Role of interleukin-18 in host defense against disseminated Candida albicans infection

In mice injected intravenously with Candida albicans, administration of anti-interleukin-18 (IL-18) antibodies increased the yeast load in the kidneys. There was no effect on the organ load with Candida when gamma interferon (IFN-gamma)-deficient mice were treated with anti-IL-18 antibodies, suggesting that the protective effect of IL-18 is mediated through endogenous IFN-gamma.     

Differential role of IL-18 and IL-12 in the host defense against disseminated Candida albicans infection

IFN-gamma plays a crucial role in the defense against infection with Candida albicans. Since IL-18 and IL-12 are strong stimuli of IFN-gamma production, we investigated whether endogenous IL-18 and IL-12 are involved in the host defense during disseminated candidiasis. IL-18 knockout (IL-18-/-) mice, but not IL-12-/- mice, displayed an increased mortality due to C. albicans infection, accompanied by a decreased clearance of the yeasts from the kidneys late during the course of infection. Histopathology of the organs, combined with phagocyte recruitment experiments, showed a decreased influx of monocytes at the sites of Candida infection, mainly in the IL-18-/- mice. Whereas production of the chemokine KC was decreased in both IL-18-/- and IL-12-/- mice, MIP-2 production was deficient only in IL-18-/- animals, which may explain the differences in phagocyte recruitment. In addition, although IFN-gamma production capacity, as a parameter of the Th1-protective immunity, was reduced by 65 to 80% in the IL-12-/- mice, this defect was even more pronounced in the IL-18-/- mice (85 to 95% down-modulation). In conclusion, the anticandidal effects of endogenous IL-18 are mediated late during the infection by assuring a proper IFN-gamma response and promoting the infiltration of the site of infection by monocytes.     

Commensal enteric bacteria lipopolysaccharide impairs host defense against disseminated Candida albicans fungal infection

Commensal enteric bacteria maintain systemic immune responsiveness that protects against disseminated or localized infection in extra-intestinal tissues caused by pathogenic microbes. However, as shifts in infection susceptibility after commensal bacteria eradication have primarily been probed using viruses, the broader applicability to other pathogen types remains undefined. In sharp contrast to diminished antiviral immunity, we show commensal bacteria eradication bolsters protection against disseminated Candida albicans fungal infection. Enhanced antifungal immunity reflects more robust systemic expansion of Ly6G^hiLy6C^int neutrophils, and their mobilization into infected tissues among antibiotic-treated compared with commensal bacteria-replete control mice. Reciprocally, depletion of neutrophils from expanded levels or intestinal lipopolysaccharide reconstitution overrides the antifungal protective benefits conferred by commensal bacteria eradication. This discordance in antifungal compared with antiviral immunity highlights intrinsic differences in how commensal bacteria control responsiveness for specific immune cell subsets, because pathogen-specific CD8⁺ T cells that protect against viruses were suppressed similarly after C. albicans and influenza A virus infection. Thus, positive calibration of antiviral immunity by commensal bacteria is counterbalanced by restrained activation of other immune components that confer antifungal immunity.     

IL-17 signaling in host defense against Candida albicans

The discovery of the Th17 lineage in 2005 triggered a major change in how immunity to infectious diseases is viewed. Fungal infections, in particular, have long been a relatively understudied area of investigation in terms of the host immune response. Candida albicans is a commensal yeast that colonizes mucosal sites and skin. In healthy individuals, it is non-pathogenic, but in conditions of immune deficiency, this organism can cause a variety of infections associated with considerable morbidity. Candida can also cause disseminated infections that have a high mortality rate and are a major clinical problem in hospital settings. Although immunity to Candida albicans was long considered to be mediated by Th1 cells, new data in both rodent models and in humans have revealed an essential role for the Th17 lineage, and in particular its signature cytokine IL-17.     

