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1.
Front Immunol ; 13: 815609, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35173729

RESUMO

Conventional vaccines are very efficient in the prevention of bacterial infections caused by extracellular pathogens due to effective stimulation of pathogen-specific antibodies. In contrast, considering that intracellular surveillance by antibodies is not possible, they are typically less effective in preventing or treating infections caused by intracellular pathogens such as Mycobacterium tuberculosis. The objective of the current study was to use so-called photochemical internalization (PCI) to deliver a live bacterial vaccine to the cytosol of antigen-presenting cells (APCs) for the purpose of stimulating major histocompatibility complex (MHC) I-restricted CD8 T-cell responses. For this purpose, Mycobacterium bovis BCG (BCG) was combined with the photosensitiser tetraphenyl chlorine disulfonate (TPCS2a) and injected intradermally into mice. TPCS2a was then activated by illumination of the injection site with light of defined energy. Antigen-specific CD4 and CD8 T-cell responses were monitored in blood, spleen, and lymph nodes at different time points thereafter using flow cytometry, ELISA and ELISPOT. Finally, APCs were infected and PCI-treated in vitro for analysis of their activation of T cells in vitro or in vivo after autologous vaccination of mice. Combination of BCG with PCI induced stronger BCG-specific CD4 and CD8 T-cell responses than treatment with BCG only or with BCG and TPCS2a without light. The overall T-cell responses were multifunctional as characterized by the production of IFN-γ, TNF-α, IL-2 and IL-17. Importantly, PCI induced cross-presentation of BCG proteins for stimulation of antigen-specific CD8 T-cells that were particularly producing IFN-γ and TNF-α. PCI further facilitated antigen presentation by causing up-regulation of MHC and co-stimulatory proteins on the surface of APCs as well as their production of TNF-α and IL-1ß in vivo. Furthermore, PCI-based vaccination also caused local inflammation at the site of vaccination, showing strong infiltration of immune cells, which could contribute to the stimulation of antigen-specific immune responses. This study is the first to demonstrate that a live microbial vaccine can be combined with a photochemical compound and light for cross presentation of antigens to CD8 T cells. Moreover, the results revealed that PCI treatment strongly improved the immunogenicity of M. bovis BCG.


Assuntos
Vacina BCG/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Pulmão/imunologia , Animais , Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Vacina BCG/administração & dosagem , Apresentação Cruzada , Feminino , Inflamação/imunologia , Injeções Intradérmicas , Interferon gama/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mycobacterium bovis/imunologia , Fármacos Fotossensibilizantes/administração & dosagem , Fator de Necrose Tumoral alfa/biossíntese , Vacinação/métodos
2.
Lancet Infect Dis ; 22(1): e2-e12, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506734

RESUMO

Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination.


Assuntos
Vacina BCG/história , Vacina BCG/imunologia , Mycobacterium bovis/imunologia , Tuberculose Bovina/epidemiologia , Tuberculose Bovina/imunologia , Animais , Vacina BCG/efeitos adversos , Bovinos , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Mycobacterium bovis/patogenicidade , Tuberculose Bovina/microbiologia , Tuberculose Bovina/prevenção & controle , Vacinas Atenuadas/imunologia
3.
Cell Stress Chaperones ; 27(1): 37-43, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34755305

RESUMO

The Bacillus Calmette-Guérin (BCG) vaccine is known to have protective effects not only against tuberculosis but also against other unrelated infectious diseases caused by different pathogens. Several epidemiological studies have also documented the beneficial influence of BCG vaccine in reducing both susceptibility to and severity of SARS-CoV-2 infection. The protective, non-specific effects of BCG vaccination would be related to an antigen-independent enhancement of the innate immunity, termed trained immunity. However, the knowledge that heat shock protein (HSP)65 is the main antigen of Mycobacterium bovis BCG prompted us to verify whether sequence similarity existed between HSP65 and SARS-CoV-2 spike (S) and nuclear (N) proteins that could support an antigen-driven immune protection of BCG vaccine. The results of the in silico investigation showed an extensive sequence similarity of HSP65 with both the viral proteins, especially SARS-CoV-2 S, that also involved the regions comprising immunodominant epitopes. The finding that the predicted B cell and CD4+ T cell epitopes of HSP65 shared strong similarity with the predicted B and T cell epitopes of both SARS-CoV-2 S and N would support the possibility of a cross-immune reaction of HSP65 of BCG with SARS-CoV-2.


