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1.
Cell Mol Life Sci ; 79(11): 567, 2022 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-36283989

RESUMEN

Mycobacterium tuberculosis (Mtb) is a smart and successful pathogen since it can persist in the intimidating environment of the host by taming and tuning the immune system. Mtb releases MPT64 (Rv1980c) protein in high amounts in patients with active tuberculosis (TB). Consequently, we were curious to decipher the role of MPT64 on the differentiating dendritic cells (DCs) and its relation to evading the immune system. We observed that pre-exposure of differentiating DCs to MPT64 (DCMPT64) transformed them into a phenotype of myeloid-derived suppressor cells (MDSCs). DCMPT64 expressed a high level of immunosuppressive molecules PD-L1, TIM-3, nitric oxide (NO), arginase 1, IDO-1, IL-10 and TGF-ß, but inhibited the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-12. DCMPT64 chemotaxis function was diminished due to the reduced expression of CCR7. DCMPT64 promoted the generation of regulatory T cells (Tregs) but inhibited the differentiation of Th1 cells and Th17 cells. Further, high lipid and methylglyoxal content, and reduced glucose consumption by DCMPT64, rendered them metabolically quiescent and consequently, reduced DCMPT64 ability to phagocytose Mtb and provided a safer shelter for the intracellular survival of the mycobacterium. The mechanism identified in impairing the function of DCMPT64 was through the increased production and accumulation of methylglyoxal. Hence, for the first time, we demonstrate the novel role of MPT64 in promoting the generation of MDSCs to favor Mtb survival and escape its destruction by the immune system.


Asunto(s)
Mycobacterium tuberculosis , Células Supresoras de Origen Mieloide , Células Supresoras de Origen Mieloide/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Arginasa , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Antígeno B7-H1/metabolismo , Óxido Nítrico/metabolismo , Piruvaldehído/metabolismo , Interleucina-6/metabolismo , Receptores CCR7/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Células TH1 , Citocinas/metabolismo , Interleucina-12/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Glucosa/metabolismo , Lípidos , Células Dendríticas/metabolismo
2.
Eur J Immunol ; 50(12): 1976-1987, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32673409

RESUMEN

Tuberculosis (TB) continues to remain a global threat due to the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains and toxicity associated with TB drugs. Intestinal microbiota has been reported to affect the host response to immunotherapy and drugs. However, how it affects the potency of first-line TB drug isoniazid (INH) is largely unknown. Here, we examined the impact of gut microbial dysbiosis on INH efficiency to kill Mtb. In this study, we employed in vivo mouse model, pretreated with broad-spectrum antibiotics (Abx) cocktail to disrupt their intestinal microbial population prior to Mtb infection and subsequent INH therapy. We demonstrated that microbiota disruption results in the impairment of INH-mediated Mtb clearance, and aggravated TB-associated tissue pathology. Further, it suppressed the innate immunity and reduced CD4 T-cell response against Mtb. Interestingly, a distinct shift of gut microbial profile was noted with abundance of Enterococcus and reduction of Lactobacillus and Bifidobacterium population. Our results show that the intestinal microbiota is crucial determinant in efficacy of INH to kill Mtb and impacts the host immune response against infection. This work provides an intriguing insight into the potential links between host gut microbiota and potency of INH.


Asunto(s)
Microbioma Gastrointestinal/inmunología , Intestinos/inmunología , Intestinos/microbiología , Isoniazida/inmunología , Microbiota/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Tuberculosis/microbiología , Animales , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Disbiosis/inmunología , Disbiosis/microbiología , Femenino , Inmunidad Innata/inmunología , Pulmón/inmunología , Pulmón/microbiología , Ratones , Ratones Endogámicos C57BL
3.
J Proteome Res ; 19(11): 4655-4669, 2020 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-33103906

