Systemic Candida Albicans Infection Research Articles

Paeoniflorin augments systemic Candida albicans infection through inhibiting Th1 and Th17 cell expression in a mouse model

Paeoniflorin (PF), a Chinese herbal medicine, has been widely used in clinical practice in China because of its dual immunoregulatory effects. A previous study found that PF inhibited the biofilm formation of Candida albicans (C. albicans) in vitro; however, whether PF plays an antifungal role in vivo is still unexplored. In this study, we sought to examine the effect of PF alone or in combination with an antifungal agent, fluconazole (FCZ), using a mouse model of systemic candidiasis. The results showed that the survival time of mice treated with PF alone or PF + FCZ decreased compared with the Infected alone and FCZ treated groups, respectively (8.20 ± 1.75 vs 10.40 ± 2.50 days, P < 0.05; 24.60 ± 6.55 vs 29.00 ± 3.16 days, P < 0.05). The fungal burden in the kidney of mice increased in the PF alone and PF + FCZ treated groups compared with the Infected alone or FCZ treated group. Furthermore, it was found that the PF and PF + FCZ treated groups showed significantly decreased levels of serum interferon gamma (IFN-γ), interleukin (IL)-17, and IL-22, and an increased level of serum IL-4; PF had no effect on the production of tumor necrosis factor alpha (TNF-α). PF alone or in combination with FCZ decreased the proliferation of Th1 (IFN-γ+CD4+) and Th17 cells (IL-17+CD4+) and increased the expression of Th2 cells (IL-4+CD4+). These results suggested that PF treatment could be detrimental to the host response to systemic C. albicans infection in mice. Thus, caution might be required for clinical use of PF in patients with fungal infection.

Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic Candida albicans Infection.

ABSTRACTA balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminated Candida albicans. Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, and C. albicans is a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically with C. albicans, they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasive C. albicans appears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67phox. Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-β to mice prior to C. albicans infection. IFN-β treatment promoted pathology and death from C. albicans infection. We provide evidence that IFIT2 increases the pathological effects of invasive C. albicans and that administration of IFN-β has deleterious effects during infection.

Silencing SOCS1 in dendritic cells promote survival of mice with systemic Candida albicans infection via inducing Th1-cell differentiation

Enhancing the immunity conferred by dendritic cells (DCs) to fungal infection represents a promising strategy in the number of immunocompromised individuals. In a previous study, we demonstrated that suppressor of cytokine signaling 1 (SOCS1) silencing can promote the maturation of DCs and induce an immune response against Candida albicans (C. albicans) in vitro. Herein, the effectiveness of SOCS1 suppression administered by SOCS1-siRNA-treated DCs is further evaluated in systemic candidiasis mouse model. The SOCS1-silenced DCs increase mouse survival and significantly decrease fungal colonization in the kidneys. We confirm that the serum IFN-γ levels in SOCS1-siRNA-treated mice are higher than in all other infected groups at the early stages of infection, which correlates with a higher differentiation of IFN-γ+CD4+ T cells (Th1) in the spleen. Meanwhile, the differentiation of IL-4-producing CD4+ T (Th2) or IL-17-producing CD4+ T cells (Th17 cells) remain unaffected under the same treatment, suggesting that SOCS1-silenced DCs significantly affect the IFN-γ-producing CD4+ T cells (Th1). However, at the late stages of infection when the differentiation of Th1, Th2 and Th17 cells decreases in SOCS1-silenced-DCs-treated mice, all the serum cytokines (IFN-γ, IL-4 and IL-17) are also reduced. In summary, treatment of mice with SOCS1-silenced DCs can protect mice from systemic infection during the early stages and thereby increase overall survival. We conclude that the increase in Th1 response in early stages avoids the cascade inflammatory response in later stages that is known to place such a large fungal load on the kidneys and cause subsequent death.

MicroRNAs That Contribute to Coordinating the Immune Response in Drosophila melanogaster.