Assuntos
Vacina BCG/imunologia , COVID-19/imunologia , Proteínas de Choque Térmico/imunologia , Imunidade Inata/imunologia , Mycobacterium bovis/virologia , Vacina BCG/farmacologia , COVID-19/prevenção & controle , Humanos , Mycobacterium bovis/imunologia , Proteínas Nucleares/imunologia , SARS-CoV-2/imunologia
4.
Pediatrics ; 148(6)2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34851422

RESUMO

Tuberculosis (TB) remains an important problem among children in the United States and throughout the world. There is no diagnostic reference standard for latent tuberculosis infection (also referred to as tuberculosis infection [TBI]). The tuberculin skin test (TST) has many limitations, including difficulty in administration and interpretation, the need for a return visit by the patient, and false-positive results caused by cross-reaction with Mycobacterium bovis-bacille Calmette-Guerin vaccines and many nontuberculous mycobacteria. Interferon-gamma release assays (IGRAs) are blood tests that use antigens specific for M tuberculosis; as a result, IGRAs yield fewer false-positive results than the TST. Both IGRAs and the TST have reduced sensitivity in immunocompromised children, including children with severe TB disease. Both methods have high positive predictive value when applied to children with risk factors for TBI, especially recent contact with a person who has TB disease. The advantages of using IGRAs and diminished experience with the placement and interpretation of the TST favor expanded use of IGRAs in children in the United States. There are now several effective and safe regimens for the treatment of TBI in children. For improved adherence to therapy, the 3 rifamycin-based regimens are preferred because of their short duration. Daily isoniazid can be used if there is intolerance or drug interactions with rifamycins. A TB specialist should be involved when there are questions regarding testing interpretation, selection of an appropriate treatment regimen, or management of adverse effects.


Assuntos
Antituberculosos/uso terapêutico , Testes de Liberação de Interferon-gama/métodos , Tuberculose Latente/diagnóstico , Tuberculose Latente/tratamento farmacológico , Teste Tuberculínico/métodos , Adolescente , Fatores Etários , Antituberculosos/efeitos adversos , Vacina BCG/imunologia , Criança , Pré-Escolar , Reações Cruzadas , Reações Falso-Positivas , Humanos , Hospedeiro Imunocomprometido/imunologia , Lactente , Isoniazida/uso terapêutico , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Micobactérias não Tuberculosas/imunologia , Rifampina/análogos & derivados , Rifampina/uso terapêutico , Sensibilidade e Especificidade
5.
Nat Commun ; 12(1): 6658, 2021 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-34795205

RESUMO

Given the encouraging clinical results of both candidate subunit vaccines and revaccination with Bacillus Calmette-Guérin (BCG) against tuberculosis (TB), there is support for combining BCG and subunit vaccination for increased efficacy. BCG and Mycobacterium tuberculosis (Mtb) share ~98% of their genome and current subunit vaccines are almost exclusively designed as BCG boosters. The goal of this study is to design a TB subunit vaccine composed of antigens not shared with BCG and explore the advantages of this design in a BCG + subunit co-administration vaccine strategy. Eight protective antigens are selected to create an Mtb-specific subunit vaccine, named H107. Whereas traditional vaccines containing BCG-shared antigens exhibit in vivo cross-reactivity to BCG, H107 shows no cross-reactivity and does not inhibit BCG colonization. Instead, co-administering H107 with BCG leads to increased adaptive responses against both H107 and BCG. Importantly, rather than expanding BCG-primed T cells, H107 broadens the overall vaccine repertoire with new T cell clones and introduces 'adjuvant-imprinted' qualities including Th17 responses and less-differentiated Th1 cells. Collectively, these features of H107 are associated with a substantial increase in long-term protection.


Assuntos
Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/administração & dosagem , Tuberculose/prevenção & controle , Vacinação/métodos , Animais , Antígenos de Bactérias/imunologia , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Humanos , Imunogenicidade da Vacina , Camundongos , Mycobacterium bovis/imunologia , Células Th1/imunologia , Células Th17/imunologia , Tuberculose/imunologia , Vacinas contra a Tuberculose/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia
6.
Front Immunol ; 12: 687044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630380