RESUMEN

Vaccines remain the most efficacious means to avoid and eliminate morbid diseases associated with high morbidity and mortality. Clinical trials indicate the gaining impetus of peptide vaccines against diseases for which an effective treatment still remains obscure. CD4 T-cell-based peptide vaccines involve immunization with antigenic determinants from pathogens or neoplastic cells that possess the ability to elicit a robust T helper cell response, which subsequently activates other arms of the immune system. The available in silico predictors of human leukocyte antigen II (HLA-II) binding peptides are sequence-based techniques, which ostensibly have balanced sensitivity and specificity. Structural analysis and understanding of the cognate peptide and HLA-II interactions are essential to empirically derive a successful peptide vaccine. However, the availability of structure-based epitope prediction algorithms is inadequate compared with sequence-based prediction methods. The present study is an attempt to understand the structural aspects of HLA-II binders by analyzing the Protein Data Bank (PDB) complexes of pHLA-II. Furthermore, we mimic the peptide exchange mechanism and demonstrate the structural implication of an acidic environment on HLA-II binders. Finally, we discuss a structure-guided approach to decipher potential HLA-II binders within an antigenic protein. This strategy may accurately predict the peptide epitopes and thus aid in designing successful peptide vaccines.


Asunto(s)
Epítopos de Linfocito T , Péptidos , Antígenos HLA/metabolismo , Humanos , Péptidos/metabolismo , Unión Proteica , Vacunas de Subunidad
4.
Cancer Immunol Immunother ; 68(12): 1995-2004, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31690954

RESUMEN

Glioblastoma is a highly prevalent and aggressive form of primary brain tumor. It represents approximately 56% of all the newly diagnosed gliomas. Macrophages are one of the major constituents of tumor-infiltrating immune cells in the human gliomas. The role of immunosuppressive macrophages is very well documented in correlation with the poor prognosis of patients suffering from breast, prostate, bladder and cervical cancers. The current study highlights the correlation between the tumor-associated macrophage phenotypes and glioma progression. We observed an increase in the pool of M2 macrophages in high-grade gliomas, as confirmed by their CD68 and CD163 double-positive phenotype. In contrast, less M1 macrophages were noticed in high-grade gliomas, as evidenced by the down-regulation in the expression of CCL3 marker. In addition, we observed that higher gene expression ratio of CD163/CCL3 is associated with glioma progression. The Kaplan-Meier survival plots indicate that glioma patients with lower expression of M2c marker (CD163), and higher expression of M1 marker (CCL3) had better survival. Furthermore, we examined the systemic immune response in the peripheral blood and noted a predominance of M2 macrophages, myeloid-derived suppressor cells and PD-1+ CD4 T cells in glioma patients. Thus, the study indicates a high gene expression ratio of CD163/CCL3 in high-grade gliomas as compared to low-grade gliomas and significantly elevated frequency of M2 macrophages and PD-1+ CD4 T cells in the blood of tumor patients. These parameters could be used as an indicator of the early diagnosis and prognosis of the disease.


Asunto(s)
Neoplasias Encefálicas/inmunología , Linfocitos T CD4-Positivos/patología , Glioblastoma/inmunología , Macrófagos/inmunología , Células Supresoras de Origen Mieloide/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Neoplasias Encefálicas/mortalidad , Carcinogénesis , Quimiocina CCL3/metabolismo , Citocinas/metabolismo , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Glioblastoma/mortalidad , Humanos , Tolerancia Inmunológica , Inmunidad Humoral , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Superficie Celular/metabolismo , Análisis de Supervivencia , Células Th2/inmunología
5.
BMC Microbiol ; 19(1): 64, 2019 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-30894125