Autophagy is redundant for the host defense against systemic Candida albicans infections

Autophagy has been demonstrated to play an important role in the immunity against intracellular pathogens, but very little is known about its role in the host defense against fungal pathogens such as Candida albicans. Therefore, the role of autophagy for the host defense against C. albicans was assessed by complementary approaches using mice defective in autophagy, as well as immunological and genetic studies in humans. Although C. albicans induced LC3-II formation in macrophages, myeloid cell-specific ATG7^?/? mice with defects in autophagy did not display an increased susceptibility to disseminated candidiasis. In in vitro experiments in human blood mononuclear cells, blocking autophagy modulated cytokine production induced by lipopolysaccharide, but not by C. albicans. Furthermore, autophagy modulation in human monocytes did not influence the phagocytosis and killing of C. albicans. Finally, 18 single-nucleotide polymorphisms in 13 autophagy genes were not associated with susceptibility to candidemia or clinical outcome of disease in a large cohort of patients, and there was no correlation between these genetic variants and cytokine production in either candidemia patients or healthy controls. Based on these complementary in vitro and in vivo studies, it can be concluded that autophagy is redundant for the host response against systemic infections with C. albicans.     

Mice lacking both G-CSF and IL-6 are more susceptible to Candida albicans infection: Critical role of neutrophils in defense against Candida albicans

Neutrophils play an important role in the host's defense against infection with various pathogenic organisms. Granulocyte colony stimulating factor (G-CSF) is regarded as a major regulator of neutrophil production and function. Mice lacking G-CSF or its receptor are neutropenic. IL-6 is another cytokine that has been shown to promote neutrophil production and modulate the function of many types of immune cells. We have analyzed G-CSF/IL-6 double deficient (G-CSF^{? / ?} /IL-6^{? / ?} ) mice to gain an insight into the possible contribution of IL-6 to the residual granulopoiesis in G-CSF-deficient (G-CSF^{? / ?} ) mice. Furthermore, we have evaluated the ability of G-CSF^{? / ?} /IL-6^{? / ?} mice to combat an experimental infection with Candida albicans. Our data shows that IL-6 plays a role in granulopoiesis during early post natal period but it is dispensable for steady-state granulopoiesis in adult mice. However, adult G-CSF^{? / ?} /IL-6^{? / ?} mice are more susceptible to Candida infection than similarly infected G-CSF^{? / ?} mice. Although, the candidacidal function of neutrophils of G-CSF^{? / ?} /IL-6^{? / ?} mice is deficient, the ability to produce IFN-γ and TNF-α in response to Candida infection is not compromised. Similarly, nitric oxide production by peritoneal macrophages from G-CSF^{? / ?} /IL-6^{? / ?} mice in response to Candida is comparable to G-CSF^{? / ?} mice.     

Mice lacking both G-CSF and IL-6 are more susceptible to Candida albicans infection: critical role of neutrophils in defense against Candida albicans

Neutrophils play an important role in the host's defense against infection with various pathogenic organisms. Granulocyte colony stimulating factor (G-CSF) is regarded as a major regulator of neutrophil production and function. Mice lacking G-CSF or its receptor are neutropenic. IL-6 is another cytokine that has been shown to promote neutrophil production and modulate the function of many types of immune cells. We have analyzed G-CSF/IL-6 double deficient (G-CSF(- / - )/IL-6(- / - )) mice to gain an insight into the possible contribution of IL-6 to the residual granulopoiesis in G-CSF-deficient (G-CSF(- / - )) mice. Furthermore, we have evaluated the ability of G-CSF(- / - )/IL-6(- / - ) mice to combat an experimental infection with Candida albicans. Our data shows that IL-6 plays a role in granulopoiesis during early post natal period but it is dispensable for steady-state granulopoiesis in adult mice. However, adult G-CSF(- / - )/IL-6(- / - ) mice are more susceptible to Candida infection than similarly infected G-CSF(- / - ) mice. Although, the candidacidal function of neutrophils of G-CSF(- / - )/IL-6(- / - ) mice is deficient, the ability to produce IFN-gamma and TNF-alpha in response to Candida infection is not compromised. Similarly, nitric oxide production by peritoneal macrophages from G-CSF(- / - )/IL-6(- / - ) mice in response to Candida is comparable to G-CSF(- / - ) mice.     