RESUMO

Phagosome-lysosome fusion in innate immune cells like macrophages and neutrophils marshal an essential role in eliminating intracellular microorganisms. In microbe-challenged macrophages, phagosome-lysosome fusion occurs 4 to 6 h after the phagocytic uptake of the microbe. However, live pathogenic mycobacteria hinder the transfer of phagosomes to lysosomes, up to 20 h post-phagocytic uptake. This period is required to evade pro-inflammatory response and upregulate the acid-stress tolerant proteins. The exact sequence of events through which mycobacteria retards phagolysosome formation remains an enigma. The macrophage coat protein Coronin1(Cor1) is recruited and retained by mycobacteria on the phagosome membrane to retard its maturation by hindering the access of phagosome maturation factors. Mycobacteria-infected macrophages exhibit an increased cAMP level, and based on receptor stimulus, Cor1 expressing cells show a higher level of cAMP than non-Cor1 expressing cells. Here we have shown that infection of bone marrow-derived macrophages with H37Rv causes a Cor1 dependent rise of intracellular cAMP levels at the vicinity of the phagosomes. This increased cAMP fuels cytoskeletal protein Cofilin1 to depolymerize F-actin around the mycobacteria-containing phagosome. Owing to reduced F-actin levels, the movement of the phagosome toward the lysosomes is hindered, thus contributing to the retarded phagosome maturation process. Additionally, Cor1 mediated upregulation of Cofilin1 also contributes to the prevention of phagosomal acidification, which further aids in the retardation of phagosome maturation. Overall, our study provides first-hand information on Cor1 mediated retardation of phagosome maturation, which can be utilized in developing novel peptidomimetics as part of host-directed therapeutics against tuberculosis.


Assuntos
Cofilina 1/metabolismo , AMP Cíclico/metabolismo , Macrófagos/microbiologia , Proteínas dos Microfilamentos/metabolismo , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium bovis/patogenicidade , Mycobacterium smegmatis/patogenicidade , Mycobacterium tuberculosis/patogenicidade , Fagossomos/microbiologia , Tuberculose/microbiologia , Animais , Linhagem Celular , Interações Hospedeiro-Patógeno , Concentração de Íons de Hidrogênio , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Proteínas dos Microfilamentos/genética , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/metabolismo , Mycobacterium bovis/imunologia , Mycobacterium smegmatis/imunologia , Mycobacterium tuberculosis/imunologia , Fagossomos/imunologia , Fagossomos/metabolismo , Sistemas do Segundo Mensageiro , Tuberculose/imunologia , Tuberculose/metabolismo
7.
Biomolecules ; 11(9)2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34572519

RESUMO

The widely administered tuberculosis (TB) vaccine, Bacillus Calmette-Guerin (BCG), is the only licensed vaccine, but has highly variable efficiency against childhood and pulmonary TB. Therefore, the BCG prime-boost strategy is a rational solution for the development of new TB vaccines. Studies have shown that Mycobacterium tuberculosis (Mtb) culture filtrates contain proteins that have promising vaccine potential. In this study, Rv1876 bacterioferritin was identified from the culture filtrate fraction with strong immunoreactivity. Its immunobiological potential has not been reported previously. We found that recombinant Rv1876 protein induced dendritic cells' (DCs) maturation by MAPK and NF-κB signaling activation, induced a T helper type 1 cell-immune response, and expanded the population of the effector/memory T cell. Boosting BCG with Rv1876 protein enhanced the BCG-primed Th1 immune response and reduced the bacterial load in the lung compared to those of BCG alone. Thus, Rv1876 is a good target for the prime-boost strategy.


Assuntos
Proteínas de Bactérias/imunologia , Células Dendríticas/imunologia , Imunidade , Mycobacterium bovis/imunologia , Células Th1/imunologia , Animais , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/genética , Proliferação de Células , Citocinas/metabolismo , Feminino , Memória Imunológica , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Mutação/genética , Mycobacterium bovis/crescimento & desenvolvimento , Vacinação
8.
Sci Rep ; 11(1): 17981, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504238