RESUMEN

BACKGROUND: Mycobacterium tuberculosis (Mtb) is an etiological agent of tuberculosis (TB). Tuberculosis is a mounting problem worldwide. The only available vaccine BCG protects the childhood but not adulthood form of TB. Therefore, efforts are made continuously to improve the efficacy of BCG by supplementing it with other therapies. Consequently, we explored the possibility of employing Mycobacterium immunogenum (Mi) to improve BCG potential to protect against Mtb. RESULTS: We report here the genome mining, comparative genomics, immunological and protection studies employing strain CD11_6 of Mi. Mycobacterium immunogenum was isolated from duodenal mucosa of a celiac disease patient. The strain was whole genome sequenced and annotated for identification of virulent genes and other traits that may make it suitable as a potential vaccine candidate. Virulence profile of Mi was mapped and compared with two other reference genomes i.e. virulent Mtb strain H37Rv and vaccine strain Mycobacterium bovis (Mb) AFF2122/97. This comparative analysis revealed that Mi is less virulent, as compared to Mb and Mtb, and contains comparable number of genes encoding for the antigenic proteins that predict it as a probable vaccine candidate. Interestingly, the animals vaccinated with Mi showed significant augmentation in the generation of memory T cells and reduction in the Mtb burden. CONCLUSION: The study signifies that Mi has a potential to protect against Mtb and therefore can be a future vaccine candidate against TB.


Asunto(s)
Genoma Bacteriano , Activación de Linfocitos , Mycobacteriaceae/genética , Linfocitos T/inmunología , Tuberculosis/inmunología , Animales , Femenino , Genómica , Humanos , Memoria Inmunológica , Ratones Endogámicos C57BL , Mycobacteriaceae/patogenicidad , Mycobacterium bovis/genética , Mycobacterium bovis/patogenicidad , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidad , Factores de Virulencia/genética , Secuenciación Completa del Genoma
6.
J Transl Med ; 16(1): 279, 2018 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-30305097

RESUMEN

BACKGROUND: The clinical trials conducted at Chingleput India suggest that BCG fails to protect against tuberculosis (TB) in TB-endemic population. Recent studies advocate that non-tuberculous mycobacteria and latent Mycobacterium tuberculosis (Mtb) infection interferes in the antigen processing and presentation of BCG in inducing protective immunity against Mtb. Thereby, indicating that any vaccine that require extensive antigen processing may not be efficacious in TB-endemic zones. Recently, we have demonstrated that the vaccine candidate L91, which is composed of lipidated promiscuous MHC-II binder epitope, derived from latency associated Acr1 antigen of Mtb is immunogenic in the murine and Guinea pig models of TB and conferred better protection than BCG against Mtb. METHODS: In this study, we have used a multi-stage based bi-epitope vaccine, namely L4.8, comprising of MHC-I and MHC-II binding peptides of active (TB10.4) and latent (Acr1) stages of Mtb antigens, respectively. These peptides were conjugated to the TLR-2 agonist Pam2Cys. RESULTS: L4.8 significantly elicited both CD8 T cells and CD4 T cells immunity, as evidenced by increase in the enduring polyfunctional CD8 T cells and CD4 T cells. L4.8 efficiently declined Mtb-burden and protected animals better than BCG and L91, even at the late stage of Mtb infection. CONCLUSIONS: The BCG-L4.8 prime boost strategy imparts a better protection against TB than the BCG alone. This study emphatically denotes that L4.8 can be a promising future vaccine candidate for controlling active and latent TB.


Asunto(s)
Vacuna BCG/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epítopos/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Lípidos/química , Mycobacterium tuberculosis/inmunología , Animales , Femenino , Inmunidad , Inmunización , Memoria Inmunológica , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones Endogámicos BALB C , Linfocitos T Citotóxicos/inmunología , Tuberculosis/inmunología
7.
Bioconjug Chem ; 29(4): 1102-1110, 2018 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-29489340

