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1.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445367

RESUMO

Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)-an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO-control, AIA-untreated adjuvant-induced arthritis, AIA-BIL-adjuvant-induced arthritis administrated UCB, CO-BIL-control with administrated UCB. UCB was administered intraperitoneally 200 mg/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund's adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Bilirrubina/administração & dosagem , Adjuvante de Freund/efeitos adversos , Lipídeos/efeitos adversos , Mycobacterium/imunologia , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Bilirrubina/farmacologia , Proteína C-Reativa , Ceruloplasmina/metabolismo , Injeções Intraperitoneais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Resultado do Tratamento
2.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299217

RESUMO

The mycobacterial cell wall is composed of large amounts of lipids with varying moieties. Some mycobacteria species hijack host cells and promote lipid droplet accumulation to build the cellular environment essential for their intracellular survival. Thus, lipids are thought to be important for mycobacteria survival as well as for the invasion, parasitization, and proliferation within host cells. However, their physiological roles have not been fully elucidated. Recent studies have revealed that mycobacteria modulate the peroxisome proliferator-activated receptor (PPAR) signaling and utilize host-derived triacylglycerol (TAG) and cholesterol as both nutrient sources and evasion from the host immune system. In this review, we discuss recent findings that describe the activation of PPARs by mycobacterial infections and their role in determining the fate of bacilli by inducing lipid metabolism, anti-inflammatory function, and autophagy.


Assuntos
Infecções por Mycobacterium/microbiologia , Mycobacterium/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Autofagia/fisiologia , Colesterol/metabolismo , Humanos , Metabolismo dos Lipídeos , Mycobacterium/crescimento & desenvolvimento , Mycobacterium/imunologia , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Transdução de Sinais
4.
Vet Immunol Immunopathol ; 237: 110268, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34023615

RESUMO

In the present study, calves were infected with Mycobacterium avium subsp. paratuberculosis (MAP), Mycobacterium avium subsp. avium (M. avium), Mycobacterium kansasii (M. kansasii), or Mycobacterium bovis (M. bovis) to determine differences in cellular immunity. Comparative cellular responses were assessed upon stimulation of cells with mycobacterial whole cell sonicates respective of each infection group. Antigen-specific whole blood interferon gamma (IFN-γ) responses were observed in all infection groups compared to noninfected control calves, however, responses were more robust for M. bovis calves. Upon antigen stimulation of PBMCs, secretion of IFN-γ and IL-10 was higher for M. bovis calves compared to other infection groups. In contrast, IL-12 secretion was lower for M. bovis calves compared to MAP infected calves. Within the total PBMC population, higher numbers of CD4+, CD8+, and γδ TCR + T cells were observed for MAP and M. avium calves compared to M. bovis calves. This aligned with higher expression of CD26 on these subpopulations for MAP and M. avium calves, as well. In contrast, greater expression of CD25 was observed on CD4+ and γδ TCR + T cells and natural killer cells for M. bovis calves. Overall, similarities in cellular immune responses were observed between the closely related MAP and M. avium during infection of calves. In contrast, significant differences were noted between calves infected with MAP and M. bovis. This suggests that host immune responses to different mycobacteria may impact interpretation of diagnostic tools based upon their cellular immunity.


Assuntos
Doenças dos Bovinos/microbiologia , Imunidade Celular , Infecções por Mycobacterium/veterinária , Animais , Bovinos , Doenças dos Bovinos/imunologia , Reações Cruzadas , Citocinas/imunologia , Citometria de Fluxo/veterinária , Interferon gama/imunologia , Subpopulações de Linfócitos/imunologia , Masculino , Mycobacterium/imunologia , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia , Mycobacterium avium subsp. paratuberculosis/imunologia , Mycobacterium bovis/imunologia , Mycobacterium kansasii/imunologia , Especificidade da Espécie
5.
Front Immunol ; 12: 632304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953709

