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Effectiveness of a vaccine composed of heat-killed Candida albicans and a novel mucosal adjuvant, LT(R192G), against systemic candidiasis.

ABSTRACT: The incidence of fungal infections caused by the opportunistic yeast Candida albicans has increased significantly in recent years. The ability to vaccinate selected patients against the organism would be advantageous. In this paper we describe a potential anti-C. albicans vaccine consisting of heat-killed C. albicans (HK-CA) in combination with the novel mucosal adjuvant LT(R192G), a genetically detoxified form of the heat-labile toxin of enterotoxigenic Escherichia coli. Groups of male CBA/J mice were immunized intranasally on three occasions at weekly intervals with 2 x 10(7) HK-CA per dose, alone or in conjunction with 10 micrograms of LT(R192G) per dose. Two weeks following the last application of antigen, some animals were challenged intravenously (i.v.) with 10(4), 10(5), or 10(6) viable C. albicans to assess protection as measured by survival and/or culture. Some groups of animals were footpad tested with C. albicans mannan to assess delayed-type hypersensitivity (DTH), and all the animals were bled for antibody assays. In two independent studies, all the animals immunized with HK-CA plus LT(R192G) were able to eradicate 10(4) C. albicans completely, as determined by kidney culture 4 weeks after challenge. Animals immunized with HK-CA only had reduced levels of C. albicans compared to the adjuvant or saline-only control. Greatly enhanced survival was observed when mice immunized with HK-CA plus LT(R192G) were challenged with 10(5) live C. albicans as well. Animals immunized with HK-CA plus LT(R192G) developed a significant DH response, while those given HK-CA alone developed only marginal DH responses. High immunoglobulin G (IgG) levels to cytoplasmic antigens developed in mice immunized with HK-CA plus LT(R192G), but they were found only after i.v. challenge. Addition of adjuvant shifted the antibody isotype production in i.v.-challenged animals to a response dominated by IgG2a. Clearly, intranasal immunization with killed C. albicans in conjunction with LT(R192G) afforded significant levels of protection. This novel approach offers new possibilities for the development of an effective vaccine against candidiasis for use in humans.

SUBMITTER: Cardenas-Freytag L

PROVIDER: S-EPMC96393 | biostudies-literature | 1999 Feb

REPOSITORIES: biostudies-literature

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Effectiveness of a vaccine composed of heat-killed Candida albicans and a novel mucosal adjuvant, LT(R192G), against systemic candidiasis.

Cárdenas-Freytag L L Cheng E E Mayeux P P Domer J E JE Clements J D JD

Infection and immunity 19990201 2

The incidence of fungal infections caused by the opportunistic yeast Candida albicans has increased significantly in recent years. The ability to vaccinate selected patients against the organism would be advantageous. In this paper we describe a potential anti-C. albicans vaccine consisting of heat-killed C. albicans (HK-CA) in combination with the novel mucosal adjuvant LT(R192G), a genetically detoxified form of the heat-labile toxin of enterotoxigenic Escherichia coli. Groups of male CBA/J mi ...[more]

PMID: 9916097

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Project description:Oropharyngeal candidiasis (OPC) is the most prevalent oral infection in immunocompromised patients, primarily associated with Candida albicans. Increasing evidence points to a significant role of mucosal bacteria on the transition of C. albicans from commensal to pathogenic. In this work, we hypothesized that changes in the abundance or composition of the mucosal bacterial microbiota induced by dietary sucrose during the development of OPC can modulate C. albicans virulence. C. albicans burdens and mucosal lesions were evaluated in a mouse cortisone immunosuppression model amended with sucrose. We also analyzed the mucosal bacterial composition using 16S rRNA gene sequencing and culture methods. In immunocompetent mice, sucrose significantly increased total bacterial burdens and reduced alpha diversity, by increasing the relative abundance of mitis group streptococci. In immunocompromised mice, C. albicans infection was associated with a significantly reduced bacterial alpha diversity due to an increase in the relative abundance of enterococci. When exposed to dietary sucrose, these mice had reduced C. albicans burdens and reduced bacterial alpha diversity, associated with an increase in the relative abundance of Lactobacillus. SparCC correlation networks showed a significant negative correlation between Lactobacillus and Enterococcus in all Candida-infected mice. Depletion of lactobacilli with antibiotic treatment partially restored C. albicans burdens in mice receiving sucrose. In coculture in vitro experiments, mouse oral Lactobacillus johnsonii isolates inhibited growth of Enterococcus faecalis isolates and C. albicans. These results support the hypothesis that the sucrose-induced attenuation of C. albicans virulence was a result of changes in the mucosal bacterial microbiome characterized by a reduction in enterococci and an increase in lactobacilli. IMPORTANCE By comparing Candida albicans virulence and the mucosal bacterial composition in a mouse oral infection model, we were able to dissect the effects of the host environment (immunosuppression), infection with C. albicans, and local modulating factors (availability of sucrose as a carbon source) on the mucosal bacterial microbiome and its role on fungal virulence. We showed that changes in endogenous microbial communities in response to sucrose can lead to attenuation of fungal disease. We also showed that Lactobacillus johnsonii may curtail Candida virulence both by inhibiting its growth and by inhibiting the growth of potentially synergistic bacteria such as enterococci. Our results support the concept that Candida pathogenesis should be viewed in the contexts of both a susceptible host and a mucosal bacterial microbiota conducive to virulence.

Project description:The development of an effective subunit vaccine is frequently complicated by the difficulty of eliciting protective immune responses, often requiring the co-administration of an adjuvant. Heat-labile toxin (LT), an enterotoxin expressed by enterotoxigenic E. coli (ETEC) with an AB5 structure similar to cholera toxin, is a strong adjuvant. While the mucosa represents the natural route of exposure to LT and related toxins, the clinical utility of LT and similar adjuvants given by mucosal routes has been limited by toxicity, as well as the association between intranasal delivery of LT and Bell's palsy. Single and double amino acid mutants of LT, LT(R192G)/mLT and LT(R192G/L211A)/dmLT respectively, have been proposed as alternatives to reduce the toxicity associated with the holotoxin. In the present study, we compared mLT and dmLT given via a non-mucosal route (i.e. intradermally) to investigate their adjuvanticity when co-administrated with an enterotoxigenic E. coli vaccine candidate, CfaEB. Antigenicity (i.e. ability to elicit response against LT) and reactogenicity at the injection site were also evaluated. BALB/c mice were immunized by the intradermal route with CfaEB plus increasing doses of either mLT or dmLT (0.01 to 2.5 μg). Both adjuvants induced dose-dependent skin reactogenicity, with dmLT being less reactogenic than mLT. Both adjuvants significantly boosted the anti-CfaE IgG and functional hemagglutination inhibiting (HAI) antibody responses, compared to the antigen alone. In addition to inducing anti-LT responses, even at the lowest dose tested (0.01 μg), the adjuvants also prompted in vitro cytokine responses (IFN-γ, IL-4, IL-5, IL-10 and IL-17) that followed different patterns, depending on the protein used for stimulation (CfaE or LTB) and/or the dose used for immunization. The two LT mutants evaluated here, mLT and dmLT, are potent adjuvants for intradermal immunization and should be further investigated for the intradermal delivery of subunit ETEC vaccines.

Dataset Information

Effectiveness of a vaccine composed of heat-killed Candida albicans and a novel mucosal adjuvant, LT(R192G), against systemic candidiasis.

Publications

Effectiveness of a vaccine composed of heat-killed Candida albicans and a novel mucosal adjuvant, LT(R192G), against systemic candidiasis.

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