RESUMEN

Peptide-based drug delivery systems have become a mainstay in the contemporary medicinal field, resulting in the design and development of better pharmaceutical formulations. However, most of the available reports employ tedious multiple reaction steps for the conjugation of bioactive cationic peptides with drug delivery vehicles. To overcome these limitations, the present work describes a one-step approach for facile and time efficient synthesis of highly cationic cell penetrating peptide functionalized gold nanoparticles and their intracellular delivery. The nanoconstruct was synthesized by the reduction of gold metal ions utilizing cell penetrating peptide (CPP), which facilitated the simultaneous synthesis of metal nanoparticles and the capping of the peptide over the nanoparticle surface. The developed nanoconstruct was thoroughly characterized and tested for intracellular delivery into HeLa cells. Intriguingly, a high payload of cationic peptide over gold particles was achieved, in comparison to conventional conjugation methods. Moreover, this method also provides the ability to control the size and peptide payload of nanoparticles. The nanoconstructs produced showed enhanced cancer cell penetration (µM) and significant cytotoxic effect compared to unlabeled gold nanoparticles. Therefore, this novel approach may also have significant future potential to kill intracellular hidden dreaded pathogens like the human immunodeficiency virus, Mycobacterium tuberculosis, and so forth.


Asunto(s)
Péptidos de Penetración Celular/administración & dosificación , Oro/química , Nanopartículas del Metal/química , Péptidos/síntesis química , Cationes , Proliferación Celular/efectos de los fármacos , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacología , Coloides/química , Sistemas de Liberación de Medicamentos , Estabilidad de Medicamentos , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Péptidos/química , Temperatura , Agua
8.
J Transl Med ; 15(1): 201, 2017 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-28985739

RESUMEN

BACKGROUND: The current BCG vaccine induces only short-term protection against Mycobacterium tuberculosis (Mtb), suggesting its failure to generate long-lasting memory T cells. Previously, we have demonstrated that a self-adjuvanting peptide of Mtb (L91), successfully generated enduring memory Th1 cells. Consequently, we investigated if L91 was able to recuperate BCG potency in perpetuating the generation of memory T cells and protection against Mtb infected mice. METHODS: In the present study, we evaluated the potency of a self adjuvanting Mtb peptide vaccine L91 in invigorating BCG immune response against Mtb in mice. Female BALB/c mice were immunized with BCG. Later, they were boosted twice with L91 or an antigenically irrelevant lipidated influenza virus hemagglutinin peptide (LH). Further, PBMCs obtained from BCG vaccinated healthy subjects were cultured in vitro with L91. T cell responses were determined by surface markers and intracellular cytokine staining. Secretion of cytokines was estimated in the culture supernatants (SNs) by ELISA. RESULTS: Compared to the BCG-vaccinated controls, L91 booster significantly enhanced the percentage of memory Th1 cells and Th17 cells and reduced the mycobacterial burden in BCG primed and L91-boosted (BCG-L91) group, even after 229 days of BCG vaccination. Further, substantial augmentation in the central (CD44hiCD62LhiCD127hi) and effector memory (CD44hiCD62LloCD127lo) CD4 T cells was detected. Furthermore, greater frequency of polyfunctional Th1 cells (IFN-γ+TNF-α+) and Th17 cells (IFN-γ+IL-17A+) was observed. Importantly, BCG-L91 successfully prevented CD4 T cells from exhaustion by decreasing the expression of PD-1 and Tim-3. Additionally, augmentation in the frequency of Th1 cells, Th17 cells and memory CD4 T cells was observed in the PBMCs of the BCG-vaccinated healthy individuals following in vitro stimulation with L91. CONCLUSIONS: Our study demonstrated that L91 robustly reinvigorate BCG potency to invoke enduring protection against Mtb. This novel vaccination stratagem involving BCG-priming followed by L91-boosting can be a future prophylactic measure to control TB.