RESUMO

Cross-reactive vaccines recognize common molecular patterns in pathogens and are able to confer broad spectrum protection against different infections. Antigens common to pathogenic bacteria that induce broad immune responses, such as the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of the genera Listeria, Mycobacterium, or Streptococcus, whose sequences present more than 95% homology at the N-terminal GAPDH1-22 peptide, are putative candidates for universal vaccines. Here, we explore vaccine formulations based on dendritic cells (DC) loaded with two molecular forms of Listeria monocytogenes GAPDH (LM-GAPDH), such as mRNA carriers or recombinant proteins, and compare them with the same molecular forms of three other antigens used in experimental vaccines, listeriolysin O of Listeria monocytogeness, Ag85A of Mycobacterium marinum, and pneumolysin of Streptococcus pneumoniae. DC loaded with LM-GAPDH recombinant proteins proved to be the safest and most immunogenic vaccine vectors, followed by mRNA encoding LM-GAPDH conjugated to lipid carriers. In addition, macrophages lacked sufficient safety as vaccines for all LM-GAPDH molecular forms. The ability of DC loaded with LM-GAPDH recombinant proteins to induce non-specific DC activation explains their adjuvant potency and their capacity to trigger strong CD4+ and CD8+ T cell responses explains their high immunogenicity. Moreover, their capacity to confer protection in vaccinated mice against challenges with L. monocytogenes, M. marinum, or S. pneumoniae validated their efficiency as cross-reactive vaccines. Cross-protection appears to involve the induction of high percentages of GAPDH1-22 specific CD4+ and CD8+ T cells stained for intracellular IFN-γ, and significant levels of peptide-specific antibodies in vaccinated mice. We concluded that DC vaccines loaded with L. monocytogenes GAPDH recombinant proteins are cross-reactive vaccines that seem to be valuable tools in adult vaccination against Listeria, Mycobacterium, and Streptococcus taxonomic groups.


Assuntos
Vacinas Bacterianas/imunologia , Gliceraldeído-3-Fosfato Desidrogenases/imunologia , Lipídeos/imunologia , Listeria/imunologia , Mycobacterium/imunologia , RNA Mensageiro/imunologia , Streptococcus/imunologia , Adjuvantes Imunológicos , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Infecções Bacterianas/prevenção & controle , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteção Cruzada , Reações Cruzadas , Células Dendríticas/imunologia , Gliceraldeído-3-Fosfato Desidrogenases/genética , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Interferon gama/imunologia , Lipídeos/química , Listeria/enzimologia , Listeria/genética , Camundongos , RNA Mensageiro/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia
6.
mSphere ; 6(3)2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952660

RESUMO

Mycobacterium tuberculosis infections claim more than a million lives each year, and better treatments or vaccines are required. A crucial pathogenicity factor is translocation from phagolysosomes to the cytosol upon phagocytosis by macrophages. Translocation from the phagolysosome to the cytosol is an ESX-1-dependent process, as previously shown in vitro Here, we show that in vivo, mycobacteria also translocate to the cytosol but mainly when host immunity is compromised. We observed only low numbers of cytosolic bacilli in mice, armadillos, zebrafish, and patient material infected with M. tuberculosis, M. marinum, or M. leprae In contrast, when innate or adaptive immunity was compromised, as in severe combined immunodeficiency (SCID) or interleukin-1 receptor 1 (IL-1R1)-deficient mice, significant numbers of cytosolic M. tuberculosis bacilli were detected in the lungs of infected mice. Taken together, in vivo, translocation to the cytosol of M. tuberculosis is controlled by adaptive immune responses as well as IL-1R1-mediated signals.IMPORTANCE For decades, Mycobacterium tuberculosis has been one of the deadliest pathogens known. Despite infecting approximately one-third of the human population, no effective treatment or vaccine is available. A crucial pathogenicity factor is subcellular localization, as M. tuberculosis can translocate from phagolysosome to the cytosol in macrophages. The situation in vivo is more complicated. In this study, we establish that high-level cytosolic escape of mycobacteria can indeed occur in vivo but mainly when host resistance is compromised. The IL-1 pathway is crucial for the control of the number of cytosolic mycobacteria. The establishment that immune signals result in the clearance of cells containing cytosolic mycobacteria connects two important fields, cell biology and immunology, which is vital for the understanding of the pathology of M. tuberculosis.


