterium tuberculosis. However, Mycobacterium bovis has been known to grow poorly in glycerol media because of a base insertion in the glpK gene. Methods: We analyzed the glpK gene sequences of 60 clinical M. bovis isolates, and determined the minimum inhibitory concentration of 14 drugs by microdilution method to evaluate the effect of frameshift mutations on drug sensitivity. The effect of M. bovis growth rate on its drug sensitivity was investigated using bacteria grown on glycerol or pyruvate. Results: A total of 44 (73.33%) clinical M. bovis isolates have frameshift mutations in a homopolymeric tract of 7 cytosines in the glpK gene. 15.00% M. bovis isolates showed phenotypic drug resistance. Glycerol metabolism-deficient M. bovis showed reduced susceptibility to 9 out of 14 tested drugs. Mutations in the glpK gene can lead to impaired growth in glycerol-based media, while the minimal inhibitory concentration values of slow-growing M. bovis were higher. Conclusion: Mutations in the glpK gene can lead to slowed growth and reduced susceptibility to drugs in M. bovis, which may contribute to the emergence of drug-resistant M. bovis and pose a threat to human health owing to the zoonotic capacity of M. bovis.
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Prion disease represents a group of fatal neurogenerative diseases in humans and animals that are associated with energy loss, axonal degeneration, and mitochondrial dysfunction. Axonal degeneration is an early hallmark of neurodegeneration and is triggered by SARM1. We found that depletion or dysfunctional mutation of SARM1 protected against NAD+ loss, axonal degeneration, and mitochondrial functional disorder induced by the neurotoxic peptide PrP106-126. NAD+ supplementation rescued prion-triggered axonal degeneration and mitochondrial dysfunction and SARM1 overexpression suppressed this protective effect. NAD+ supplementation in PrP106-126-incubated N2a cells, SARM1 depletion, and SARM1 dysfunctional mutation each blocked neuronal apoptosis and increased cell survival. Our results indicate that the axonal degeneration and mitochondrial dysfunction triggered by PrP106-126 are partially dependent on SARM1 NADase activity. This pathway has potential as a therapeutic target in the early stages of prion disease.
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Mitophagy is a selective autophagy mechanism for eliminating damaged mitochondria and plays a crucial role in the immune evasion of some viruses and bacteria. Here, we report that Mycobacterium bovis (M. bovis) utilizes host mitophagy to suppress host xenophagy to enhance its intracellular survival. M. bovis is the causative agent of animal tuberculosis and human tuberculosis. In the current study, we show that M. bovis induces mitophagy in macrophages, and the induction of mitophagy is impaired by PINK1 knockdown, indicating the PINK1-PRKN/Parkin pathway is involved in the mitophagy induced by M. bovis. Moreover, the survival of M. bovis in macrophages and the lung bacterial burden of mice are restricted by the inhibition of mitophagy and are enhanced by the induction of mitophagy. Confocal microscopy analysis reveals that induction of mitophagy suppresses host xenophagy by competitive utilization of p-TBK1. Overall, our results suggest that induction of mitophagy enhances M. bovis growth while inhibition of mitophagy improves growth restriction. The findings provide a new insight for understanding the intracellular survival mechanism of M. bovis in the host.Abbreviations: BMDM: mouse bone marrow-derived macrophage; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; BCL2L13: BCL2-like 13 (apoptosis facilitator); CCCP: carbonyl cyanide m-cholorophenyl hydrazone; FUNDC1: FUN14 domain-containing 1; FKBP8: FKBP506 binding protein 8; HCV: hepatitis C virus; HBV: hepatitis B virus; IFN: interferon; L. monocytogenes: Listeria monocytogenes; M. bovis: Mycobacterium bovis; Mtb: Mycobacterium tuberculosis; Mdivi-1: mitochondrial division inhibitor 1; PINK1: PTEN-induced putative kinase 1; TBK1: TANK-binding kinase 1; TUFM: Tu translation elongation factor, mitochondrial; TEM: transmission electron microscopy.