RESUMO

Tumor budding is defined as a single cell or a cluster of up to 5 tumor cells at the invasion front. Due to the difficulty of identifying patients at high risk for pT1 non-muscle-invasive bladder cancer (NMIBC) and the difficulties in T1 substaging, tumor budding was evaluated as a potential alternative and prognostic parameter in these patients. Tumor budding as well as growth pattern, invasion pattern and lamina propria infiltration were retrospectively evaluated in transurethral resection of the bladder (TURB) specimens from 92 patients with stage pT1 NMIBC. The presence of tumor budding correlated with multifocal tumors (p = 0.003), discontinuous invasion pattern (p = 0.039), discohesive growth pattern (p < 0.001) and extensive lamina propria invasion (p < 0.001). In Kaplan-Meier analysis, tumor budding was associated with significantly worse RFS (p = 0.005), PFS (p = 0.017) and CSS (p = 0.002). In patients who received BCG instillation therapy (n = 65), the absence of tumor budding was associated with improved RFS (p = 0.012), PFS (p = 0.011) and CSS (p = 0.022), with none of the patients suffering from progression or dying from the disease. Tumor budding is associated with a more aggressive and invasive stage of pT1 NMIBC and a worse outcome. This easy-to-assess parameter could help stratify patients into BCG therapy or early cystectomy treatment groups.


Assuntos
Membrana Mucosa/patologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Idoso , Idoso de 80 Anos ou mais , Cistectomia/métodos , Progressão da Doença , Feminino , Seguimentos , Humanos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Masculino , Mycobacterium bovis/imunologia , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/cirurgia
9.
Microbiol Spectr ; 9(2): e0109821, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-34494864

RESUMO

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is a live attenuated vaccine which can result in local or disseminated infection, most commonly in immunocompromised individuals. Differentiation of BCG from other members of the Mycobacterium tuberculosis complex (MTBC) is required to diagnose BCG disease, which requires specific management. Current methods for BCG diagnosis are based on mycobacterial culture and conventional PCR; the former is time-consuming and the latter often unavailable. Further, there are reports that certain BCG strains may be associated with a higher rate of adverse events. This study describes the development of a two-step multiplex real-time PCR assay which uses single nucleotide polymorphisms to detect BCG and identify early or late BCG strains. The assay has a limit of detection of 1 pg BCG boiled lysate DNA and was shown to detect BCG in both pure cultures and experimentally infected tissue. Its performance was assessed on 19 suspected BCG clinical isolates at Christian Medical College in Vellore, India, taken from January 2018 to August 2020. Of these 19 isolates, 10 were identified as BCG (6 early and 4 late strains), and 9 were identified as other MTBC members. Taken together, the results demonstrate the ability of this assay to identify and characterize BCG disease from cultures and infected tissue. The capacity to identify BCG may improve patient management, and the ability to discriminate between BCG strains may enable BCG vaccine pharmacovigilance. IMPORTANCE Vaccination against tuberculosis with bacillus Calmette-Guérin (BCG) can lead to adverse events, including a rare but life-threatening complication of disseminated BCG. This complication often occurs in young children with immunodeficiencies and is associated with an ∼60% mortality rate. A rapid method of reliably identifying BCG infection is important because BCG requires treatment unique to tuberculosis. BCG is resistant to the first-line antituberculosis drug pyrazinamide. Additionally, diagnosis of BCG disease would lead to further investigation of a possible underlying immune condition. We have developed a diagnostic assay to identify BCG which improves upon previously published methods and can reliably identify BCG from bacterial culture or directly from infected tissue. This assay can also differentiate between strains of BCG, which have been suggested to be associated with different rates of adverse events. This assay was validated on 19 clinical isolates collected at Christian Medical College in Vellore, India.


Assuntos
Infecções por Mycobacterium não Tuberculosas/diagnóstico , Mycobacterium bovis/genética , Mycobacterium bovis/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Vacinas Atenuadas/efeitos adversos , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Humanos , Limite de Detecção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Mycobacterium não Tuberculosas/microbiologia , Infecções por Mycobacterium não Tuberculosas/terapia , Mycobacterium bovis/imunologia , Polimorfismo de Nucleotídeo Único/genética , Tuberculose/prevenção & controle , Vacinas Atenuadas/imunologia , Adulto Jovem
10.
Vet Immunol Immunopathol ; 240: 110320, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34479106

