Abstract
Mycobacterium tuberculosis (Mtb) remains a global health challenge due to the limited efficacy of the Mtb vaccine in current use, Bacillus Calmette–Guérin (BCG). To date, there is no available vaccine for immunocompromised individuals. Thus, there is an urgent need to develop a new vaccine candidate which can induce mucosal immunity in hosts with different immune statuses. DnaK (HSP70) has been shown to induce protective immunity against Mtb infection when administered by DNA vaccine; however, the protection is inferior to that induced by the BCG vaccine. In our study, we vaccinated C57BL/6J mice with DnaK protein alone. Subcutaneous or intranasal vaccination with DnaK generated IFNγ-secreting CD4+ T cells in the spleen, but only intranasal vaccination generated IL-17-releasing CD4+ T cells in the lungs, even when circulating CD4+ T cells were diminished. Furthermore, intranasal vaccination with DnaK generated tissue resident CD4+ T cells in the lungs. Vaccination with DnaK alone resulted in protective immunity comparable to BCG vaccination against tuberculosis in mice. Our results demonstrate that intranasal vaccination with DnaK can generate mucosal immunity in immunocompromised or immunocompetent mice and DnaK vaccination can generate protection against Mtb similar to BCG, underscoring its potential utility as an Mtb vaccine candidate in humans.
Highlights
Tuberculosis (TB) is one of the primary causes of morbidity and mortality due to infectious diseases worldwide
Intracellular cytokine staining revealed that DnaK vaccination by the SC or IN routes generated a significant increase in IFNγ-secreting CD4+ T cells in the spleen after stimulation with recombinant protein but there was no significant difference between the SC and IN groups (Figure 1C)
Previous studies have shown that DNA vaccination targeting mycobacterial DnaK (HSP70) protects mice against challenge with Mycobacterium tuberculosis (Mtb), this protection was inferior to that afforded by Bacillus Calmette–Guérin (BCG) (Lowrie et al, 1997)
Summary
Tuberculosis (TB) is one of the primary causes of morbidity and mortality due to infectious diseases worldwide. The BCG vaccine may protect children against some forms of TB, including central nervous system infections, its protective efficacy is highly variable and the vaccine does not confer protection against pulmonary TB in adults (Andersen and Doherty, 2005). The suboptimal efficacy of the BCG vaccine has been attributed to previous exposure to cross-reacting non-tuberculosis mycobacteria (Andersen and Doherty, 2005), chronic helminth infections (Elias et al, 2008), and the absence of key Mycobacterium tuberculosis (Mtb)-related antigens in the vaccine strain (Kalra et al, 2007). Intranasal DnaK Vaccination during CD4-Deficiency attenuated strain M. bovis BCG can escape host immunity and interfere with antigen presentation, contributing to reduced activation of T cells (Sendide et al, 2005; Russell et al, 2007; Pecora et al, 2009). Toll-like receptor (TLR) agonists, which can activate innate immunity and promote antigen presentation (Lahiri et al, 2008), have shown promise as adjuvants in preclinical studies, their immunological effects are variable (Gupta et al, 2016), and they may induce toxicity in humans (Steinhagen et al, 2011)
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