Assuntos
Citosol/microbiologia , Mycobacterium/imunologia , Mycobacterium/patogenicidade , Fagossomos/microbiologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Transdução de Sinais/imunologia , Animais , Tatus/microbiologia , Translocação Bacteriana , Citosol/imunologia , Feminino , Humanos , Hanseníase/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Mycobacterium/classificação , Fagossomos/imunologia , Pele/microbiologia , Pele/patologia , Células THP-1 , Peixe-Zebra
7.
Front Immunol ; 12: 662128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34012446

RESUMO

NK cells play an important role in the control of tuberculosis infection: they are not only able to kill the infected cells, but also control the activity of macrophages and development of the adaptive immune response. Still, there is little information on the role of specific NK cell subsets in this network. In this study, we focused on the mycobacteria-driven responses of the NK cells expressing HLA-DR - a type of MHC class II. We have revealed that this subset is increased in the peripheral blood of patients with primary diagnosed tuberculosis, and expands in response to in vitro stimulation with ultrasonically destroyed Mycobacterium tuberculosis cells (sonicate). The expanded HLA-DR+ NK cells had less differentiated phenotype, higher proliferative activity and increased expression of NKp30 and NKp46 receptors. HLA-DR+CD56dim NK cells showed higher IFNγ production and degranulation level than the respective HLA-DR- NK cells in response to both 24 h and 7 day stimulation with sonicate, while HLA-DR+CD56bright NK cells mostly demonstarted similar high responsiveness to the same stimulating conditions as their HLA-DR-CD56bright counterparts. After preliminary incubation with destroyed mycobacteria, cytokine-activated HLA-DR-expressing NK cells were able to mediate mycobacteria-induced and HLA-DR-dependent cytokine production in autologous CD4+ T cells. Thus, functionally active HLA-DR+ cells seem to be one of the NK cell subsets providing an important link to the adaptive immunity.


Assuntos
Antígenos de Bactérias/imunologia , Antígenos HLA-DR/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Mycobacterium/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa , Antígenos de Bactérias/farmacologia , Antígenos HLA-DR/genética , Humanos , Interferon gama/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Mycobacterium/química , Fenótipo , Linfócitos T/efeitos dos fármacos
8.
Nat Commun ; 12(1): 2027, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795674

RESUMO

The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type. We previously found that multinucleated giant cells result from Toll-like receptor-induced DNA damage and cell autonomous cell cycle modifications. However, the giant cell progenitor identity remained unclear. Here, we show that the giant cell-forming potential is a particular trait of monocyte progenitors. Common monocyte progenitors potently produce cytokines in response to mycobacteria and their immune-active molecules. In addition, common monocyte progenitors accumulate cholesterol and lipids, which are prerequisites for giant cell transformation. Inducible monocyte progenitors are so far undescribed circulating common monocyte progenitor descendants with high giant cell-forming potential. Monocyte progenitors are induced in mycobacterial infections and localize to granulomas. Accordingly, they exhibit important immunological functions in mycobacterial infections. Moreover, their signature trait of high cholesterol metabolism may be piggy-backed by mycobacteria to create a permissive niche.


Assuntos
Citocinas/imunologia , Células Gigantes/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Células-Tronco/imunologia , Animais , Células Cultivadas , Citocinas/metabolismo , Feminino , Células Gigantes/metabolismo , Células Gigantes/microbiologia , Granuloma/imunologia , Granuloma/metabolismo , Humanos , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Monócitos/metabolismo , Monócitos/microbiologia , Mycobacterium/imunologia , Mycobacterium/fisiologia , Células-Tronco/metabolismo , Células-Tronco/microbiologia
9.
Vet Microbiol ; 253: 108952, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33370619

