<i>Mycobacterium tuberculosis</i>ESAT6 Drives the Activation and Maturation of Bone Marrow-Derived Dendritic Cells via TLR4-Mediated Signaling

Jang, Ah Ra; Kim, Green; Hong, Jung Joo; Kang, Si Mook; Shin, Sung Jae; Park, Jong Hwan

doi:10.4110/in.2019.19.e13

Cited by 16 publications

(8 citation statements)

References 30 publications

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“…To understand the relevance of ESAT-6 rich EVs obtained from SN-PTB subjects, we performed two experiments: first, EVs of patient #2 and #7 containing equivalent of 1-50 ng/ml ESAT-6 was added to bone marrow derived immature dendritic cells (DC) on day-6 culture (5×10^4 mouse BM mononuclear cells treated with GM-CSF 20ng/ml for 6 days; (52), and 48 hours after, In-cell western assay (53) was performed to evaluate the activation of MHC II and CD11c, two markers for DC activation. The values of MHC II and CD11c were compared with the results obtained by using recombinant ESAT-6 protein in a 50ng-10 ug dose range.…”

Section: Resultsmentioning

confidence: 99%

Stem cell basis of a host driven transmission of antigen packed aerosols: a novel mechanism of natural vaccination for tuberculosis

Das

Pathak

Gayan

et al. 2020

Preprint

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Natural vaccination against pathogens are known to be achieved by herd-immunity i.e. infected human host provide immunity to the community by spreading the pathogen. Whether, infected human hosts transmit vesicle packed aerosols of pathogen’s antigen for natural vaccination of the community has not yet been considered. We have explored a traditional healing method of aerosol-inoculation against small pox and tuberculosis in the Sualkuchi-Hajo cultural complex of Kamarupa, an ancient Indian region known for tantra-based healing and spirituality. In the aerosol-inoculation method against TB, selected persons with TB (later identified as smear negative TB subject) are encouraged to spread good nigudah in the community by Kirtan chanting; the good Nigudah are thought to be present within bad-nigudah or invisible krimis (tiny flesh eating living being mentioned in ancient India’s medicinal text Caraka Samhita and Atharva Veda). A 15-years of contact TB investigation study, as well as laboratory study of aerosol obtained from smear negative PTB (SN-PTB) subjects led to the identification of good Nigudah as extracellular vesicles (EVs) filled with Mtb-antigen ESAT-6. We then developed a mouse model of aerosol-inoculation using SN-PTB subject derived aerosol EVs, and identified Mtb infected mesenchymal stem cells (MSCs) of the lung as the putative source of the ESAT-6+ EVs. These Mtb infected MSCs reprogram to altruistic stem cell (ASC) phenotype, which then secrete ESAT-6+ EVs to the aerosols; healthy mice receiving the aerosol develop Mtb specific herd immunity. These results expedite our ongoing work on the innate defense mechanism of ASCs against pathogen, and provide a novel mechanism of natural vaccination, where the host extracts appropriate antigens from a pathogen, and then spread it in the community via aerosols.

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Section: Resultsmentioning

confidence: 99%

Stem cell basis of a host driven transmission of antigen packed aerosols: a novel mechanism of natural vaccination for tuberculosis

Das

Pathak

Gayan

et al. 2020

Preprint

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“…BMDCs were generated from bone marrow (BM) using conventional methods [ 57 , 58 ]. Furthermore, we established an asthma model via the intravenous (i.v.)…”

Section: Methodsmentioning

confidence: 99%

Fms-Like Tyrosine Kinase 3-Independent Dendritic Cells Are Major Mediators of Th2 Immune Responses in Allergen-Induced Asthmatic Mice

