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Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases.

ABSTRACT: Bacille Calmette-Guerin (BCG) vaccination is widely practiced around the world to protect against the mycobacterial infection tuberculosis. BCG is also effective against the pathogenic mycobacteria that cause leprosy and Buruli's ulcer. BCG is part of the standard of care for bladder cancer where, when given as an intravesicular irrigant, BCG acts as an immunomodulating agent and lessens the risk of recurrence. Mycobacterium avium ss. paratuberculosis (MAP) causes a fatal enteritis of ruminant animals and is the putative cause of Crohn's disease of humans. MAP has been associated with an increasingly long list of inflammatory/autoimmune diseases: Crohn's, sarcoidosis, Blau syndrome, Hashimoto's thyroiditis, autoimmune diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, lupus and Parkinson's disease. Epidemiologic evidence points to BCG providing a "heterologous" protective effect on assorted autoimmune diseases; studies using BCG vaccination for T1D and MS have shown benefit in these diseases. This article proposes that the positive response to BCG in T1D and MS is due to a mitigating action of BCG upon MAP. Other autoimmune diseases, having a concomitant genetic risk for mycobacterial infection as well as cross-reacting antibodies against mycobacterial heat shock protein 65 (HSP65), could reasonably be considered to respond to BCG vaccination. The rare autoimmune disease, relapsing polychondritis, is one such disease and is offered as an example. Recent studies suggesting a protective role for BCG in Alzheimer's disease are also explored. BCG-induced energy shift from oxidative phosphorylation to aerobic glycolysis provides the immunomodulating boost to the immune response and also mitigates mycobacterial infection-this cellular mechanism unifies the impact of BCG on the disparate diseases of this article.

SUBMITTER: Dow CT

PROVIDER: S-EPMC7074941 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases.

Dow Coad Thomas CT

Microorganisms 20200205 2

Bacille Calmette-Guerin (BCG) vaccination is widely practiced around the world to protect against the mycobacterial infection tuberculosis. BCG is also effective against the pathogenic mycobacteria that cause leprosy and Buruli's ulcer. BCG is part of the standard of care for bladder cancer where, when given as an intravesicular irrigant, BCG acts as an immunomodulating agent and lessens the risk of recurrence. Mycobacterium avium ss. paratuberculosis (MAP) causes a fatal enteritis ...[more]

PMID: 32033287

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Project description:Mycobacterium avium subsp. paratuberculosis (MAP) is an understudied pathogen worldwide with continuous implications in human autoimmune diseases (ADs). The awareness of MAP appears to be low in many places and its research is at infant stage in many countries. The lack of worldwide coverage of the MAP research landscape calls for urgent research attention and prioritization. This present study aimed to assess MAP global research productivity with an emphasis on its implications in ADs via bibliometric and growth analytic frameworks from authors, countries, institutions, international, disciplines and collaboration network perspectives. MAP primary articles were retrieved from the Scopus database and the Web of Science from 1911 to 2019 via title-specific algorithm. Analytic results of dataset yielded a total of 3889 articles from 581 journals and 20.65 average citations per documents. The annual growth rate of MAP research for the period was 6.31%. Based on a country's productivity (articles (%), freq. of publication (%)), the USA (887 (22.81%), 26.72%), and Australia (236 (6.07%), 6.07%) ranked the top 2 countries but Egypt and Germany had the highest average growth rate (AGR, 170%) in the last 3 years. MAP studies are generally limited to Europe, Australia, Asia, South America and few nations in Africa. It had positive growth rate (30%-100%) in relation to type 1 diabetes mellitus and rheumatoid arthritis ADs; food science and technology, immunology, agriculture, pathology, and research and experimental medicine, wildlife, environments, virulence, disease resistance, meat and meat products, osteopontin, waste milk and slurry/sludge digestion subjects; but negative growth (-130% to -30%) in ulcerative colitis and Parkinson's disease and no growth in multiple sclerosis, sarcoidosis, thyroid disorders, psoriasis, and lupus. The mapping revealed a gross lack of collaboration networking in terms of authorship, (intra- and inter-) nationally and institutionally with a generalized collaboration index of 1.82. In conclusion, inadequate resources-, knowledge- and scientific-networking hampered growth and awareness of MAP research globally. The study recommends further research to strengthen evidence of MAP's epidemiologic prevalence in ADs and proffer practical solution(s) for drug development and point-of-care diagnostics amongst other extended themes.

