Cholera Toxin Enhances Vaccine-Induced Protection against Mycobacterium Tuberculosis Challenge in Mice

Abstract

Interleukin (IL)-17 is emerging as an important cytokine in vaccine-induced protection against tuberculosis disease in animal models. Here we show that compared to parenteral delivery, BCG delivered mucosally enhances cytokine production, including interferon gamma and IL-17, in the lungs. Furthermore, we find that cholera toxin, delivered mucosally along with BCG, further enhances IL-17 production by CD4+ T cells over mucosal BCG alone both in the lungs and systemically. This boosting effect of CT is also observed using a vaccine regimen of BCG followed by the candidate vaccine MVA85A. Using a murine Mycobacterium tuberculosis (M.tb) aerosol challenge model, we demonstrate the ability of cholera toxin delivered at the time of a priming BCG vaccination to improve protection against tuberculosis disease in a manner at least partially dependent on the observed increase in IL-17. This observed increase in IL-17 in the lungs has no adverse effect on lung pathology following M.tb challenge, indicating that IL-17 can safely be boosted in murine lungs in a vaccine/M.tb challenge setting.

A novel nanoemulsion vaccine induces mucosal Interleukin-17 responses and confers protection upon Mycobacterium tuberculosis challenge in mice

“…Substantial recent evidence demonstrates a pivotal role for Th17 cells and IL-17 in vaccine-mediated immunity against TB [8, 10, 17]. Several mucosally delivered adjuvants such as cholera toxin [26, 27], heat labile enterotoxin [8], Monophosporyl lipid A (MPL) along with chitosan [25], when delivered with Mtb antigens in experimental models have all been shown to induce potent lung Th17 responses and confer Mtb control.…”

“…vaccines induce better mucosal immunity and confer superior protection against mucosal infectious diseases, including TB [12-15], when compared to systemic routes of immunization [16]. Importantly, we and others have recently demonstrated that mucosal vaccination of Mtb antigens in Heat Labile enterotoxin (HLT) [8] or cholera toxin [17] induced mucosal Th17 responses, which confer protection upon Mtb challenge. Our mechanistic studies demonstrated that IL-17 induced chemokines localize cytokine-producing T-cells near Mtb -infected macrophages, forming lymphoid follicles within granulomas to mediate Mtb control [11, 18].…”

“…Our mechanistic studies demonstrated that IL-17 induced chemokines localize cytokine-producing T-cells near Mtb -infected macrophages, forming lymphoid follicles within granulomas to mediate Mtb control [11, 18]. In combination with DC transfer, a HLT-TB mucosal vaccine can provide superior near-sterilizing vaccine-induced protection against Mtb infection [8, 17, 19]. Despite the ability of these experimental mucosal adjuvants to induce protective Th17 responses and confer vaccine-induced protection, there are serious concerns regarding the safety of toxin subunits as mucosal adjuvants in human vaccines.…”

Novel vaccine approaches for protection against intracellular pathogens

“…The attenuated SchuS4 strains induced improved protection over LVS, which was associated with increased IL-17 production in the lungs of challenged mice [40], however intranasal delivery did not improve on intranasal challenge [41]. This is in contrast to results from Mtb vaccine studies in which intranasal delivery confers improved protection over parenteral delivery [7,8], suggesting that the site of T cell induction for optimal responses may differ between pathogens. Provided there is no risk of reversion, thus, live attenuated vaccines represent a valid approach for T cell-inducing vaccines given the potential for induction of an immune response to a broad range of antigens.…”

Mucosal vaccines

“…In preclinical models, the most largely employed adjuvants to induce mucosal immune responses have been non-toxic derivatives of cholera toxin (CT) and Escherichia coli heat labile enterotoxin (LT). 102,103 Although devoid of their enterotoxicity and capable to efficiently increase both antibody and cellular immune responses, LT-derivatives proved to be toxic to humans after i.n. delivery due to the nerve tissue tropism leading to accumulation in the olfactory nerve and the bulb and inducing transient facial paralysis.…”