Park

Shim

Kim

et al. 2020

IJMS

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Dendritic cells (DCs) are the main mediators of Th2 immune responses in allergic asthma, and Fms-like tyrosine kinase 3 ligand (Flt3L) is an important growth factor for the development and homeostasis of DCs. This study identified the DC populations that primarily cause the initiation and development of allergic lung inflammation using Fms-like tyrosine kinase 3 (Flt3) knockout (KO) mice with allergen-induced allergic asthma. We observed type 2 allergic lung inflammation with goblet cell hyperplasia in Flt3 KO mice, despite a significant reduction in total DCs, particularly CD103+ DCs, which was barely detected. In addition, bone marrow-derived dendritic cells (BMDCs) from Flt3 KO mice directed Th2 immune responses in vitro, and the adoptive transfer of these BMDCs exacerbated allergic asthma with more marked Th2 responses than that of BMDCs from wild-type (WT) mice. Furthermore, we found that Flt3L regulated the in vitro expression of OX40 ligand (OX40L) in DCs, which is correlated with DC phenotype in in vivo models. In conclusion, we revealed that Flt3-independent CD11b+ DCs direct Th2 responses with the elevated OX40L and are the primary cause of allergic asthma. Our findings suggest that Flt3 is required to control type 2 allergic inflammation.

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“…Heat shock protein 70 kDa (Hsp70) is one of the M. tuberculosis Ags that stimulate the secretion of IL‐6, IL‐12p40, and TNF via MyD88‐ and TRIF‐dependent pathways in DCs 160 . The maturation of DCs and induction of the Th1 immune response elicited by the ESAT6 Ag was found to be dependent on TLR4 but not on TLR2 161 . The apyrase conserved region 1 (Acr1) or heat shock protein X (sHSPX) M. tuberculosis , a latency Ag, induced a tolerogenic phenotype in DCs, which was characterized by the expression of programmed death‐ligand 1 (PD‐L1), T‐cell Ig and mucin‐domain containing‐3 (Tim‐3) inhibitory molecule, IDO, and IL‐10.…”

Section: Mouse Dendritic Cells and M Tuberculosis Infectionmentioning

confidence: 99%

“…160 The maturation of DCs and induction of the Th1 immune response elicited by the ESAT6 Ag was found to be dependent on TLR4 but not on TLR2. 161 The apyrase con- Tables and Figures.…”

Section: Experimental Evidence Supports the Claim That M Tuberculosimentioning

confidence: 99%

Interplay between alveolar epithelial and dendritic cells and Mycobacterium tuberculosis

Rodrigues

Conti

Fraga-Silva

et al. 2020

Journal of Leukocyte Biology

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The innate response plays a crucial role in the protection against tuberculosis development. Moreover, the initial steps that drive the host-pathogen interaction following Mycobacterium tuberculosis infection are critical for the development of adaptive immune response. As alveolar M s, airway epithelial cells, and dendritic cells can sense the presence of M. tuberculosis and are the first infected cells. These cells secrete mediators, which generate inflammatory signals that drive the differentiation and activation of the T lymphocytes necessary to clear the infection. Throughout this review article, we addressed the interaction between epithelial cells and M. tuberculosis, as well as the interaction between dendritic cells and M. tuberculosis. The understanding of the mechanisms that modulate those interactions is critical to have a complete view of the onset of an infection and may be useful for the development of dendritic cell-based vaccine or immunotherapies.

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Mycobacterium tuberculosisESAT6 Drives the Activation and Maturation of Bone Marrow-Derived Dendritic Cells via TLR4-Mediated Signaling

Cited by 16 publications

References 30 publications

Stem cell basis of a host driven transmission of antigen packed aerosols: a novel mechanism of natural vaccination for tuberculosis

Stem cell basis of a host driven transmission of antigen packed aerosols: a novel mechanism of natural vaccination for tuberculosis

Fms-Like Tyrosine Kinase 3-Independent Dendritic Cells Are Major Mediators of Th2 Immune Responses in Allergen-Induced Asthmatic Mice

Interplay between alveolar epithelial and dendritic cells and Mycobacterium tuberculosis

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