Vaccination with recombinant N-terminal domain of Als1p improves survival during murine disseminated candidiasis by enhancing cell-mediated, not humoral, immunity - PubMed (original) (raw)

Vaccination with recombinant N-terminal domain of Als1p improves survival during murine disseminated candidiasis by enhancing cell-mediated, not humoral, immunity

Ashraf S Ibrahim et al. Infect Immun. 2005 Feb.

Abstract

Candida spp. are opportunistic fungal pathogens that are among the most common causes of nosocomial bloodstream infections. The mortality attributable to disseminated candidiasis is 40 to 50% despite antifungal therapy. Clearly, new strategies are needed to prevent this life-threatening infection. Because risk factors for disseminated candidiasis are well defined and frequently of limited duration, vaccination is an appealing prophylactic strategy. We have identified a cell surface protein, Als1p, that mediates adherence of Candida albicans to a variety of human substrates and plastic. Here we report that immunizing BALB/c mice with the recombinant N-terminal domain of Als1p (rAls1p-N) improved survival during a subsequent challenge with a lethal inoculum of C. albicans. The protective 20-mug dose of rAls1p-N significantly increased Candida stimulation of Th1 splenocytes and increased in vivo delayed-type hypersensitivity. In contrast, antibody titers did not correlate with protection. Finally, the vaccine was not protective in T-cell-deficient mice but was protective in B-cell-deficient mice. These data indicate that the mechanism of action of the rAls1p-N vaccine is stimulation of cell-mediated, rather than humoral, immunity against C. albicans. The majority of efforts to date have focused on the development of passive immunization strategies to prevent or treat disseminated candidiasis. In contrast, our results provide proof of principle for vaccination with an adhesin of C. albicans and emphasize the potential for cell-mediated immune modulation as a prophylactic or therapeutic strategy against disseminated candidiasis.

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Figures

FIG. 1.

FIG. 1.

Immunization of mice (retired breeders) with rAls1p-N improves survival during subsequent disseminated candidiasis. Survival of mice immunized with Als1p plus adjuvant was measured. Sixteen mice per group were used in duplicate experiments on different days. Adj. = adjuvant. *, P < 0.05 versus adjuvant.

FIG. 2.

FIG. 2.

Immunization with rAls1p-N improves the survival of both retired breeder and juvenile mice. Survival of retired breeder (A) and juvenile (B) mice infected with a rapidly fatal inoculum of 106 blastospores of C. albicans was measured. Sixteen mice per group were used in duplicate experiments on different days. Adj. = adjuvant. *, P < 0.05 versus adjuvant control.

FIG. 3.

FIG. 3.

Anti-rAls1p-N titers do not correlate with survival. Titers of anti-rAls1p-N polyclonal antibodies (Ab) raised in BALB/c mice immunized with various doses of rAls1p-N with or without adjuvant were measured. Adj. = adjuvant. *, P ≤ 0.005 for the 200-μg dose versus all others.

FIG. 4.

FIG. 4.

Only the protective dose of rAls1p-N induces an increase in _C. albicans_-stimulated Th1 splenocytes. Induction of Th1 (CD4+ IFN-γ+ IL-4−) and Th2 (CD4+ IFN-γ− IL-4+) splenocytes by different doses of the rAls1p-N vaccine was measured. Splenocytes from immunized mice (nine per group) were stimulated for 48 h with heat-killed pregerminated C. albicans and then analyzed by three-color flow cytometry. *, P = 0.03 versus adjuvant.

FIG. 5.

FIG. 5.

Only the protective dose of rAls1p-N induces an increase in rAls1p-N-stimulated delayed-type hypersensitivity. Delayed-type hypersensitivity was assessed by measuring footpad swelling in mice (9 to 12 per group) vaccinated with rAls1p-N and CFA or with CFA alone. Mice were immunized with the indicated amount of rAls1p-N and then injected in the footpad with 50 μg of rAls1p-N. Footpad swelling was assessed 24 h later. *, P < 0.05 versus adjuvant, 0.2 μg, and 200 μg.

FIG. 6.

FIG. 6.

The rAls1p-N vaccine requires T cells, but not B cells, to induce protective immunity. Survival of B-cell-deficient, T-cell-deficient (nude), and congenic wild-type BALB/c control mice (seven or eight per group) was simultaneously assessed after vaccination with rAls1p-N plus adjuvant or with adjuvant alone. *, P < 0.04 versus adjuvant alone; ¶, P = 0.003 versus adjuvant-treated wild type.

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