Severe impairment in early host defense against Candida albicans in mice deficient in myeloperoxidase

Myeloperoxidase (MPO) catalyzes the reaction of hydrogen peroxide with chloride ion to produce hypochlorous acid (HOCl), which is used for microbial killing by phagocytic cells. Despite the important role of MPO in host defense, however, MPO deficiency is relatively common in humans, and most of these individuals are in good health. To define the in vivo role of MPO, we have generated by gene targeting mice having no MPO activity in their neutrophils and monocytes. The mice without MPO developed normally, were fertile, and showed normal clearance of intraperitoneal Staphylococcus aureus. However, they showed increased susceptibility to pneumonia and death following intratracheal infection with Candida albicans. Furthermore, the lack of MPO significantly enhanced the dissemination of intraperitoneally injected C. albicans into various organs during the first 7 days. Thus, MPO is important for early host defense against fungal infection, and the inability to generate HOCl cannot be compensated for by other oxygen-dependent systems in vivo in mice. The mutant mice serve as a model for studying pulmonary and systemic candidiasis.     

The emerging role of CD40 ligand in HIV infection

CD40 ligand (also called CD40L, CD154, or TNFSF5) is a membrane protein expressed mainly by activated CD4+ T cells, which interacts with its receptor, CD40, on a variety of cells. The crucial importance of the CD40L-CD40 system for many immune responses has been extensively described. This review focuses on the multiple roles that this system may play in HIV infection. In early HIV infection, CD40L expression contributes to the immunological control of viral replication by inducing HIV-suppressive chemokines and supporting the production of anti-HIV antibodies and cytotoxic T cells. However, by activating antigen-presenting cells, such as dendritic cells and macrophages, CD40L can also lead to increased CD4+ T cell activation, which promotes the replication of HIV in these lymphocytes. Later, with the development of AIDS, CD40L-expressing CD4+ T cells become selectively depleted, perhaps as a result of a gp120-induced signal through CD4 that down-regulates CD40L expression. This acquired CD40L deficiency may explain the similarity between the types of opportunistic infections that occur in AIDS and in congenital CD40L deficiency. Vaccines or other strategies that promote the growth of CD4+ T cells capable of expressing CD40L may help to sustain host immunity against HIV and prevent AIDS-defining opportunistic infections.     

Antiarthritic effect of VIP in relation to the host resistance against Candida albicans infection

Vasoactive intestinal peptide (VIP) is one of the prospective candidates for clinical application in rheumatoid arthritis (RA). Its antiarthritic effect is associated with the suppression of inflammatory and autoimmune responses. The ability of VIP to trigger a shift towards Th2 immunity suggests that anti-infectious host resistance might be affected. In the present study VIP was applied at the initiation and at the established phase of collagen-induced arthritis (CIA). Mice developed Th2 dominant anti-collagen response. The susceptibility to primary and secondary Candida albicans infection was determined after VIP administration at the established CIA. The percentage of survivors, kidney colonization, cytokine secretion by splenocytes and specific antibody synthesis were assessed. Reduced TNF-alpha production but not IFN-gamma and IL-10 was observed after the first challenge with the pathogen in CIA mice treated with VIP while the percentage of survivors was not significantly changed. The adaptive immune response was impaired in VIP-treated mice as they were more susceptible to reinfection, showed increased kidney colonization and suppressed anti-Candida IgG antibody production.     