Small noncoding RNAs called microRNAs (miRNAs) have emerged as post-transcriptional regulators of gene expression related to host defenses. Here, we have used Drosophila melanogaster to explore the contribution of individual or clusters of miRNAs in countering systemic Candida albicans infection. From a total of 72 tested, we identify 6 miRNA allelic mutant backgrounds that modulate the survival response to infection and the ability to control pathogen number. These mutants also exhibit dysregulation of the Toll pathway target transcripts Drosomycin (Drs) and Immune-Induced Molecule 1 (IM1). These are characteristics of defects in Toll signaling, and consistent with this, we demonstrate dependency for one of the miRNA mutants on the NF-κΒ homolog Dif. We also quantify changes in the miRNA expression profile over time in response to three pathogen types, and identify 13 mature miRNA forms affected by pathogens that stimulate Toll signaling. To complement this, we provide a genome-wide map of potential NF-κB sites in proximity to miRNA genes. Finally, we demonstrate that systemic C. albicans infection contributes to a reduction in the total amount of branch-chained amino acids, which is miRNA-regulated. Overall, our data reveal a new layer of miRNA complexity regulating the fly response to systemic fungal infection.

A pre-therapeutic coating for medical devices that prevents the attachment of Candida albicans

BackgroundHospital acquired fungal infections are defined as “never events”—medical errors that should never have happened. Systemic Candida albicans infections results in 30–50% mortality rates. Typically, adhesion to abiotic medical devices and implants initiates such infections. Efficient adhesion initiates formation of aggressive biofilms that are difficult to treat. Therefore, inhibitors of adhesion are important for drug development and likely to have a broad spectrum efficacy against many fungal pathogens. In this study we further the development of a small molecule, Filastatin, capable of preventing C. albicans adhesion. We explored the potential of Filastatin as a pre-therapeutic coating of a diverse range of biomaterials.MethodsFilastatin was applied on various biomaterials, specifically bioactive glass (cochlear implants, subcutaneous drug delivery devices and prosthetics); silicone (catheters and other implanted devices) and dental resin (dentures and dental implants). Adhesion to biomaterials was evaluated by direct visualization of wild type C. albicans or a non-adherent mutant edt1−/− that were stained or fluorescently tagged. Strains grown overnight at 30 °C were harvested, allowed to attach to surfaces for 4 h and washed prior to visualization. The adhesion force of C. albicans cells attached to surfaces treated with Filastatin was measured using Atomic Force Microscopy. Effectiveness of Filastatin was also demonstrated under dynamic conditions using a flow cell bioreactor. The effect of Filastatin under microfluidic flow conditions was quantified using electrochemical impedance spectroscopy. Experiments were typically performed in triplicate.ResultsTreatment with Filastatin significantly inhibited the ability of C. albicans to adhere to bioactive glass (by 99.06%), silicone (by 77.27%), and dental resin (by 60.43%). Atomic force microcopy indicated that treatment with Filastatin decreased the adhesion force of C. albicans from 0.23 to 0.017 nN. Electrochemical Impedance Spectroscopy in a microfluidic device that mimic physiological flow conditions in vivo showed lower impedance for C. albicans when treated with Filastatin as compared to untreated control cells, suggesting decreased attachment. The anti-adhesive properties were maintained when Filastatin was included in the preparation of silicone materials.ConclusionWe demonstrate that Filastatin treated medical devices prevented adhesion of Candida, thereby reducing nosocomial infections.

Targeting CBLB as a potential therapeutic approach for disseminated candidiasis.

Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here, we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and -2, two key pattern recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1/2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of Candida albicans, and deficiency of dectin-1, -2, or both, in Cblb−/− mice abrogates this protection. Importantly, silencing the Cblb gene in vivo protects mice from lethal systemic Candida albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and -2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis.

Host-Imposed Copper Poisoning Impacts Fungal Micronutrient Acquisition during Systemic Candida albicans Infections.