Project description:Mycobacterium avium subsp. paratuberculosis is a host-adapted pathogen that evolved from the environmental bacterium M. avium subsp. hominissuis through gene loss and gene acquisition. Growth of M. avium subsp. paratuberculosis in the laboratory is enhanced by supplementation of the media with the iron-binding siderophore mycobactin J. Here we examined the production of mycobactins by related organisms and searched for an alternative iron uptake system in M. avium subsp. paratuberculosis. Through thin-layer chromatography and radiolabeled iron-uptake studies, we showed that M. avium subsp. paratuberculosis is impaired for both mycobactin synthesis and iron acquisition. Consistent with these observations, we identified several mutations, including deletions, in M. avium subsp. paratuberculosis genes coding for mycobactin synthesis. Using a transposon-mediated mutagenesis screen conditional on growth without myobactin, we identified a potential mycobactin-independent iron uptake system on a M. avium subsp. paratuberculosis-specific genomic island, LSP(P)15. We obtained a transposon (Tn) mutant with a disruption in the LSP(P)15 gene MAP3776c for targeted study. The mutant manifests increased iron uptake as well as intracellular iron content, with genes downstream of the transposon insertion (MAP3775c to MAP3772c [MAP3775-2c]) upregulated as the result of a polar effect. As an independent confirmation, we observed the same iron uptake phenotypes by overexpressing MAP3775-2c in wild-type M. avium subsp. paratuberculosis. These data indicate that the horizontally acquired LSP(P)15 genes contribute to iron acquisition by M. avium subsp. paratuberculosis, potentially allowing the subsequent loss of siderophore production by this pathogen.Many microbes are able to scavenge iron from their surroundings by producing iron-chelating siderophores. One exception is Mycobacterium avium subsp. paratuberculosis, a fastidious, slow-growing animal pathogen whose growth needs to be supported by exogenous mycobacterial siderophore (mycobactin) in the laboratory. Data presented here demonstrate that, compared to other closely related M. avium subspecies, mycobactin production and iron uptake are different in M. avium subsp. paratuberculosis, and these phenotypes may be caused by numerous deletions in its mycobactin biosynthesis pathway. Using a genomic approach, supplemented by targeted genetic and biochemical studies, we identified that LSP(P)15, a horizontally acquired genomic island, may encode an alternative iron uptake system. These findings shed light on the potential physiological consequence of horizontal gene transfer in M. avium subsp. paratuberculosis evolution.

Project description:Mycobacterium avium subspecies paratuberculosis (MAP) infection is established following the ingestion of bacteria, their penetration of the intestinal mucosa and subsequent events of the host-parasite interaction. These bacteria invade M cells, macrophages and are capable of resisting host defenses and multiply to reach very high numbers intracellular. Mycobactrium avium subsp. avium (MAA) is an antigenically and genetically similar organisms but is relatively nonpathogenic for cattle. MAA organisms appear to infect cattle, but unlike cattle infected with MAP, cattle infected with MAA typically mount an effective systemic immune response, form caseous granuloma, and eliminate the infection. This study was designed to understand the similarities and differences in the host responses during MAP and MAA infection. Neonatal calves were infected (ligated ileal loops) with PBS, MAP, or avirulent MAA following which samples were collected at 30 min, 1h, 2h, 4h, 8h, or 12h. Post-infection, RNA was collected, processed, and then hybridized to custom bovine gene expression arrays, each of which represented 13,258 transcripts spotted in duplicate. Arrays were normalized by scaling against the average reference intensity value (i.e., average across all arrays), normalized by global mean, and then log transformed before statistical analyses were performed. Pairwise comparisons of averaged signal values and Student’s t test were performed using GeneSifter software (VizX Labs, Seattle, WA). A fold-change of at least 1.5-fold and a p value of 0.05 or less was required for a difference in signal to be considered statistically significant. When comparing the transcriptional responses of calves infected with the MAA versus MAP, unique patterns of expression were clearly visible. In general, numbers of transcripts altered in response to infection were much greater for MAA-infected animals than for those infected with the MAP. No genes were significantly up-regulated in MAP-infected animals at the earliest time point tested (30 min), and only modest numbers of genes were increased in expression over the experimental time course. On the other hand, up-regulated transcripts were detected by 30 min in MAA-infected animals and peaked by 2 hr. Differences in the numbers of down-regulated genes between MAP-infected and MAA-infected animals (compared to PBS-infected controls) were less pronounced. At the earliest time points, MAP-infected calves had a greater number of down-regulated genes than did animals infected with MAA. This trend was reversed at 8 and 12 hr post-infection. Keywords: Gene expression profiling by microarray

Dataset Information

Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases.

Publications

Proposing BCG Vaccination for <i>Mycobacterium avium</i> ss. <i>paratuberculosis</i> (MAP) Associated Autoimmune Diseases.

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