Asunto(s)
Vacuna BCG/inmunología , Inmunidad , Memoria Inmunológica , Lípidos/química , Mycobacterium tuberculosis/inmunología , Péptidos/farmacología , Sustancias Protectoras/farmacología , Linfocitos T Reguladores/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Inmunidad/efectos de los fármacos , Memoria Inmunológica/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/efectos de los fármacos , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fenotipo , Receptores de Quimiocina/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Tuberculosis/inmunología , Tuberculosis/microbiología
9.
J Infect Dis ; 211(3): 486-96, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25156558

RESUMEN

Chronic infections result in T-cell exhaustion, a state of functional unresponsiveness. To control the infection, it is important to salvage the exhausted T cells. In this study, we delivered signals through Toll-like receptor 2 (TLR-2) to reinvigorate functionality in chronically activated T-helper type 1 (Th1) cells. This process significantly augmented the expression of T-bet, interferon γ, interleukin 2, and the antiapoptotic molecule Bcl-2, whereas it dampened the display of the exhaustion markers programmed death receptor 1 (PD-1) and lymphocyte activation gene 3 (Lag-3). Additionally, TLR-2 signaling bolstered the ability of chronically stimulated Th1 cells to activate B cells. Finally, the results were substantiated by observing reduced lung pathology upon administration of TLR-2 agonist in the chronic infection model of tuberculosis. These data demonstrated the importance of TLR-2 in rescuing chronically activated Th1 cells from undergoing exhaustion. This study will pave a way for targeting TLR-2 in developing therapeutic strategies to treat chronic diseases involving loss of Th1 cell function.


Asunto(s)
Células TH1/inmunología , Receptor Toll-Like 2/inmunología , Animales , Antígenos CD/inmunología , Femenino , Interferón gamma/inmunología , Interleucina-2/inmunología , Pulmón/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Transducción de Señal/inmunología , Tuberculosis Pulmonar/inmunología , Proteína del Gen 3 de Activación de Linfocitos
10.
J Biol Chem ; 289(25): 17515-28, 2014 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-24811173

RESUMEN

Cytokines play a very important role in the regulation of immune homeostasis. Regulatory T cells (Tregs) responsible for the generation of peripheral tolerance are under the tight regulation of the cytokine milieu. In this study, we report a novel role of a bipyridyl compound, Caerulomycin A (CaeA), in inducing the generation of Tregs. It was observed that CaeA substantially up-regulated the pool of Tregs, as evidenced by an increased frequency of CD4(+) Foxp3(+) cells. In addition, CaeA significantly suppressed the number of Th1 and Th17 cells, as supported by a decreased percentage of CD4(+)/IFN-γ(+) and CD4(+)/IL-17(+) cells, respectively. Furthermore, we established the mechanism and observed that CaeA interfered with IFN-γ-induced STAT1 signaling by augmenting SOCS1 expression. An increase in the TGF-ß-mediated Smad3 activity was also noted. Furthermore, CaeA rescued Tregs from IFN-γ-induced inhibition. These results were corroborated by blocking Smad3 activity, which abolished the CaeA-facilitated generation of Tregs. In essence, our results indicate a novel role of CaeA in inducing the generation of Tregs. This finding suggests that CaeA has enough potential to be considered as a potent future drug for the treatment of autoimmunity.


Asunto(s)
Interferón gamma/metabolismo , Piridinas/farmacología , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Interferón gamma/genética , Interferón gamma/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Proteína smad3/genética , Proteína smad3/inmunología , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/inmunología , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología
11.
Proteins ; 83(10): 1813-22, 2015 10.
Artículo en Inglés | MEDLINE | ID: mdl-26214268

RESUMEN

Although unglycosylated HuEpo is fully functional, it has very short serum half-life. However, the mechanism of in vivo clearance of human Epo (HuEpo) remains largely unknown. In this study, the relative importance of protease-sensitive sites of recombinant HuEpo (rHuEpo) has been investigated by analysis of structural data coupled with in vivo half-life measurements. Our results identify α3-α4 inter-helical loop region as a target site of lysosomal protease Cathepsin L. Consistent with previously-reported lysosomal degradation of HuEpo, these results for the first time identify cleavage sites of rHuEpo by specific lysosomal proteases. Furthermore, in agreement with the lowered exposure of the peptide backbone around the cleavage site, remarkably substitutions of residues with bulkier amino acids result in significantly improved in vivo stability. Together, these results have implications for the mechanism of in vivo clearance of the protein in humans.