RESUMO

Recent studies have demonstrated potential for serologic assays to improve surveillance and control programs for bovine tuberculosis. Due to the animal-to-animal variation of the individual antibody repertoires observed in bovine tuberculosis, it has been suggested that serodiagnostic sensitivity can be maximized by use of multi-antigen cocktails or genetically engineered polyproteins expressing immunodominant B-cell epitopes. In the present study, we designed three novel multiepitope polyproteins named BID109, TB1f, and TB2f, with each construct representing a unique combination of four full-length peptides of Mycobacterium bovis predominantly recognized in bovine tuberculosis. Functional performance of the fusion antigens was evaluated using multi-antigen print immunoassay (MAPIA) and Dual Path Platform (DPP) technology with panels of monoclonal and polyclonal antibodies generated against individual proteins included in the fusion constructs as well as with serum samples from M. bovis-infected and non-infected cattle, American bison, and domestic pigs. It was shown that epitopes of each individual protein were expressed in the fusion antigens and accessible for efficient binding by the respective antibodies. The three fusion antigens demonstrated stronger immunoreactivity in MAPIA than that of single protein antigens. Evaluation of the fusion antigens in DPP assay using serum samples from 125 M. bovis-infected and 57 non-infected cattle showed the best accuracy (∼84 %) for TB2f antigen composed of MPB70, MPB83, CFP10, and Rv2650c proteins. Thus, the study results suggest a potential for the multiepitope polyproteins to improve diagnostic sensitivity of serologic assays for bovine tuberculosis.


Assuntos
Testes Sorológicos , Tuberculose Bovina , Animais , Anticorpos , Antígenos de Bactérias , Bovinos , Epitopos de Linfócito B , Mycobacterium bovis/imunologia , Poliproteínas , Testes Sorológicos/veterinária , Tuberculose Bovina/diagnóstico
11.
BMC Immunol ; 22(1): 63, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535083

RESUMO

BACKGROUND: Immuno-epidemiologists are often faced with multivariate outcomes, measured repeatedly over time. Such data are characterised by complex inter- and intra-outcome relationships which must be accounted for during analysis. Scientific questions of interest might include determining the effect of a treatment on the evolution of all outcomes together, or grouping outcomes that change in the same way. Modelling the different outcomes separately may not be appropriate because it ignores the underlying relationships between outcomes. In such situations, a joint modelling strategy is necessary. This paper describes a pairwise joint modelling approach and discusses its benefits over more simple statistical analysis approaches, with application to data from a study of the response to BCG vaccination in the first year of life, conducted in Entebbe, Uganda. METHODS: The study aimed to determine the effect of maternal latent Mycobacterium tuberculosis infection (LTBI) on infant immune response (TNF, IFN-γ, IL-13, IL-10, IL-5, IL-17A and IL-2 responses to PPD), following immunisation with BCG. A simple analysis ignoring the correlation structure of multivariate longitudinal data is first shown. Univariate linear mixed models are then used to describe longitudinal profiles of each outcome, and are then combined into a multivariate mixed model, specifying a joint distribution for the random effects to account for correlations between the multiple outcomes. A pairwise joint modelling approach, where all possible pairs of bivariate mixed models are fitted, is then used to obtain parameter estimates. RESULTS: Univariate and pairwise longitudinal analysis approaches are consistent in finding that LTBI had no impact on the evolution of cytokine responses to PPD. Estimates from the pairwise joint modelling approach were more precise. Major advantages of the pairwise approach include the opportunity to test for the effect of LTBI on the joint evolution of all, or groups of, outcomes and the ability to estimate association structures of the outcomes. CONCLUSIONS: The pairwise joint modelling approach reduces the complexity of analysis of high-dimensional multivariate repeated measures, allows for proper accounting for association structures and can improve our understanding and interpretation of longitudinal immuno-epidemiological data.


Assuntos
Tuberculose Latente/imunologia , Mycobacterium tuberculosis/fisiologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Simulação por Computador , Citocinas/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Tuberculose Latente/epidemiologia , Masculino , Exposição Materna/efeitos adversos , Modelos Teóricos , Análise Multivariada , Mycobacterium bovis/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Uganda/epidemiologia , Vacinação
12.
Front Immunol ; 12: 714179, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421917