The role of Toll-like receptors in host defense against microbial infection

The Toll family of proteins is central to Drosophila host defense against microbial infection. Maintained throughout evolution, mammalian Toll-like receptors (TLRs) are proteins that participate in innate immunity to bacteria in at least four ways. First, TLRs participate in the recognition of molecular patterns present on microorganisms. Second, TLRs are expressed at the interface with the environment, the site of microbial invasion. Third, activation of TLRs induces expression of co-stimulatory molecules and the release of cytokines that instruct the adaptive immune response. Fourth, activation of TLRs leads to direct antimicrobial effector pathways that can result in elimination of the foreign invader. The recent investigation of TLRs in these areas has provided new insights into mechanisms of innate immunity.     

Detrimental role of endogenous nitric oxide in host defence against Sporothrix schenckii

Dendritic cells (DCs) play a key role in the type and course of an immune response. The manipulation of human DCs to produce therapeutic agents by transduction with viral vectors is a growing area of research. We present an investigation into the effects of adenoviral vector infection on human DCs and other cell types, and on their subsequent ability to induce T-cell proliferation. We show that infection with replication-deficient adenovirus results in impaired proliferation of T cells in a mixed lymphocyte reaction (MLR). We show this to be an active suppression rather than a defect in the DCs as T cells also fail to proliferate in response to phytohaemagglutinin in the presence of adenoviral vector-infected DCs. This suppression is not attributable to phenotypic changes, death or inability of the DCs to produce cytokines on stimulation. By separation of DCs from T cells, and addition of conditioned supernatants, we show that suppression is mediated by a soluble factor. Blocking of interleukin (IL)-10 but not transforming growth factor (TGF)-beta could overcome the suppressive effect in some donors, and the source of the suppressive IL-10 was lymphocytes exposed to conditioned supernatant. Together our data suggest that infection of DCs by adenoviral vectors leads to suppression of the resulting immune response.     

Differential role of NK cells against Candida albicans infection in immunocompetent or immunocompromised mice

Little is known regarding the role of NK cells during primary and secondary disseminated Candida albicans infection. We assessed the role of NK cells for host defense against candidiasis in immunocompetent, as well as immunodeficient, hosts. Surprisingly, depletion of NK cells in immunocompetent WT mice did not increase susceptibility to systemic candidiasis, suggesting that NK cells are redundant for antifungal defense in otherwise immunocompetent hosts. NK‐cell‐depleted mice were found to be protected as a consequence of attenuation of systemic inflammation. In contrast, the absence of NK cells in T/B/NK‐cell‐deficient NSG (NOD SCID gamma) mice led to an increased susceptibility to both primary and secondary systemic C. albicans infections compared with T/B‐cell‐deficient SCID mice. In conclusion, this study demonstrates that NK cells are an essential and nonredundant component of anti‐C. albicans host defense in immunosuppressed hosts with defective T/B‐lymphocyte immunity, while contributing to hyperinflammation in immunocompetent hosts. The discovery of the importance of NK cells in hosts with severe defects of adaptive immunity might have important consequences for the design of adjunctive immunotherapeutic approaches in systemic C. albicans infections targeting NK‐cell function.     

The crucial role of granulocytes in the early host defense against Strongyloides ratti infection in mice

The involvement of granulocytes in the host early defense against the nematode, Strongyloides ratti, was studied. It was confirmed that granulocytes were effectively depleted for 4 days by anti-granulocyte monoclonal antibody (anti-Gr-1). To examine the involvement of granulocytes in the host defense against migrating larvae, 2000 S. ratti infective larvae (L³) were inoculated subcutaneously 1 day after antibody treatment. The number of S. ratti eggs secreted in feces (EPG) was higher in the granulocyte-depleted group than in the control group. The number of migrating larvae also increased in the granulocyte-depleted group in accordance with the increase in EPG. Therefore granulocytes are crucial for the host early defense against migrating larvae of S. ratti. Next, the involvement of granulocytes in the intestinal early defense was examined. Mice were treated with the antibody on day 3 post-infection. On that day, almost all inoculated larvae reached the intestine and molted to become adults. EPG on day 5 post-infection was increased by the antibody treatment, but no effect was observed on intestinal worm numbers. The fecundity (EPG/worm number) of S. ratti adult worms in the granulocyte-depleted group was higher than that in the control group. Thus granulocytes are also involved in the intestinal early defense through suppressing fecundity of the adult worms. On the other hand, the depletion of granulocytes had no effect on the late adaptive response against S. ratti adult worms (e.g. number of intestinal mucosal mast cells, time of worm expulsion). These results suggest that granulocytes are mainly involved in the host early defense against parasites. Received: 28 September 1999 / Accepted: 12 October 1999     