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Macroautofagia , Macrófagos , Mitofagia , Mycobacterium bovis , Animales , Macrófagos/microbiología , Proteínas de la Membrana , Ratones , Proteínas Mitocondriales/metabolismo , Mycobacterium bovis/metabolismoRESUMEN
Bacillus Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB). However, BCG has variable efficacy and cannot completely prevent TB infection and transmission. Therefore, the worldwide prevalence of TB calls for urgent development of a more effective TB vaccine. In the absence of other approved vaccines, it is also necessary to improve the efficacy of BCG itself. Intravenous (IV) BCG administration and BCG revaccination strategies have recently shown promising results for clinical usage. Therefore, it is necessary for us to revisit the BCG vaccination strategies and summarize the current research updates related to BCG vaccination. This literature review provides an updated overview and perspectives of the immunization strategies against TB using BCG, which may inspire the following research on TB vaccine development.
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Mycobacterium bovis , Mycobacterium tuberculosis , Vacunas contra la Tuberculosis , Tuberculosis , Vacuna BCG , Humanos , Inmunización Secundaria , Tuberculosis/epidemiología , Tuberculosis/prevención & control , VacunaciónRESUMEN
Mycobacterium bovis is the causative agent of bovine tuberculosis and also responsible for serious threat to public health. Koumiss is a fermented mare's milk product, used as traditional drink. Here, we explored the effect of koumiss on gut microbiota and the host immune response against M bovis infection. Therefore, mice were treated with koumiss and fresh mare milk for 14 days before M bovis infection and continue for 5 weeks after infection. The results showed a clear change in the intestinal flora of mice treated with koumiss, and the lungs of mice treated with koumiss showed severe edema, inflammatory infiltration, and pulmonary nodules in M bovis-infected mice. Notably, we found that the content of short-chain fatty acids was significantly lower in the koumiss-treated group compared with the control group. However, the expression of endoplasmic reticulum stress and apoptosis-related proteins in the lungs of koumiss-treated mice were significantly decreased. Collectively, these findings suggest that koumiss treatment disturb the intestinal flora of, which is associated with disease severity and the possible mechanism that induces lungs pathology. Our current findings can be exploited further to establish the "gut-lung" axis which might be a novel strategy for the control of tuberculosis.
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Estrés del Retículo Endoplásmico/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Kumis/efectos adversos , Mycobacterium bovis/efectos de los fármacos , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patología , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Ácidos Grasos/análisis , Heces/química , Heces/microbiología , Femenino , Microbioma Gastrointestinal/inmunología , Caballos , Pulmón/efectos de los fármacos , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Mycobacterium bovis/inmunología , Tuberculosis Pulmonar/dietoterapia , Tuberculosis Pulmonar/metabolismoRESUMEN
Mycobacterium bovis (M. bovis) infection triggers cytokine production via pattern recognition receptors. These cytokines include type I interferons (IFNs) and interleukin-1ß (IL-1ß). Excessive type I IFN levels impair host resistance to M. bovis infection. Therefore, strict control of type I IFN production is helpful to reduce pathological damage and bacterial burden. Here, we found that a deficiency in caspase-1, which is the critical component of the inflammasome responsible for IL-1ß production, resulted in increased IFN-ß production upon M. bovis infection. Subsequent experiments demonstrated that caspase-1 activation reduced cyclic GMP-AMP synthase (cGAS) expression, thereby inhibiting downstream TANK-binding kinase 1 (TBK1)- interferon regulatory factor 3 (IRF3) signaling and ultimately reducing IFN production. A deficiency in caspase-1 activation enhanced the bacterial burden during M. bovis infection in vitro and in vivo and aggravated pathological lesion formation. Thus, caspase-1 activation reduced IFN-ß production upon M. bovis infection by dampening cGAS-TBK1-IRF3 signaling, suggesting that the inflammasome protects hosts by negatively regulating harmful cytokines.