Asunto(s)
Eritropoyetina/química , Proteínas Recombinantes/química , Secuencia de Aminoácidos , Catepsina L/metabolismo , Línea Celular Tumoral , Eritropoyetina/metabolismo , Humanos , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , Estabilidad Proteica , Estructura Secundaria de Proteína , Proteínas Recombinantes/metabolismo
12.
Crit Rev Microbiol ; 41(3): 389-98, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-24495096

RESUMEN

Vaccines have been successful for global eradication or control of dreaded diseases such as smallpox, diphtheria, tetanus, yellow fever, whooping cough, polio, and measles. Unfortunately, this success has not been achieved for controlling tuberculosis (TB) worldwide. Bacillus Calmette Guérin (BCG) is the only available vaccine against TB. Paradoxically, BCG has deciphered success in the Western world but has failed in TB-endemic areas. In this article, we highlight and discuss the aspects of immunity responsible for controlling Mycobacterium tuberculosis infection and factors responsible for the failure of BCG in TB-endemic countries. In addition, we also suggest strategies that contribute toward the development of successful vaccine in protecting populations where BCG has failed.


Asunto(s)
Inmunidad Adaptativa/inmunología , Vacuna BCG/inmunología , Inmunidad Innata/inmunología , Tuberculosis Pulmonar/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Humanos , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/prevención & control
13.
J Infect Dis ; 209(9): 1436-45, 2014 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-24218502

RESUMEN

Mycobacterium tuberculosis (M. tuberculosis) in latently infected individuals survives and thwarts the attempts of eradication by the immune system. During latency, Acr1 is predominantly expressed by the bacterium. However, whether M. tuberculosis exploits its Acr1 in impairing the host immunity remains widely unexplored. Hence, currently we have investigated the role of Acr1 in influencing the differentiation and function of dendritic cells (DCs), which play a cardinal role in innate and adaptive immunity. Therefore, for the first time, we have revealed a novel mechanism of mycobacterial Acr1 in inhibiting the maturation and differentiation of DCs by inducing tolerogenic phenotype by modulating the expression of PD-L1; Tim-3; indoleamine 2, 3-dioxygenase (IDO); and interleukin 10. Furthermore, Acr1 interferes in the differentiation of DCs by targeting STAT-6 and STAT-3 pathways. Continuous activation of STAT-3 inhibited the translocation of NF-κB in Acr1-treated DCs. Furthermore, Acr1 also augmented the induction of regulatory T cells. These DCs displayed decline in their antigen uptake capacity and reduced ability to help T cells. Interestingly, M. tuberculosis exhibited better survival in Acr1-treated DCs. Thus, this study provides a crucial insight into a strategy adopted by M. tuberculosis to survive in the host by impairing the function of DCs.


Asunto(s)
Células Dendríticas/citología , Células Dendríticas/inmunología , Mycobacterium tuberculosis/inmunología , alfa-Cristalinas/inmunología , Animales , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/farmacología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Evasión Inmune , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Fenotipo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT6/antagonistas & inhibidores , Factor de Transcripción STAT6/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Tuberculosis/inmunología , Tuberculosis/microbiología , alfa-Cristalinas/farmacología
14.
J Biol Chem ; 288(41): 29987-99, 2013 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-23983123