Nutritional immunity is a process whereby an infected host manipulates essential micronutrients to defend against an invading pathogen. We reveal a dynamic aspect of nutritional immunity during infection that involves copper assimilation. Using a combination of laser ablation inductively coupled mass spectrometry (LA-ICP MS) and metal mapping, immunohistochemistry, and gene expression profiling from infected tissues, we show that readjustments in hepatic, splenic and renal copper homeostasis accompany disseminated Candida albicans infections in the mouse model. Localized host-imposed copper poisoning manifests itself as a transient increase in copper early in the kidney infection. Changes in renal copper are detected by the fungus, as revealed by gene expression profiling and fungal virulence studies. The fungus responds by differentially regulating the Crp1 copper efflux pump (higher expression during early infection and down-regulation late in infection) and the Ctr1 copper importer (lower expression during early infection, and subsequent up-regulation late in infection) to maintain copper homeostasis during disease progression. Both Crp1 and Ctr1 are required for full fungal virulence. Importantly, copper homeostasis influences other virulence traits—metabolic flexibility and oxidative stress resistance. Our study highlights the importance of copper homeostasis for host defence and fungal virulence during systemic disease.

CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival.

Systemic Candida albicans infection causes high morbidity and mortality and is now the leading cause of nosocomial bloodstream infection in the United States. Neutropenia is a major risk factor for poor outcome in infected patients; however, the molecular factors that mediate neutrophil trafficking and effector function during infection are poorly defined. Using a mouse model of systemic candidiasis, we found that the neutrophil-selective CXC chemokine receptor Cxcr1 and its ligand, Cxcl5, are highly induced in the Candida-infected kidney, the target organ in the model. To investigate the role of Cxcr1 in antifungal host defense in vivo, we generated Cxcr1(-/-) mice and analyzed their immune response to Candida. Mice lacking Cxcr1 exhibited decreased survival with enhanced Candida growth in the kidney and renal failure. Increased susceptibility of Cxcr1(-/-) mice to systemic candidiasis was not due to impaired neutrophil trafficking from the blood into the infected kidney but was the result of defective killing of the fungus by neutrophils that exhibited a cell-intrinsic decrease in degranulation. In humans, the mutant CXCR1 allele CXCR1-T276 results in impaired neutrophil degranulation and fungal killing and was associated with increased risk of disseminated candidiasis in infected patients. Together, our data demonstrate a biological function for mouse Cxcr1 in vivo and indicate that CXCR1-dependent neutrophil effector function is a critical innate protective mechanism of fungal clearance and host survival in systemic candidiasis.

Inhibiting the immunoproteasome exacerbates the pathogenesis of systemic Candida albicans infection in mice.

Apart from its role in MHC class I antigen processing, the immunoproteasome has recently been implicated in the modulation of T helper cell differentiation under polarizing conditions in vitro and in the pathogenesis of autoimmune diseases in vivo. In this study, we investigated the influence of LMP7 on T helper cell differentiation in response to the fungus Candida albicans. We observed a strong effect of ONX 0914, an LMP7-selective inhibitor of the immunoproteasome, on IFN-γ and IL-17A production by murine splenocytes and human peripheral blood mononuclear cells (PBMCs) stimulated with C. albicans in vitro. Using a murine model of systemic candidiasis, we could confirm reduced generation of IFN-γ- and IL-17A-producing cells in ONX 0914 treated mice in vivo. Interestingly, ONX 0914 treatment resulted in increased susceptibility to systemic candidiasis, which manifested at very early stages of infection. Mice treated with ONX 0914 showed markedly increased kidney and brain fungal burden which resulted in enhanced neutrophil recruitment and immunopathology. Together, these results strongly suggest a role of the immunoproteasome in promoting proinflammatory T helper cells in response to C. albicans but also in affecting the innate antifungal immunity in a T helper cell-independent manner.

6-O-Branched Oligo-β-glucan-Based Antifungal Glycoconjugate Vaccines.