RESUMO

This article prosecutes a case against the zoonotic pathogen Mycobacterium avium ss. paratuberculosis (MAP) as a precipitant of Alzheimer's disease (AD). Like the other major neurodegenerative diseases AD is, at its core, a proteinopathy. Aggregated extracellular amyloid protein plaques and intracellular tau protein tangles are the recognized protein pathologies of AD. Autophagy is the cellular housekeeping process that manages protein quality control and recycling, cellular metabolism, and pathogen elimination. Impaired autophagy and cerebral insulin resistance are invariant features of AD. With a backdrop of age-related low-grade inflammation (inflammaging) and heightened immune risk (immunosenescence), infection with MAP subverts glucose metabolism and further exhausts an already exhausted autophagic capacity. Increasingly, a variety of agents have been found to favorably impact AD; they are agents that promote autophagy and reduce insulin resistance. The potpourri of these therapeutic agents: mTOR inhibitors, SIRT1 activators and vaccines are seemingly random until one recognizes that all these agents also suppress intracellular mycobacterial infection. The zoonotic mycobacterial MAP causes a common fatal enteritis in ruminant animals. Humans are exposed to MAP from contaminated food products and from the environment. The enteritis in animals is called paratuberculosis or Johne's disease; in humans, it is the putative cause of Crohn's disease. Beyond Crohn's, MAP is associated with an increasing number of inflammatory and autoimmune diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis, multiple sclerosis, and rheumatoid arthritis. Moreover, MAP has been associated with Parkinson's disease. India is one county that has extensively studied the human bio-load of MAP; 30% of more than 28,000 tested individuals were found to harbor, or to have harbored, MAP. This article asserts an unfolding realization that MAP infection of humans 1) is widespread in its presence, 2) is wide-ranging in its zoonosis and 3) provides a plausible link connecting MAP to AD.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Suscetibilidade a Doenças , Imunossenescência , Inflamação/complicações , Resistência à Insulina , Paratuberculose/complicações , Doença de Alzheimer/patologia , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/metabolismo , Animais , Autofagia , Biomarcadores , Humanos , Mycobacterium avium subsp. paratuberculosis , Mycobacterium bovis/imunologia , Paratuberculose/imunologia , Paratuberculose/microbiologia
13.
Front Immunol ; 12: 674643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335572

RESUMO

Bovine tuberculosis is an important animal and zoonotic disease caused by Mycobacterium bovis. The innate immune response is the first line of defense against pathogens and is also crucial for the development of an efficient adaptive immune response. In this study we used an in vitro co-culture model of antigen presenting cells (APC) and autologous lymphocytes derived from peripheral blood mononuclear cells to identify the cell populations and immune mediators that participate in the development of an efficient innate response capable of controlling the intracellular replication of M. bovis. After M. bovis infection, bovine immune cell cultures displayed upregulated levels of iNOS, IL-22 and IFN-γ and the induction of the innate immune response was dependent on the presence of differentiated APC. Among the analyzed M. bovis isolates, only a live virulent M. bovis isolate induced an efficient innate immune response, which was increased upon stimulation of cell co-cultures with the M. bovis culture supernatant. Moreover, we demonstrated that an allelic variation of the early secreted protein ESAT-6 (ESAT6 T63A) expressed in the virulent strain is involved in this increased innate immune response. These results highlight the relevance of the compounds secreted by live M. bovis as well as the variability among the assessed M. bovis strains to induce an efficient innate immune response.


Assuntos
Imunidade Inata/imunologia , Mycobacterium bovis/imunologia , Tuberculose Bovina/imunologia , Animais , Antígenos de Bactérias/imunologia , Bovinos , Técnicas de Cocultura , Citocinas/metabolismo , Interferon gama/metabolismo , Macrófagos , Cultura Primária de Células
14.
Front Immunol ; 12: 696268, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34413849

RESUMO

Context: Disseminated infections due to Mycobacterium bovis Bacillus Calmette-Guérin (BCG) are unusual and occur mostly in patients with inborn error of immunity (IEI) or acquired immunodeficiency. However, cases of secondary BCGosis due to intravesical BCG instillation have been described. Herein, we present a case of severe BCGosis occurring in an unusual situation. Case Description: We report one case of severe disseminated BCG disease occurring after hematological malignancy in a 48-year-old man without BCG instillation and previously vaccinated in infancy with no complication. Laboratory investigations demonstrated that he was not affected by any known or candidate gene of IEI or intrinsic cellular defect involving IFNγ pathway. Whole genome sequencing of the BCG strain showed that it was most closely related to the M. bovis BCG Tice strain, suggesting an unexpected relationship between the secondary immunodeficiency of the patient and the acquired BCG infection. Conclusion: This case highlights the fact that, in addition to the IEI, physicians, as well as microbiologists and pharmacists should be aware of possible acquired disseminated BCG disease in secondary immunocompromised patients treated in centers that administrate BCG for bladder cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Reconstituição Imune , Hospedeiro Imunocomprometido , Mycobacterium bovis/patogenicidade , Infecções Oportunistas/microbiologia , Tuberculose Pulmonar/microbiologia , Administração Intravesical , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antituberculosos/uso terapêutico , Vacina BCG/administração & dosagem , Vacina BCG/efeitos adversos , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium bovis/imunologia , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/imunologia , Fatores de Risco , Resultado do Tratamento , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/imunologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia
15.
FASEB J ; 35(9): e21777, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403519