RESUMO

Mycobacterium caprae, a member of the Mycobacterium tuberculosis complex, infects humans and animals causing lesions and disease like that of Mycobacterium bovis. The aim of this study was to evaluate antibody responses in European Bison (EB, Bison bonasus; a vulnerable species) naturally infected with M. caprae using dual path platform (DPP) BovidTB test and multi-antigen print immunoassay (MAPIA). Study cohorts consisted of naturally M. caprae-infected EB (n = 4), M. caprae-exposed but uninfected (n = 3), EB infected with non-tuberculous mycobacteria or other respiratory pathogens (n = 3), and negative controls (n = 19). M. caprae-infected EB were seropositive by both DPP and MAPIA; 3/4 were seropositive by DPP; and 4/4 were seropositive by MAPIA. One M. caprae-infected animal that developed generalized disease with most advanced gross lesions in the group produced the most robust antibody response. All 25 EB with no culture-confirmed M. caprae infection, including three animals exposed to M. caprae and three other animals infected with non-tuberculous pathogens, were seronegative on both tests. Antibody responses to M. caprae infection included IgM antibodies against MPB70/MPB83 and IgG antibodies to both MPB70/MPB83 and CFP10/ESAT-6. This study demonstrates the potential for use of serological assays in the ante-mortem diagnosis of M. caprae infection in EB.


Assuntos
Anticorpos Antibacterianos/sangue , Formação de Anticorpos , Bison/microbiologia , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/veterinária , Mycobacterium/imunologia , Animais , Animais Selvagens/microbiologia , Bison/imunologia , Imunoensaio , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Mycobacterium/classificação
10.
Cell ; 183(7): 1826-1847.e31, 2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33296702

RESUMO

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αß T and non-classic CD4+ αß TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αß T, and CD4+ αß TH1∗ cells unable to compensate for this deficit.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Interferon gama/imunologia , Mycobacterium/imunologia , Proteínas com Domínio T/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Linhagem da Célula , Pré-Escolar , Cromatina/metabolismo , Ilhas de CpG/genética , Metilação de DNA/genética , Células Dendríticas/metabolismo , Epigênese Genética , Feminino , Homozigoto , Humanos , Mutação INDEL/genética , Lactente , Interferon gama/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Mutação com Perda de Função/genética , Masculino , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia , Linhagem , Proteínas com Domínio T/química , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/genética , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma/genética
12.
Sci Rep ; 10(1): 20369, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33230112

RESUMO

Vaccination of goats against tuberculosis (TB) has been promoted as an ancillary tool for controlling the disease in infected livestock herds. A three-year trial to assess the efficacy of BCG vaccine was carried out in five goat herds. At the beginning of the trial (month 0), all animals were tested for TB using thee different diagnostic tests. Animals negative to all tests were vaccinated with BCG and all replacement goat kids were also systematically vaccinated throughout the trial. All animals were tested by Interferon-gamma release assay (IGRA) using vaccine compatible reagents at months 6, 12, 24, and 36. The risk factors for TB infection were also evaluated. At the end of the study, four out of five farms showed variable reductions of the initial prevalence (93.5%, 28.5%, 23.2%, and 14.3% respectively), and an overall incidence reduction of 50% was observed in BCG vaccinated goats, although adult vaccinated goats showed higher incidences than vaccinated goat kids. The unvaccinated positive animals remaining in herds and adult BCG vaccinated goats significantly enhanced the risk of infection in vaccinated animals. A systematic vaccination of goats with BCG, together with the removal of positive unvaccinated animals, may contribute to reducing the TB prevalence in goat herds.


Assuntos
Vacina BCG/administração & dosagem , Doenças das Cabras/epidemiologia , Cabras/microbiologia , Mycobacterium bovis/imunologia , Tuberculose/epidemiologia , Tuberculose/veterinária , Criação de Animais Domésticos/organização & administração , Animais , Fazendas/organização & administração , Doenças das Cabras/imunologia , Doenças das Cabras/prevenção & controle , Humanos , Imunogenicidade da Vacina , Interferon gama/biossíntese , Mycobacterium/imunologia , Mycobacterium/patogenicidade , Mycobacterium bovis/química , Mycobacterium bovis/patogenicidade , Prevalência , Espanha/epidemiologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinação/métodos , Potência de Vacina
13.
PLoS Pathog ; 16(10): e1008969, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33119725