A role for lymphotoxin beta receptor in host defense against Mycobacterium bovis BCG infection

To investigate the role of membrane lymphotoxin (LT)alpha1 / beta2 and its LTbeta receptor (LTbetaR) in the protective immune response to Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection, we have used a soluble fusion molecule (LTbetaR-IgG1). LTbetaR-Ig treatment interferes with granuloma formation mainly in the spleen by inhibiting macrophage activation and nitric oxide synthase activity. In addition, a large accumulation of eosinophils was observed in the spleen of LTbetaR-Ig-treated infected mice. Decreased blood levels of IFN-gamma and increased IL-4 were also observed, suggesting that the LTbetaR pathway is important in BCG infection to favor a Th1 type of immune response. The treatment of transgenic mice expressing high blood levels of a soluble TNFR1-IgG3 fusion protein with LTbetaR-Ig resulted in a still higher sensitivity to BCG infection, and extensive necrosis in the spleen. In conclusion, these results suggest that the LTbetaR and the TNFR pathways are not redundant in the course of BCG infection and protective granuloma formation: the LTbetaR pathway appears to be important in spleen granuloma formation, whereas the TNFR pathway has a predominant role in other tissues.     

Role of nitric oxide in host defense against an extracellular, metazoan parasite, Brugia malayi.

The mechanisms by which mammalian hosts eliminate microparasites such as bacteria and viruses are well established. In viral infections, these mechanisms include the interferons, neutralizing and opsonizing antibodies, and cytotoxic T lymphocytes. In bacterial infections, polymorphonuclear leukocytes and macrophages, often facilitated by opsonizing antibodies, ingest the infectious agent and mediate host defense. In addition, complement, in the presence of specific antibodies directed against surface antigens, can lyse certain bacterial pathogens. In contrast, our understanding of the host defenses against metazoan, extracellular parasites is less well grounded. We obtained data by two different approaches to document the role of nitric oxide (NO) as a mediator of host defense against a human nematode parasite. First, treatment of immunocompetent, nonpermissive mice with an inhibitor of NO synthase abrogated resistance to Brugia malayi, one of the causative agents of human lymphatic filariasis. Second, treatment of permissive, immunodeficient mice with a compound that releases NO conferred resistance to infection. These data reinforce studies by James and her coworkers (I. P. Oswald, T. A. Wynn, A. Sher, and S. L. James, Comp. Biochem. Physiol. Pharmacol. Toxicol. Endocrinol. 108:11-18, 1994) on the role of NO in defense against trematode parasites and of Kanazawa et al. (T. Kanazawa, H. Asahi, H. Hata; K. Machida, N. Kagei, and M. J. Stadecker, Parasite Immunol. 15: 619-623, 1993) on cestode parasites.     

What's new in the mechanisms of host resistance to Candida albicans infection?

Despite extensive investigation, the mechanisms of host resistance against C. albicans infection remain poorly understood. Granulocytes and macrophages are the major effector cell types; however, their intrinsic candidacidal activity is rather limited, and its full expression requires augmentation by components of the T cell-initiated lymphokine cascade. Consequently, susceptibility to recurrent mucocutaneous infections may be associated with aberrant T cell function. In contrast, protection from systemic infection appears to be mediated by candida-specific antibodies.