With the rapid growth in fungal infections and drug-resistant fungal strains, antifungal vaccines have become an especially attractive strategy to tackle this important health problem. β-Glucans, a class of extracellular carbohydrate antigens abundantly and consistently expressed on fungal cell surfaces, are intriguing epitopes for antifungal vaccine development. β-Glucans have a conserved β-1,3-glucan backbone with sporadic β-1,3- or β-1,6-linked short glucans as branches at the 6-O-positions, and the branches may play a critical role in their immunologic functions. To study the immunologic properties of branched β-glucans and develop β-glucan-based antifungal vaccines, three branched β-glucan oligosaccharides with 6-O-linked β-1,6-tetraglucose, β-1,3-diglucose, and β-1,3-tetraglucose branches on a β-1,3-nonaglucan backbone, which mimic the structural epitopes of natural β-glucans, were synthesized and coupled with keyhole limpet hemocyanin (KLH) to form novel synthetic conjugate vaccines. These glycoconjugates were proved to elicit strong IgG antibody responses in mice. It was also discovered that the number, size, and structure of branches linked to the β-glucan backbone had a significant impact on the immunologic property. Moreover, antibodies induced by the synthetic oligosaccharide-KLH conjugates were able to recognize and bind to natural β-glucans and fungal cells. Most importantly, these conjugates elicited effective protection against systemic Candida albicans infection in mice. Thus, branched oligo-β-glucans were identified as functional epitopes for antifungal vaccine design and the corresponding protein conjugates as promising antifungal vaccine candidates.

IL-33 Enhances Host Tolerance to Candida albicans Kidney Infections through Induction of IL-13 Production by CD4+ T Cells.

Susceptibility to systemic Candida albicans infection is determined by immune resistance, as well as by the ability to control Candida-induced immunopathologies. We showed previously that exogenous IL-33 can increase resistance to peritoneal C. albicans infection by regulating multiple steps of the neutrophil anti-Candida response. In this study, using a mouse model of systemic candidiasis, we observed that IL-33 administration limited fungal burden and inflammation and increased survival. In kidneys, IL-33 seemed to directly act on neutrophils and CD4(+) T cells: IL-33 administration enhanced fungal clearance by increasing neutrophil phagocytic activity without which Candida proliferation was uncontrollable. In contrast, IL-33 stimulated CD4(+) T cells to produce IL-13, which, in turn, drove the polarization of macrophages toward the M2 type. Furthermore, the absence of IL-13 abolished IL-33-mediated polarization of M2 macrophages and renal functional recovery. In addition, IL-33 and IL-13 acted synergistically to increase M2 macrophage polarization and its phagocytic activity. Overall, this study identifies IL-33 as a cytokine that is able to induce resistance and tolerance and suggests that targeting resistance and tolerance simultaneously with therapeutic IL-33 may benefit patients with systemic candidiasis.

LRH-1 mediates anti-inflammatory and antifungal phenotype of IL-13-activated macrophages through the PPARγ ligand synthesis.

Liver receptor homologue-1 (LRH-1) is a nuclear receptor involved in the repression of inflammatory processes in the hepatointestinal tract. Here we report that LRH-1 is expressed in macrophages and induced by the Th2 cytokine IL-13 via a mechanism involving STAT6. We show that loss-of-function of LRH-1 in macrophages impedes IL-13-induced macrophage polarization due to impaired generation of 15-HETE PPARγ ligands. The incapacity to generate 15-HETE metabolites is at least partially caused by the compromised regulation of CYP1A1 and CYP1B1. Mice with LRH-1-deficient macrophages are, furthermore, highly susceptible to gastrointestinal and systemic Candida albicans infection. Altogether, these results identify LRH-1 as a critical component of the anti-inflammatory and fungicidal response of alternatively activated macrophages that acts upstream from the IL-13-induced 15-HETE/PPARγ axis.

A second stimulus required for enhanced antifungal activity of human neutrophils in blood is provided by anaphylatoxin C5a.