RESUMO

Protective variables for Coronavirus Disease 2019 (COVID-19) are unknown. "Trained immunity" of the populace as a result of Bacille Calmette-Guérin (BCG) vaccination policy implementation and coverage had been suggested to be one of the factors responsible for the differential impact of COVID-19 on different countries. Several trials are underway to evaluate the potential protective role of BCG vaccination in COVID-19. However, the lack of clarity on the use of appropriate controls concerning the measures of "trained immunity" or the heterologous cell-mediated immunity conferred by BCG vaccination has been a cause of concern leading to more confusion as exemplified by a recently concluded trial in Israel that failed to find any protective correlation with regard to BCG vaccination. Whereas, when we analyze the COVID-19 epidemiological data of European countries without any regard for BCG vaccination policy but with similar age distribution, comparable confounding variables, and the stage of the pandemic, the prevalence of tuberculin immunoreactivity-a measure of cell-mediated immunity persistence as a result of Mycobacterium spp. (including BCG vaccine) exposure of the populations-is found consistently negatively correlated with COVID-19 infections and mortality. We seek to draw attention toward the inclusion of controls for underlying "trained immunity" and heterologous cell-mediated immunity prevalence that may be preexisting or resulting from the intervention (e.g., BCG vaccine) in such trials to arrive at more dependable conclusions concerning potential benefit from them.


Assuntos
Vacina BCG/imunologia , Infecções por Coronavirus/imunologia , Imunidade Celular , Mycobacterium/imunologia , Pneumonia Viral/imunologia , Vacinação , Betacoronavirus , COVID-19 , Humanos , Pandemias , SARS-CoV-2
14.
FASEB J ; 34(9): 12820-12833, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32738179

RESUMO

Pathogenic mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium marinum, can trigger NLRP3 inflammasome activation leading to maturation and secretion of interleukin 1ß (IL-1ß). However, the mycobacterial factors involved in the activation of NLRP3 inflammasome are not fully understood. Here, we identified that the PPE family protein PPE13 was responsible for the induction of IL-1ß secretion in a NLRP3 inflammasome-dependent manner. We found that the recombinant Mycobacterium smegmatis expressing PPE13 activates NLRP3 inflammasome, thereby inducing caspase-1 cleavage and IL-1ß secretion in J774A.1, BMDMs, and THP-1 macrophages. To examine whether this inflammasome activation was triggered by PPE13 rather than components of M. smegmatis, PPE13 was introduced into the aforementioned macrophages by lentivirus as a delivery vector. Similarly, this led to the activation of NLRP3 inflammasome, indicating that PPE13 is a direct activator of NLRP3 cascade. We further demonstrated that the NLRP3 complex activated the inflammasome cascade, and the assembly of this complex was facilitated by PPE13 through interacting with the LRR and NATCH domains of NLRP3. Finally, we found that all PPE13 proteins isolated from M. tuberculosis, M. bovis, and M. marinum can activate NLRP3 inflammasome through binding to NLRP3, which requires C-terminal repetitive MPTR domain of PPE13. Thus, we, for the first time, revealed that PPE13 triggers the inflammasome-response by interacting with the MPTR domain of PPE13 and the LRR and NATCH domains of NLRP3. These findings provide a novel perspective on the function of PPE proteins in the immune system during mycobacteria invasion.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Mycobacterium/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Linhagem Celular , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Domínios Proteicos , Células THP-1
15.
Ann Diagn Pathol ; 48: 151600, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32805515

RESUMO

The vaccine BCG has been reported to offer protection against SARS-CoV-2 infection. It has been hypothesized this is based on nonspecific enhancement of innate immunity. This study addressed whether there is strong homology between a SARS-CoV-2 capsid protein and a Mycobacterium bovis protein that would allow for stronger, more specific immune protection. The study also showed the utility of immunohistochemistry in the diagnostic pathology laboratory for elucidating this information. Immunohistochemistry documented that an antibody directed against the SARS-CoV-2 envelope, but not the spike or membrane proteins, strongly cross hybridized to 11/11 Mycobacterial species tested, including M. bovis. BlastP analysis showed high homology of the SARS-CoV-2 envelope protein with 12 consecutive amino acids of the protein LytR C, which is a consensus protein unique to Mycobacteria. Six additional cases of human tuberculosis with few organisms showed that the viral envelope specific antibody (5/6) was more accurate than the AFB stain (2/6) for diagnostic purposes. These data indicate BCG vaccination induces a specific immunity against SARS CoV-2 that targets the viral envelope protein that is essential for infectivity. Thus, a concurrent booster or first use of the BCG vaccine may reduce the severity of the current COVID-19 pandemic. The data also suggests the value of using the SARS-CoV-2 envelope antibody in the diagnosis of Mycobacterial infections in formalin fixed, paraffin embedded tissues by the diagnostic pathologist.