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Caspasa 1/metabolismo , Animales , Inhibidores de Caspasas/farmacología , Supervivencia Celular , Dipéptidos/farmacología , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Inflamasomas , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Interferón beta , Ratones , Ratones Endogámicos C57BL , Mycobacterium bovis , Nucleotidiltransferasas , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Distribución Aleatoria , para-Aminobenzoatos/farmacologíaRESUMEN
Caspases are classified as inflammatory or apoptotic category. Inflammatory caspases participate in inflammasome activation, while apoptotic caspases mediate apoptotic activation. Previous studies have shown that apoptotic caspases prevent the production of IFN-ß during apoptosis or virus infection. However, the relationship between apoptotic caspases and IFN-ß production during intracellular bacterial infection is still unclear. Here, we investigated the role of apoptotic caspases in IFN-ß production induced by Mycobacterium bovis (M. bovis) infection. M. bovis is an intracellular bacterium and belongs to the Mycobacterium tuberculosis complex. M. bovis infection can cause tuberculosis in animals and human beings. In the current study, we found that M. bovis infection triggered mitochondrial stress, which caused the leakage of cytochrome c into the cytoplasm, and in turn, activated the downstream caspase-9 and-3. Furthermore, our results showed that activation of apoptotic caspases reduced IFN-ß production during M. bovis infection and vice versa. Confocal microscopy analysis revealed that apoptotic caspases prevented IFN-ß production by decreasing p-IRF3 nuclear translocation. Our findings demonstrate that apoptotic caspases negatively regulate the production of IFN-ß induced by an intracellular bacterial infection.
Asunto(s)
Apoptosis , Caspasas , Interferón beta/inmunología , Macrófagos/inmunología , Mycobacterium bovis , Animales , Caspasas/genética , Macrófagos/microbiología , Ratones , TuberculosisRESUMEN
BACKGROUND: The use of wheat and flaxseed to produce omega-3 (ω-3) enriched poultry meat and eggs is very popular in the world. However, wheat and flaxseed contain some anti-nutritional factors (ANFs), and enzymes are usually used to alleviate the deleterious influence of ANFs. METHOD: A 2 × 3 two factors design was used in the experiment. A total of 540 twenty-week-old Nongda-3 laying hens were randomly allocated to six dietary treatments, two diets (corn/flaxseed and wheat/flaxseed), and three enzymes (enzyme-a contains neutral protease 10,000, xylanase 35,000, ß-mannanase 1500, ß-glucanase 2000, cellulose 500, amylase 100, and pectinase 10,000 (U g-1); enzyme-b contains alkaline protease 40,000 and neutral protease 10,000 (U g-1); enzyme-c contains alkaline protease 40,000, neutral protease 10,000, and cellulase 4000 (U g-1). RESULTS: There was an interaction between dietary treatment and supplemental enzymes for liver weight and liver inflammatory cytokines of broilers. A significant increase was observed in the fat weight of birds fed a corn diet as compared with a wheat diet. A corn diet and wheat diet with the addition of enzyme-a (p < 0.001) showed the highest level of liver fat followed by enzyme-c (p < 0.01) and enzyme-b. Moreover, a high level of secretory IL-1ß, IL-6, and IL-10 and comparatively higher inflammatory changes in the liver tissue were found in birds fed a corn diet as compared with a wheat diet, and enzyme-b showed more beneficial effects as compared with enzyme-a and -c. The gut microbial composition of hens fed a corn diet was significantly different than that of birds fed a wheat diet. Bacteroides were significantly (p < 0.05) abundant in the corn-fed birds as compared with wheat-fed birds. However, Firmicutes were less abundant in the wheat-fed birds than the corn-fed birds (16.99 vs. 31.80%, respectively). The microbial community at the genus level differed significantly in the dietary groups and we observed that Bacteroides are the predominant cecal microbiota. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of co-factors, carbohydrates, vitamins, protein, and energy were expressed at slightly higher levels in the microbiota of the wheat-fed birds, whereas, metabolic pathways for nucleotides, lipids, and glycine were expressed at higher levels in the wheat-fed birds. Furthermore, expression of the growth and cellular processes pathway and endocrine system pathway levels were predicted to be higher for the wheat-fed group as compared with the corn-fed group. CONCLUSIONS: In conclusion, our findings suggest that inflammatory changes in laying birds were mediated by a corn diet with flaxseed and enzymes instead of a wheat diet. Additionally, in the wheat-fed group, enzyme-b and -c showed more encouraging results as compared to enzyme-a.