Polymorphonuclear neutrophilic granulocytes (PMN) as cellular components of innate immunity play a crucial role in the defense against systemic Candida albicans infection. To analyze stimuli that are required for PMN activity during C. albicans infection in a situation similar to in vivo, we used a human whole-blood infection model. In this model, PMN activation 10 min after C. albicans infection was largely dependent on the anaphylatoxin C5a. Most importantly, C5a enabled blood PMN to overcome filament-restricted recognition of C. albicans and allowed efficient elimination of nonfilamentous C. albicans cph1Δ/efg1Δ from blood. Major PMN effector mechanisms, including oxidative burst, release of secondary granule contents and initial fungal phagocytosis could be prevented by blocking C5a receptor signaling. Identical effects were achieved using a humanized Ab specifically targeting human C5a. Phagocytosis of C. albicans 10 min postinfection was mediated by C5a-dependent enhancement of CD11b surface expression on PMN, thus establishing the C5a-C5aR-CD11b axis as a major modulator of early anti-Candida immune responses in human blood. In contrast, phagocytosis of C. albicans by PMN 60 min postinfection occurred almost independently of C5a and mainly contributed to activation of phagocytically active PMN at later time points. Our results show that C5a is a critical mediator in human blood during C. albicans infection.

2-(2-oxo-morpholin-3-yl)-acetamide derivatives as broad-spectrum antifungal agents.

From a fungicidal screen, we identified 2-(2-oxo-morpholin-3-yl)-acetamide derivatives as fungicidal agents against Candida species, additionally characterized by antifungal activity against Aspergillus species. However, development of this series was hampered by low plasmatic stability. Introduction of a gem-dimethyl on the 6-position of the morpholin-2-one core led to considerable improvement in plasmatic stability while maintaining in vitro antifungal activity. Further optimization of the series resulted in the discovery of N-(biphenyl-3-ylmethyl)-2-(4-ethyl-6,6-dimethyl-2-oxomorpholin-3-yl)acetamide (87), which, in addition to fungicidal activity against Candida species, shows promising and broad antifungal in vitro activity against various fungi species, such as molds and dermatophytes. In vivo efficacy was also demonstrated in a murine model of systemic Candida albicans infection with a significant fungal load reduction in kidneys.

Protection from systemic Candida albicans infection by inactivation of the Sts phosphatases.

The human fungal pathogen Candida albicans causes invasive candidiasis, characterized by fatal organ failure due to disseminated fungal growth and inflammatory damage. The suppressor of TCR signaling 1 (Sts-1) and Sts-2 are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic cell lineages, including T lymphocytes, mast cells, and platelets. Functional inactivation of both Sts enzymes leads to profound resistance to systemic infection by C. albicans, such that greater than 80% of mice lacking Sts-1 and -2 survive a dose of C. albicans (2.5 × 10(5) CFU/mouse) that is uniformly lethal to wild-type mice within 10 days. Restriction of fungal growth within the kidney occurs by 24 h postinfection in the mutant mice. This occurs without induction of a hyperinflammatory response, as evidenced by the decreased presence of leukocytes and inflammatory cytokines that normally accompany the antifungal immune response. Instead, the absence of the Sts phosphatases leads to the rapid induction of a unique immunological environment within the kidney, as indicated by the early induction of a proinflammatory cytokine (CXL10). Mice lacking either Sts enzyme individually display an intermediate lethality phenotype. These observations identify an opportunity to optimize host immune responses toward a deadly fungal pathogen.

Early expression of local cytokines during systemic Candida albicans infection in a murine intravenous challenge model.

Local cytokine production is a significant indicator for disease pathogenesis or progression. Previous studies on cytokine production during systemic Candida albicans (C. albicans) infection were solely on kidney or single cell type interaction with C. albicans. Therefore, the present study aimed to assess the early cytokine expression of various target organs (kidney, spleen and brain) over a 72-h time course during systemic C. albicans infection. The local cytokine profiles of the target organs during systemic C. albicans infection were measured by cytometric bead array and ELISA analysis. The results demonstrated that interleukin-6 (IL-6) and IL-2 were statistically significant (P<0.05) in the spleen at 24 and 72 h post-infection, whereas in the kidney, IL-6 and tumor necrosis factor-α (TNF-α) were statistically significant (P<0.05) at 24 and 72 h post-infection and CXCL-1 and transforming growth factor-β (TGF-β) were statistically significant (P<0.05) at 72 h post-infection. In the brain, IL-6 and TNF-α were statistically significant (P<0.05) at 24 and 72 h post-infection, whereas TGF-β was statistically significant (P<0.05) at 72 h post-infection. These findings demonstrate that host immune responses were varied among target organs during systemic C. albicans infection. This could be important for designing targeted immunotherapy against this pathogen through immunomodulatory approaches in future exploratory research.

