Oral Tolerance to Environmental Mycobacteria Interferes with Intradermal, but Not Pulmonary, Immunization against Tuberculosis

Citation: Price DN, Kusewitt DF, Lino CA, McBride AA, Muttil P (2016) Oral Tolerance to Environmental Mycobacteria Interferes with Intradermal, but Not Pulmonary, Immunization against Tuberculosis. PLoS Pathog 12(5): e1005614. doi:10.1371/journal.ppat.1005614
Published: May 6, 2016

Abstract
Bacille Calmette–Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB) and is administered in over 150 countries worldwide. Despite its widespread use, the vaccine has a variable protective efficacy of 0–80%, with the lowest efficacy rates in tropical regions where TB is most prevalent. This variability is partially due to ubiquitous environmental mycobacteria (EM) found in soil and water sources, with high EM prevalence coinciding with areas of poor vaccine efficacy. In an effort to elucidate the mechanisms underlying EM interference with BCG vaccine efficacy, we exposed mice chronically to Mycobacterium avium (M. avium), a specific EM, by two different routes, the oral and intradermal route, to mimic human exposure. After intradermal BCG immunization in mice exposed to oral M. avium, we saw a significant decrease in the pro-inflammatory cytokine IFN-γ, and an increase in T regulatory cells and the immunosuppressive cytokine IL-10 compared to naïve BCG-vaccinated animals. To circumvent the immunosuppressive effect of oral M. avium exposure, we vaccinated mice by the pulmonary route with BCG. Inhaled BCG immunization rescued IFN-γ levels and increased CD4 and CD8 T cell recruitment into airways in M. avium-presensitized mice. In contrast, intradermal BCG vaccination was ineffective at T cell recruitment into the airway. Pulmonary BCG vaccination proved protective against Mtb infection regardless of previous oral M. avium exposure, compared to intradermal BCG immunization. In conclusion, our data indicate that vaccination against TB by the pulmonary route increases BCG vaccine efficacy by avoiding the immunosuppressive interference generated by chronic oral exposure to EM. This has implications in TB-burdened countries where drug resistance is on the rise and health care options are limited due to economic considerations. A successful vaccine against TB is necessary in these areas as it is both effective and economical.

Author Summary: The current vaccine against tuberculosis (TB), BCG, has variable efficacy (0–80%) at protecting against infection. A large body of clinical and experimental evidence implicates host exposure to environmental mycobacteria (EM) as the cause of interference with BCG vaccine-induced immunity. We explore the mechanism by which EM interferes with parenteral immunization and propose oral tolerance as a mechanism for this interference. In addition, we use the pulmonary route to vaccinate EM-exposed hosts, thus ensuring effective BCG immunization and subsequent protection against TB. This work has broad implications in the TB vaccine field as it shows that the vulnerability of the current vaccine, and that of many novel vaccine candidates, may be the route of administration and not necessarily the vaccine itself.

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