RESUMEN

Mycobacterium tuberculosis (Mtb) is a phenomenally successful human pathogen having evolved mechanisms that allow it to survive within the hazardous environment of macrophages and establish long term, persistent infection in the host against the control of cell-mediated immunity. One such mechanism is mediated by the truncated hemoglobin, HbN, of Mtb that displays a potent O2-dependent nitric oxide dioxygenase activity and protects its host from the toxicity of macrophage-generated nitric oxide (NO). Here we demonstrate for the first time that HbN is post-translationally modified by glycosylation in Mtb and remains localized on the cell membrane and the cell wall. The glycan linkage in the HbN was identified as mannose. The elevated expression of HbN in Mtb and M. smegmatis facilitated their entry within the macrophages as compared with isogenic control cells, and mutation in the glycan linkage of HbN disrupted this effect. Additionally, HbN-expressing cells exhibited higher survival within the THP-1 and mouse peritoneal macrophages, simultaneously increasing the intracellular level of proinflammatory cytokines IL-6 and TNF-α and suppressing the expression of co-stimulatory surface markers CD80 and CD86. These results, thus, suggest the involvement of HbN in modulating the host-pathogen interactions and immune system of the host apart from protecting the bacilli from nitrosative stress inside the activated macrophages, consequently driving cells toward increased infectivity and intracellular survival.


Asunto(s)
Proteínas Bacterianas/inmunología , Espacio Intracelular/inmunología , Mycobacterium tuberculosis/inmunología , Hemoglobinas Truncadas/inmunología , Secuencia de Aminoácidos , Animales , Antígeno B7-1/inmunología , Antígeno B7-1/metabolismo , Antígeno B7-2/inmunología , Antígeno B7-2/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Western Blotting , Línea Celular Tumoral , Membrana Celular/inmunología , Membrana Celular/metabolismo , Células Cultivadas , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Citometría de Flujo , Glicosilación , Interacciones Huésped-Patógeno/inmunología , Humanos , Espacio Intracelular/microbiología , Macrófagos/inmunología , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Mutación , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/fisiología , Procesamiento Proteico-Postraduccional/inmunología , Homología de Secuencia de Aminoácido , Hemoglobinas Truncadas/genética , Hemoglobinas Truncadas/metabolismo
15.
PLoS Pathog ; 8(6): e1002676, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22719245

RESUMEN

Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the "code of conduct" of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.


Asunto(s)
Infecciones Bacterianas/inmunología , Interacciones Huésped-Patógeno/inmunología , Virosis/inmunología , Animales , Presentación de Antígeno/inmunología , Infecciones Bacterianas/microbiología , Humanos , Activación de Linfocitos/inmunología , Transducción de Señal/inmunología , Virosis/microbiología
16.
Crit Rev Microbiol ; 40(3): 273-80, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23688247

RESUMEN

The gut microflora is an immense health asset for human beings. The mammalian gut harbors trillions of commensals. These microbes not only modulate local but also systemic immunity. Recently, various reports are evolving, which signify that the gut microbes can modulate, tune and tame the host immune response. Consequently, it advocates the significance of the microbial composition. Further, the microbiota provides a fine equilibrium to host by regulating immune homeostasis. Furthermore, disturbance in this population can incite imbalance in immune system, leading to molecular mimicry and therefore autoimmunity. Hence, it is imperative to understand the influence of these bugs in preventing or provoking immune system against the self-components. In this article, we highlight the interaction between different gut microbes and cells of immune system and the mechanism involved in controlling and curtailing various autoimmune diseases.


Asunto(s)
Autoinmunidad , Bacterias/inmunología , Tracto Gastrointestinal/microbiología , Humanos
17.
Amino Acids ; 46(5): 1265-74, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24549702

RESUMEN

CD4 T cells play a cardinal role in orchestrating immune system. Differentiation of CD4 T cells to Th1 and Th2 effector subsets depends on multiple factors such as relative intensity of interactions between T cell receptor with peptide-major histocompatibility complex, cytokine milieu, antigen dose, and costimulatory molecules. Literature supports the critical role of peptide's binding affinity to Human Leukocyte Antigens (HLAs) and in the differentiation of naïve CD4 T cells to Th1 and Th2 subsets. However, there exists no definite report addressing very precisely the correlation between physicochemical properties (hydrophobicity, hydrophilicity), pattern, position of amino acids in peptide and their role in skewing immune response towards Th1 and Th2 cells. This may play a significant role in designing peptide vaccines. Hence in the present study, we have evaluated the relationship between amino acid pattern and their influence in differentiation of Th1 and Th2 cells. We have used a data set of 320 peptides, whose role has been already established experimentally in the generation of either Th1 or Th2 immune response. Further, characterization was done based on binding affinity, promiscuity, amino acid pattern and binding conformation of peptides. We have observed that distinct amino acids in peptides elicit either Th1 or Th2 immunity. Consequently, this study signifies that alteration in the sequence and type of selected amino acids in the HLA class II binding peptides can modulate the differentiation of Th1 and Th2 cells. Therefore, this study may have an important implication in providing a platform for designing peptide-based vaccine candidates that can trigger desired Th1 or Th2 response.


