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

Abstract

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.

Initiation of Post-Primary Tuberculosis of the Lungs: Exploring the Secret Role of Bone Marrow Derived Stem Cells

“…In this context, sputum of smear negative subjects contains viable but non-culturable (VBNC) Mtb ( 118 ); the source of this VBNC- Mtb may be lung granuloma as bacteria in sputum reflect active pulmonary lesions ( 119 ). Our preliminary study indicates that CD271+BM-MSCs may resuscitate VBNC deep dormant Mtb ( 29 ), suggesting the ability of stem cells to contribute to resuscitating dying granulomas. Recently, CD73+ cells containing Mtb antigen Ag85B has been detected in human lung granulomas ( 96 ), suggesting the potential presence of Mtb infected MSCs in active granuloma lesions of PTB, although further testing is required to confirm the MSC phenotype of the cells by direct sorting, as well as the viability of the intracellular Mtb .…”

“…To investigate if the CD271+BM-MSCs are the dormancy site for Mtb in PPTBL cases, we recruited patients through our KaviKrishna Telemedicine care ( 22 , 29 ) located in NE India. These were successfully treated subjects for PPTBL, who donated 6–7 ml of BM for immunomagnetic separation of CD271+BM-MSCs.…”

“…Thus, MHV-1 mouse model may be useful to study whether SARS-CoV-2 infection would reactivate dormant TB infection ( 28 ). Second, ASC reprograming mechanism may be of relevance in the resuscitation of deep dormant Mtb ( 29 ), which are VBNC ( 118 ). Importantly, we showed that VBNC obtained from Mtb -m18b strain present in the sputum of smear negative PTB subjects could be resuscitated by BM-MSCs and during the resuscitation process, MSCs reprogram to ASCs ( 29 ).…”

“…Previously, we proposed that the human adult stem cell niche in bone marrow (BM) might serve as a protective niche for dormant Mtb ( 22 ), and these cells would then migrate to lungs for PPTBL development ( Figure 1 ). Surprisingly, many clinicians had already provided anecdotal evidence of finding Mtb in BM including our experience in Bhutan during 1995–1998 ( 23 , 29 ) provide “bed to benchside” rationale to examine whether Mtb may hijack the BM-stem cell niche for its transmission strategy ( 22 ). However, skeptics will point out that hijacking of the stem cell niche will lead to widespread hematological and other stem cell-related disorders, often not seen in patients with PPTBL.…”

“…These findings raise human bone marrow derived stem cells as the site of Mtb latency ( 27 ). Recently, we have shown that stem cell altruism may be involved in Mtb -reactivation ( 28 ), and in the aerosol-induced immunity ( 29 ). These recent studies indicate the emerging role of BM stem cell niche in the pathogenesis and community transmission of Mtb .…”