Assuntos
Antígenos Virais/imunologia , Vacina BCG/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Mycobacterium/imunologia , Pneumonia Viral/imunologia , Tuberculose/imunologia , Anticorpos Antivirais/imunologia , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico/métodos , Proteínas do Envelope de Coronavírus , Infecções por Coronavirus/diagnóstico , Reações Cruzadas , Humanos , Imuno-Histoquímica/métodos , Pandemias , SARS-CoV-2 , Tuberculose/diagnóstico , Proteínas do Envelope Viral/imunologia
16.
J Clin Immunol ; 40(6): 872-882, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32602053

RESUMO

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare congenital condition characterized by a selective predisposition to infections caused by weakly virulent mycobacteria and other types of intra-macrophagic pathogens. The 16 genes associated with MSMD display a considerable level of allelic heterogeneity, accounting for 31 distinct disorders with variable clinical presentations and prognosis. Most of MSMD deficiencies are isolated, referred to as selective susceptibility to mycobacterial diseases. However, other deficiencies are syndromic MSMD, defined by the combination of the mycobacterial infection with another, equally common, infectious, specific phenotypes. Herein, we described a series of 32 Iranian MSMD cases identified with seven distinct types of molecular defects, all of which are involved in the interferon gamma (IFNγ) immunity, including interleukin IL-12 receptor-ß1 (IL-12Rß1) deficiency (fifteen cases), IL-12p40 deficiency (ten cases), and IL-23R deficiency (three cases), as well as IFNγ receptor 1 (IFNγR1) deficiency, IFNγ receptor 2 (IFNγR2) deficiency, interferon-stimulated gene 15 (ISG15) deficiency, and tyrosine kinase 2 (TYK2) deficiency each in one case. Since the first report of two MSMD patients in our center, we identified 30 other affected patients with similar clinical manifestations. As the number of reported Iranian cases with MSMD diagnosis has increased in recent years and according to the national vaccination protocol, all Iranian newborns receive BCG vaccination at birth, early diagnosis, and therapeutic intervention which are required for a better outcome and also prevention of similar birth defects. Therefore, we investigated the clinical and molecular features of these 32 patients. The current report also defined novel classes of pathological mutations, further expanding our knowledge of the MSMD molecular basis and associated clinical manifestations.


Assuntos
Predisposição Genética para Doença , Infecções por Mycobacterium/genética , Mycobacterium , Adolescente , Alelos , Biomarcadores , Criança , Pré-Escolar , Diagnóstico Tardio , Feminino , Estudos de Associação Genética , Genótipo , Mutação em Linhagem Germinativa , Humanos , Irã (Geográfico) , Masculino , Técnicas de Diagnóstico Molecular , Mutação , Mycobacterium/imunologia , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/microbiologia , Infecções por Mycobacterium/terapia , Fenótipo , Receptores de Interferon/genética , Receptores de Interleucina/genética , Receptores de Interleucina-12/genética
17.
Parasitol Int ; 78: 102132, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32387542

