Four species of probiotic bacteria were assessed for their capacities to protect athymic bg/bg-nu/nu and euthymic bg/bg-nu/؉ mice from mucosal and systemic candidiasis. Each bacterial species and Candida albicans colonized the gastrointestinal tracts of both strains of mice. The presence of probiotic bacteria (Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus casei GG, or Bifidobacterium animalis) in the gastrointestinal tracts prolonged the survival of adult and neonatal bg/bg-nu/nu mice compared to that of isogenic mice colonized with C. albicans alone. The incidence of systemic candidiasis in bg/bg-nu/nu mice was significantly reduced by each of the four probiotic bacterial species. The numbers of C. albicans present in the alimentary tracts of euthymic bg/bg-nu/؉ mice were significantly reduced by L. casei GG and B. animalis. None of the probiotic bacteria species completely prevented mucosal candidiasis, but B. animalis reduced its incidence and severity. Probiotic bacteria also modulated antibody-and cell-mediated immune responses to C. albicans. The prolonged survival of mice, decreased severity of mucosal and systemic candidiasis, modulation of immune responses, decreased number of C. albicans in the alimentary tract, and reduced numbers of orogastric infections demonstrated not only that probiotic bacteria have biotherapeutic potential for prophylaxis against and therapy of this fungal disease but also that probiotic bacteria protect mice from candidiasis by a variety of immunologic (thymic and extrathymic) and nonimmunologic mechanisms in this model.

Germ-free C57BL/6 x 129 interferon-gamma knockout (IFN-gamma(-/-)) mice and their immunocompetent (+/-, +/+) counterparts were colonized with a pure culture of Candida albicans to assess their natural susceptibility to mucosal and systemic candidiasis of endogenous origin. Colonization with a pure culture of C. albicans was not lethal for adult or neonatal IFN-gamma(-/-) gnotobiotic mice over the 15-week study. The IFN-gamma(-/-) mice were more susceptible to gastric (cardia-antrum section), anorectal, and acute systemic (intravenous challenge) candidiasis than immunocompetent controls, and some IFN-gamma(-/-) mice developed intestinal adenomas after colonization with C. albicans. The enhanced susceptibility of IFN-gamma(-/-) mice, compared with immunocompetent controls, may be associated with a poor proliferative response of spleen cells to C. albicans antigens and a T helper 2 (IgG1) serum antibody response to C. albicans antigens. Thus, IFN-gamma is important for murine resistance to gastric, anorectal, and acute systemic candidiasis.

Probiotic bacteria can protect immunodeficient mice from orogastric candidiasis but cause some pathology of their own. Severely immunodeficient patients may be at risk if fed viable probiotics, so this study evaluated the probiotic potential of nonviable probiotic bacteria to protect immunodeficient mice from Candida albicans infections. Heat-killed probiotic bacteria were fed to gnotobiotic bg/bg-nu/nu and bg/bg-nu/+ mice to ascertain if they could protect the mice from mucosal and systemic candidiasis. Both heat-killed Lactobacillus acidophilus (HKLA) and heat-killed Lactobacillus casei (HKLC), in comparison to control mice not fed the probiotic bacteria but challenged (oral) with C. albicans, suppressed the severity of orogastric candidiasis in bg/bg-nu/nu mice at 2 weeks after colonization with C. albicans, inhibited disseminated candidiasis in C. albicans-colonized bg/bg-nu/+ mice at 4 weeks after colonization, and suppressed the number of viable C. albicans in the alimentary tract. HKLA, but not HKLC, treatment inhibited disseminated candidiasis in bg/bg-nu/nu mice at 2 weeks after oral challenge and enhanced the proliferative responses of splenocytes from C. albicans-colonized bg/bg-nu/+ mice to C. albicans antigens. Neither HKLA nor HKLC were able to prolong the survival of gnotobiotic bg/bg-nu/nu mice after oral challenge with C. albicans. These results demonstrate that heat-killed lactobacilli can induce some (limited) protection (probiotic effect) against candidiasis in mice.

Germ-free BALB/c mice, genetically engineered to be deficient for interleukin-8 (IL-8) receptor homolog (IL-8Rh-/-), were more susceptible to gastric candidiasis after oral challenge and to acute systemic candidiasis after intravenous challenge than IL-8Rh+/+ controls. In comparison to IL-8Rh+/+ mice, the IL-8Rh-/- mice had slower influx of polymorphonuclear neutrophils (PMN) into Candida albicans-infected tissues and a lower percentage of PMN in peritoneal exudate cells (PEC) elicited with heat-killed C. albicans. PEC from IL-8Rh-/- mice exhibited less luminol-dependent chemiluminescence in response to C. albicans and did not kill C. albicans hyphae as well as PEC from IL-8Rh+/+ mice. C. albicans-colonized IL-8Rh-/- mice showed no histological evidence of systemic candidiasis. These results suggest a role for the IL-8Rh in murine resistance to gastric and acute systemic candidiasis, but not in resistance to systemic candidiasis of endogenous origin.

Germfree transgenic epsilon 26 (Tgepsilon26) mice, which express the full-length human CD3epsilon gene, have combined defects in natural killer (NK) cells and T cells were found to be extremely susceptible to oroesophageal (palate, tongue, esophagus) and gastric (cardia-antrum section) candidiasis. The gnotobiotic Tgepsilon26 mice die, apparently from severe oroesophageal candidiasis, within 2-4 weeks after their alimentary tracts are colonized with Candida albicans. The Tgepsilon26 mice manifest resistance to acute systemic candidiasis (intravenous injection) and to systemic candidiasis of endogenous origin for the first 2 weeks after their alimentary tracts are colonized with C. albicans. Granulocyte depletion data suggest that granulocytes, in the absence of functional NK cells and T cells, can protect Tgepsilon26 mice from acute systemic candidiasis and from systemic candidiasis of endogenous origin, for at least 14 days after alimentary tract colonization. Granulocytes and macrophages, in the absence of NK cells and T cells, are unable to protect Tgepsilon26 mice from lethal oroesophageal candidiasis and systemic candidiasis of endogenous origin which was evident in moribund Tgepsilon26 mice 2-4 weeks after colonization. Thus, non-T cells (i.e., NK cells) and T cells play important roles in resistance to oroesophageal and systemic (acute and of endogenous origin) candidiasis.