Latency Antigen α-Crystallin Based Vaccination Imparts a Robust Protection against TB by Modulating the Dynamics of Pulmonary Cytokines

Abstract

BackgroundEfficient control of tuberculosis (TB) requires development of strategies that can enhance efficacy of the existing vaccine Mycobacterium bovis Bacille Calmette Guerin (BCG). To date only a few studies have explored the potential of latency-associated antigens to augment the immunogenicity of BCG.Methods/Principal FindingsWe evaluated the protective efficacy of a heterologous prime boost approach based on recombinant BCG and DNA vaccines targeting α-crystallin, a prominent latency antigen. We show that “rBCG prime - DNA boost” strategy (R/D) confers a markedly superior protection along with reduced pathology in comparison to BCG vaccination in guinea pigs (565 fold and 45 fold reduced CFU in lungs and spleen, respectively, in comparison to BCG vaccination). In addition, R/D regimen also confers enhanced protection in mice. Our results in guinea pig model show a distinct association of enhanced protection with an increased level of interleukin (IL)12 and a simultaneous increase in immuno-regulatory cytokines such as transforming growth factor (TGF)β and IL10 in lungs. The T cell effector functions, which could not be measured in guinea pigs due to technical limitations, were characterized in mice by multi-parameter flow cytometry. We show that R/D regimen elicits a heightened multi-functional CD4 Th1 cell response leading to enhanced protection.Conclusions/SignificanceThese results clearly indicate the superiority of α-crystallin based R/D regimen over BCG. Our observations from guinea pig studies indicate a crucial role of IL12, IL10 and TGFβ in vaccine-induced protection. Further, characterization of T cell responses in mice demonstrates that protection against TB is predictable by the frequency of CD4 T cells simultaneously producing interferon (IFN)γ, tumor necrosis factor (TNF)α and IL2. We anticipate that this study will not only contribute toward the development of a superior alternative to BCG, but will also stimulate designing of TB vaccines based on latency antigens.

A Booster Vaccine Expressing a Latency-Associated Antigen Augments BCG Induced Immunity and Confers Enhanced Protection against Tuberculosis

“…This heterologous prime boost regimen provides a superior and extended protection against M. tuberculosis infection in guinea pigs as well as in mice. According to our previous findings, α-crystallin based DNA vaccine, although, failed to surpass the protection conferred by BCG vaccine, when used as a standalone vaccine [14], it is was able to substantially improve the protection conferred by a recombinant BCG vaccine over-expressing this antigen [15]. Our current findings are thus, all the more important as they signify that the meager immune responses generated by BCG specific to α-crystallin can be substantially boosted by this DNA vaccine resulting in enhanced and extended protection superior to BCG.…”

“…We showed that this DNA vaccine induces Th1 response and protects guinea pigs against M. tuberculosis infection, even though, it could not surpass the protective efficacy of BCG, when employed alone in a prophylactic mode [14]. Recently, we also showed that DNAacr efficiently boosts the immunity following vaccination with a recombinant BCG vaccine over-expressing α-crystallin [15]. However, as majority of global population represents BCG vaccinated individuals, in this study, we have evaluated the ability of a booster DNA vaccine expressing α-crystallin to strengthen the immune responses and enhance and prolong the protective efficiency of BCG.…”

A S52P mutation in the ‘α‐crystallin domain’ of Mycobacterium leprae HSP18 reduces its oligomeric size and chaperone function

“…This protein exhibits several properties, such as refolding ability, aggregation prevention ability, etc., that are associated with other sHSPs. Direct implications of chaperone function of acr1 mycobacterial sHSP (M. tuberculosis HSP16.3) on the survival and virulence of M. tuberculosis pathogen are well documented in the literature [66,67]. Because HSP18S 52 prevents the aggregation of various stressed protein and helps E. coli to survive under thermal stress, the chaperone ability of HSP18S 52 may play an important role in the survival of M. leprae pathogen in the host.…”

Adjunctive immunotherapy with α-crystallin based DNA vaccination reduces Tuberculosis chemotherapy period in chronically infected mice

“…We also showed that DNAacr conferred a superior protection than BCG vaccination when employed either in ‘rBCG prime – DNA boost’23 or ‘BCG prime – DNA boost’24 regimen. In this study, we have evaluated the immunotherapeutic potential of adjunctive immunotherapy with DNAacr and DNAsod in a murine model of latent TB to shorten the duration of chemotherapy and to prevent the reactivation of latent infection.…”