Abstract
Brucellosis remains the most common zoonotic disease globally. Currently no vaccines for humans exist, and conventional brucellosis vaccines for livestock fail to confer complete protection; hence, an improved vaccine is needed. Although Brucella infections primarily occur following a mucosal exposure, vaccines are administered parenterally. Few studies have considered mucosal vaccinations, or even targeting of tissue-resident memory T (TRM) cells. TRM cells protect against viral infections, but less is known of their role in bacterial infections, and even less for brucellosis. Oral prime, nasal boost with a newly developed Brucella abortus double mutant (znBAZ) confers nearly complete protection against pulmonary challenge with wild-type (wt) B. abortus 2308, and its protective efficacy is >2800-fold better than the RB51 vaccine. Vaccination with znBAZ potently stimulated CD8+ T cells, whereas mucosal vaccination with RB51 induced mostly CD4+ T cells. Subsequent analysis revealed these pulmonary CD44+ CD69+ CD8+ T cells to be either CD103+ or CD103- TRM cells, and these sequestered to the lung parenchyma as CXCR3lo and to the airways as CXCR3hi. Both CD8+ TRM subsets contained single-positive IFN-γ and TNF-α, as well as, polyfunctional cells. IL-17-producing CD8+ TRM cells were also induced by znBAZ vaccination, but in vivo IL-17 neutralization had no impact upon protection. In vivo depletion of CD4+ T cells had no impact upon protection in znBAZ-vaccinated mice. In contrast, CD4+ T cell depletion reduced RB51’s protective efficacy in spleens and lungs by two- and three-logs, respectively. Although anti-CD8 mAb-treated znBAZ-vaccinated mice showed a significantly reduced pulmonary efficacy, this treatment failed to completely deplete the lung CD8+ T cells, leaving the CD103+ and CD103- CD8+ TRM cell ratios intact. Only znBAZ-vaccinated CD8-/- mice were fully sensitive to pulmonary challenge with virulent wt B. abortus 2308 since CD8+ TRM cells could not be induced. Collectively, these data demonstrate the key role of mucosal vaccination for the generation of CD8+ TRM cells in protecting against pulmonary challenge with virulent B. abortus.
Highlights
Brucella species are Gram-negative, facultative intracellular bacteria, which are responsible for the most common zoonotic disease worldwide [1,2,3]
To determine whether development of a mucosal vaccination regimen could effectively generate immunity against pulmonary challenge with virulent B. abortus, a double-mutant B. abortus vaccine was administered mucosally, and found to induce CD8+ TRM cells. These conferred complete protection against pulmonary infection and prevented systemic brucellae spread even in the absence of immune recirculating CD8+ T cells. These data show that mucosal vaccination can stimulate the induction of TRM cells, which should be considered as a more effective means to protect against brucellosis
All B. abortus strains, znBAZ, RB51, and wild-type B. abortus strain 2308 were inoculated on Potato Infusion Agar (PIA) plates, and grown for 3 days at 37 ̊C under 5% CO2
Summary
Brucella species are Gram-negative, facultative intracellular bacteria, which are responsible for the most common zoonotic disease worldwide [1,2,3]. Brucellosis in humans is not usually fatal, but it can be debilitating with an undulating fever. Protection against Brucella infection requires Th1-type immunity, characterized by the production of IFN-γ and TNF-α. CD4+ and CD8+ T cells are considered to be the primary source of these protective cytokines during Brucella infections [8,9,10]. The importance of the T cell subsets varies by the route of immunization and the vaccine components [11,12,13,14,15,16,17,18]. Recent reports showed that mucosal exposure to this pathogen stimulates IFN-γ-producing CD8+ T cells for protection against brucellosis, not by their cytotoxic function [19,20,21,22,23]
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