RESUMO

Several vaccines elicit lower efficacy or impaired immune responses in rural compared to urban settings, and in tropical low-income countries compared to high-income countries. An unresolved hypothesis is that immunomodulation by parasitic infections such as helminths (prevalent in rural tropical settings) contributes to suppression of vaccine responses. Among 1-17-year-old Ugandan residents of rural Schistosoma mansoni (Sm)-endemic islands and proximate urban communities with lower helminth exposure, we assessed plasma antibody and whole blood assay cytokine responses to tetanus toxoid (TT) and purified protein derivative of Mycobacterium tuberculosis (PPD). These were taken to represent recall responses to tetanus and BCG vaccination in infancy. PPD-specific responses are additionally induced by tuberculous and non-tuberculous mycobacterial exposure. Urban-rural comparisons showed that PPD-specific IFN-γ and IL-13 and TT-specific IL-13 and IgG concentrations were lower in the rural setting, but that PPD-specific IgE concentrations were higher. Among rural participants, Sm infection was inversely associated with PPD-specific IFN-γ, while nematode infection was positively associated with PPD-specific IgG. Among urban participants, Sm infection was positively associated with PPD-specific responses but inversely associated with TT-specific responses, while nematode infection was inversely associated with TT-specific IgG and IgG4, but no associations were observed with PPD-specific responses. Despite these associations, for the urban-rural comparisons there were no notable changes in test statistics after adjusting for current helminth infections, suggesting that helminths were not the sole explanation for the urban-rural differences observed. Helminths likely work in concert with other environmental exposures and operational factors to influence vaccine response.


Assuntos
Antígenos de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Imunidade , Imunogenicidade da Vacina , População Rural/estatística & dados numéricos , Esquistossomose mansoni/epidemiologia , População Urbana/estatística & dados numéricos , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mycobacterium/imunologia , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/parasitologia , Toxoide Tetânico/imunologia , Uganda/epidemiologia
19.
Front Immunol ; 11: 816, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431712

RESUMO

In reverse vaccinology approaches, complete proteomes of bacteria are submitted to multiple computational prediction steps in order to filter proteins that are possible vaccine candidates. Most available tools perform such analysis only in a single strain, or a very limited number of strains. But the vast amount of genomic data had shown that most bacteria contain pangenomes, i.e., their genomic information contains core, conserved genes, and random accessory genes specific to each strain. Therefore, in reverse vaccinology methods it is of the utmost importance to define core proteins and core epitopes. EpitoCore is a decision-tree pipeline developed to fulfill that need. It provides surfaceome prediction of proteins from related strains, defines core proteins within those, calculate their immunogenicity, predicts epitopes for a given set of MHC alleles defined by the user, and then reports if epitopes are located extracellularly and if they are conserved among the core homologs. Pipeline performance is illustrated by mining peptide vaccine candidates in Mycobacterium avium hominissuis strains. From a total proteome of ~4,800 proteins per strain, EpitoCore predicted 103 highly immunogenic core homologs located at cell surface, many of those related to virulence and drug resistance. Conserved epitopes identified among these homologs allows the users to define sets of peptides with potential to immunize the largest coverage of tested HLA alleles using peptide-based vaccines. Therefore, EpitoCore is able to provide automated identification of conserved epitopes in bacterial pangenomic datasets.


Assuntos
Vacinas Bacterianas/imunologia , Epitopos/imunologia , Infecções por Mycobacterium/prevenção & controle , Mycobacterium/imunologia , Mycobacterium/patogenicidade , Proteoma/imunologia , Alelos , Antígenos de Bactérias/imunologia , Biologia Computacional/métodos , Genoma Bacteriano , Genômica/métodos , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Mycobacterium/genética , Mycobacterium/metabolismo , Vacinas de Subunidades/imunologia , Vacinologia/métodos , Virulência/imunologia
20.
Med Princ Pract ; 29(5): 404-411, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32422630

RESUMO

Asthma is a cause of substantial burden of disease in the world, including both premature deaths and reduced quality of life. A leading hypothesis to explain the worldwide increase of asthma is the "hygiene hypothesis," which suggests that the increase in the prevalence of asthma is due to the reduction in exposure to infections/microbial antigens. In allergic asthma, the most common type of asthma, antigen-specific T helper (Th)2 and Th17 cells and their cytokines are primary mediators of the pathological consequences. In contrast, Th1 and T regulatory (Treg) cells and their cytokines play a protective role. This article aims to review the information on the effect of mycobacteria and their antigens in modulating Th2/Th17 responses towards Th1/Treg responses and protection against asthma in humans and animal models.


Assuntos
Asma/imunologia , Asma/prevenção & controle , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Mycobacterium/imunologia , Animais , Antígenos de Bactérias , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo
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