RESUMO

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.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Kumis/efeitos adversos , Mycobacterium bovis/efeitos dos fármacos , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Graxos/análise , Fezes/química , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Cavalos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/dietoterapia , Tuberculose Pulmonar/metabolismo
16.
J Immunol ; 207(4): 1065-1077, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34321229

RESUMO

CNS tuberculosis (CNSTB) is the most severe manifestation of extrapulmonary tuberculosis infection, but the mechanism of how mycobacteria cross the blood-brain barrier (BBB) is not well understood. In this study, we report a novel murine in vitro BBB model combining primary brain endothelial cells, Mycobacterium bovis bacillus Calmette-Guérin-infected dendritic cells (DCs), PBMCs, and bacterial Ag-specific CD4+ T cells. We show that mycobacterial infection limits DC mobility and also induces cellular cluster formation that has a similar composition to pulmonary mycobacterial granulomas. Within the clusters, infection from DCs disseminates to the recruited monocytes, promoting bacterial expansion. Mycobacterium-induced in vitro granulomas have been described previously, but this report shows that they can form on brain endothelial cell monolayers. Cellular cluster formation leads to cluster-associated damage of the endothelial cell monolayer defined by mitochondrial stress, disorganization of the tight junction proteins ZO-1 and claudin-5, upregulation of the adhesion molecules VCAM-1 and ICAM-1, and increased transmigration of bacteria-infected cells across the BBB. TNF-α inhibition reduces cluster formation on brain endothelial cells and mitigates cluster-associated damage. These data describe a model of bacterial dissemination across the BBB shedding light on a mechanism that might contribute to CNS tuberculosis infection and facilitate treatments.


Assuntos
Barreira Hematoencefálica/imunologia , Células Dendríticas/imunologia , Mycobacterium bovis/imunologia , Tuberculose/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Encéfalo/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Endoteliais/imunologia , Granuloma/imunologia , Molécula 1 de Adesão Intercelular/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Molécula 1 de Adesão de Célula Vascular/imunologia
17.
Vet Immunol Immunopathol ; 239: 110303, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34314936

RESUMO

Bovine tuberculosis (bTB) control programs can be improved by implementation of advanced ante-mortem testing algorithms. Serodiagnostic methods using traditional blood or blood-derived specimens may benefit from the use of less invasive alternative biological fluids, provided those mirror systemic antibody responses. In the present study, we used Dual Path Platform (DPP) and Multiantigen Print Immunoassay (MAPIA) to compare antibody levels in ten sample types including whole blood (fresh and hemolyzed), plasma (fresh and leftover from Bovigam testing), serum, saliva, broncho-alveolar lavage, urine, diaphragm extract, and bile collected from cattle aerosol-infected with Mycobacterium bovis. High correlation (r = 0.97-0.99) in measurements of IgG antibodies to MPB70/MPB83 fusion antigen by DPP assay was found between all blood-derived specimens, supporting matrix equivalency. Broncho-alveolar lavage and diaphragm extract yielded positive results in all the infected animals tested, showing high correlation with matching serum data (r = 0.94 and r = 0.95, respectively) and suggesting their potential use in antibody assays. Characterized by MAPIA, the antigen reactivity patterns obtained with paired sera and alternative specimens were nearly identical, with slight differences in intensity. Antibodies were also found by DPP assay in saliva, urine, and bile from some of the infected animals, but the titers were relatively low, thus reducing the diagnostic value of such specimens. The proposed approach was evaluated in a pilot field study on warthogs diagnosed with M. bovis infection. Relative levels of antibody in tissue fluid obtained from lymph nodes or lungs were consistent with those detected in sera and detectable in all infected warthogs. The findings support the diagnostic utility of non-traditional biological fluids and tissue samples when used as alternative test specimens in serologic assays for bTB.