Asunto(s)
Células TH1/inmunología , Células Th2/inmunología , Vacunas de Subunidad/química , Vacunas de Subunidad/inmunología , Secuencia de Aminoácidos , Diseño de Fármacos , Antígenos de Histocompatibilidad Clase II/química , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Modelos Moleculares
18.
J Immunol ; 188(11): 5593-603, 2012 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-22544925

RESUMEN

Mycobacterium tuberculosis-macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis-macrophage lipids can interact with host peroxisome proliferator-activated receptor γ and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor γ and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation.


Asunto(s)
Células Espumosas/inmunología , Células Espumosas/microbiología , Metabolismo de los Lípidos/inmunología , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/inmunología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , PPAR gamma/metabolismo , Animales , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Células Espumosas/metabolismo , Humanos , Ligandos
19.
Eur J Pharmacol ; 975: 176637, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38729416

RESUMEN

Macrophages play a pivotal role in safeguarding against a broad spectrum of infections, from viral, bacterial, fungal to parasitic threats and contributing to the immune defense against cancer. While morphine's immunosuppressive effects on immune cells are extensively documented, a significant knowledge gap exists regarding its influence on macrophage polarization and differentiation. Hence, we conducted a study that unveils that prior exposure to morphine significantly impedes the differentiation of bone marrow cells into macrophages. Furthermore, the polarization of macrophages toward the M1 phenotype under M1-inducing conditions experiences substantial impairment, as evidenced by the diminished expression of CD80, CD86, CD40, iNOS, and MHCII. This correlates with reduced expression of M1 phenotypical markers such as iNOS, IL-1ß, and IL-6, accompanied by noticeable morphological, size, and phagocytic alterations. Further, we also observed that morphine affected M2 macrophages. These findings emphasize the necessity for a more comprehensive understanding of the impact of morphine on compromising macrophage function and its potential ramifications for therapeutic approaches.


Asunto(s)
Diferenciación Celular , Inmunosupresores , Macrófagos , Morfina , Morfina/farmacología , Animales , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Diferenciación Celular/efectos de los fármacos , Inmunosupresores/farmacología , Polaridad Celular/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratones Endogámicos C57BL , Fagocitosis/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Masculino , Interleucina-1beta/metabolismo
20.
Int J Biol Macromol ; 274(Pt 1): 133188, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38880456

RESUMEN

Morphine addiction poses a significant challenge to global healthcare. Current opioid substitution therapies, such as buprenorphine, naloxone and methadone are effective but often lead to dependence. Thus, exploring alternative treatments for opioid addiction is crucial. We have developed a novel vaccine that presents morphine and Pam3Cys (a TLR-2 agonist) on the surface of Acr1 nanoparticles. This vaccine has self-adjuvant properties and targets TLR-2 receptors on antigen-presenting cells, particularly dendritic cells. Our vaccination strategy promotes the proliferation and differentiation of morphine-specific B-cells and Acr1-reactive CD4 T-cells. Additionally, the vaccine elicited the production of high-affinity anti-morphine antibodies, effectively eliminating morphine from the bloodstream and brain in mice. It also reduced the expression of addiction-associated µ-opioid receptor and dopamine genes. The significant increase in memory CD4 T-cells and B-cells indicates the vaccine's ability to induce long-lasting immunity against morphine. This vaccine holds promise as a prophylactic measure against morphine addiction.

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