Assuntos
Anticorpos Antibacterianos/análise , Imunoglobulina G/análise , Doenças dos Suínos , Tuberculose Bovina , Animais , Bovinos , Testes Imunológicos/veterinária , Mycobacterium bovis/imunologia , Extratos Vegetais , Suínos , Doenças dos Suínos/diagnóstico , Doenças dos Suínos/microbiologia , Tuberculose Bovina/diagnóstico
18.
Am J Physiol Lung Cell Mol Physiol ; 321(3): L566-L575, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34287085

RESUMO

The influence of smoke-derived or air pollution-derived cytoplasmic particulate matter (PM) can be detrimental and can lead to failed lung immunity. We investigated mycobacterial uptake, intracellular replication, and soluble immune-mediator responses of human bronchoalveolar lavage cells (BALCs) loaded with/without PM, to infection with mycobacterial strains. We observed that only BALCs containing PM display an ex vivo phenotypic profile dominated by spontaneous interleukin (IL)-10 production. PM-loaded BALCs retained the ability to phagocytose both Mycobacterium bovis Bacille Calmette Guérin (BCG) and Mycobacterium tuberculosis (M.tb) ΔleuDΔpanCD at equal efficacy as clear non-PM-loaded BALCs. However, immune responsiveness, such as the production of IL-6 (P = 0.015) and tumor necrosis factor-α (TNF)-α (P = 0.0172) immediately post M. bovis BCG infection, were dramatically lower in black BALCs loaded with PM versus clear non-PM-loaded BALCs. By 24 h post infection, differential immune responses to M. bovis BCG between black versus clear BALC waned, and instead, production of IL-6 (P = 0.03) and IL-1α (P = 0.04) by black BALCs was lower versus clear BALCs following M.tb ΔleuDΔpanCD infection. Considering that TNF-α and IL-6 are characterized as critical to host protection against mycobacteria, our findings suggest that BALCs loaded with inhaled PM, display lower levels of antimycobacterial mediators and that the response magnitude differs according to infective mycobacterial strain. Even though this did not translate into altered mycobacterial killing at early time points post infection, the long-term impact of such changes remains to be established.


Assuntos
Exposição por Inalação/efeitos adversos , Pulmão/imunologia , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Material Particulado/efeitos adversos , Fagócitos/imunologia , Líquido da Lavagem Broncoalveolar , Feminino , Humanos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Monocinas/imunologia , Fagócitos/microbiologia , Fagócitos/patologia
19.
Biomol Concepts ; 12(1): 94-109, 2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34304400

RESUMO

We previously reported that M. tb on its own as well as together with HIV inhibits macrophage apoptosis by upregulating the expression of Bcl2 and Inhibitor of Apoptosis (IAP). In addition, recent reports from our lab showed that stimulation of either macrophages or BMDCs results in the significant upregulation of Bcl2. In this report, we delineate the role of Bcl2 in mediating defense responses from dendritic cells (BMDCs) during mycobacterial infection. Inhibiting Bcl2 led to a significant decrease in intracellular bacterial burden in BMDCs. To further characterize the role of Bcl2 in modulating defense responses, we inhibited Bcl2 in BMDCs as well as human PBMCs to monitor their activation and functional status in response to mycobacterial infection and stimulation with M. tb antigen Rv3416. Inhibiting Bcl2 generated protective responses including increased expression of co-stimulatory molecules, oxidative burst, pro-inflammatory cytokine expression and autophagy. Finally, co-culturing human PBMCs and BMDCs with antigen-primed T cells increased their proliferation, activation and effector function. These results point towards a critical role for Bcl2 in regulating BMDCs defense responses to mycobacterial infection.


Assuntos
Células Dendríticas/imunologia , Imunidade , Macrófagos/imunologia , Infecções por Mycobacterium/imunologia , Mycobacterium bovis/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Apoptose , Autofagia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Células Dendríticas/patologia , Feminino , Humanos , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Mycobacterium/metabolismo , Infecções por Mycobacterium/microbiologia , Infecções por Mycobacterium/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética
20.
J Clin Invest ; 131(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34060492

RESUMO

First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.


Assuntos
Diabetes Mellitus Tipo 1/terapia , Imunidade Celular , Esclerose Múltipla/terapia , Mycobacterium bovis/imunologia , Linfócitos T/imunologia , Neoplasias da Bexiga Urinária/terapia , Viroses/terapia , Animais , Diabetes Mellitus Tipo 1/história , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , História do Século XX , História do Século XXI , Humanos , Esclerose Múltipla/história , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Infecções por Mycobacterium não Tuberculosas/história , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/patologia , Infecções por Mycobacterium não Tuberculosas/prevenção & controle , Tuberculose/história , Tuberculose/imunologia , Tuberculose/prevenção & controle , Neoplasias da Bexiga Urinária/história , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia , Viroses/história , Viroses/imunologia , Viroses/patologia
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