Multi-step pathogenesis and induction of local immune response by systemic Candida albicans infection in an intravenous challenge mouse model.

Different murine species differ in their susceptibility to systemic infection with Candida albicans, giving rise to varied host immune responses, and this is compounded by variations in virulence of the different yeast strains used. Hence, this study was aimed at elucidating the pathogenesis of a clinical C. albicans isolate (HVS6360) in a murine intravenous challenge model by examining the different parameters which included the counts of red blood cells and associated components as well as the organ-specific expression profiles of cytokines and chemokines. Kidneys and brains of infected mice have higher fungal recovery rates as compared to other organs and there were extensive yeast infiltration with moderate to severe inflammation seen in kidney and brain tissues. Red blood cells (RBCs) and haemoglobin (Hb) counts were reduced throughout the infection period. Pattern recognition receptors (PRRs), chemokines and cytokine transcription profiles were varied among the different organs (kidney, spleen and brain) over 72 h post infections. Transcription of most of the PRRs, cytokines and chemokines were suppressed at 72 h post infection in spleen while continuous expression of PRRs, cytokines and chemokines genes were seen in brain and kidney. Reduction in red blood cells and haemoglobin counts might be associated with the action of extracellular haemolysin enzyme and haeme oxygenase of C. albicans in conjunction with iron scavenging for the fungal growth. Renal cells responsible for erythropoietin production may be injured by the infection and hence the combined effect of haemolysis plus lack of erythropoietin-induced RBC replenishment leads to aggravated reduction in RBC numbers. The varied local host immune profiles among target organs during systemic C. albicans infection could be of importance for future work in designing targeted immunotherapy through immunomodulatory approaches.

Effect of Delta-9-tetrahydrocannabinol on mouse resistance to systemic Candida albicans infection.

Delta-9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, is known to suppress the immune responses to bacterial, viral and protozoan infections, but its effects on fungal infections have not been studied. Therefore, we investigated the effects of chronic Δ9-THC treatment on mouse resistance to systemic Candida albicans (C. albicans) infection. To determine the outcome of chronic Δ9-THC treatment on primary, acute systemic candidiasis, c57BL/6 mice were given vehicle or Δ9-THC (16 mg/kg) in vehicle on days 1–4, 8–11 and 15–18. On day 19, mice were infected with 5×105 C. albicans. We also determined the effect of chronic Δ9-THC (4–64 mg/kg) treatment on mice infected with a non-lethal dose of 7.5×104 C. albicans on day 2, followed by a higher challenge with 5×105 C. albicans on day 19. Mouse resistance to the infection was assessed by survival and tissue fungal load. Serum cytokine levels were determine to evaluate the immune responses. In the acute infection, chronic Δ9-THC treatment had no effect on mouse survival or tissue fungal load when compared to vehicle treated mice. However, Δ9-THC significantly suppressed IL-12p70 and IL-12p40 as well as marginally suppressed IL-17 versus vehicle treated mice. In comparison, when mice were given a secondary yeast infection, Δ9-THC significantly decreased survival, increased tissue fungal burden and suppressed serum IFN-γ and IL-12p40 levels compared to vehicle treated mice. The data showed that chronic Δ9-THC treatment decreased the efficacy of the memory immune response to candida infection, which correlated with a decrease in IFN-γ that was only observed after the secondary candida challenge.

Syk signaling in dendritic cells orchestrates innate resistance to systemic fungal infection.

Host protection from fungal infection is thought to ensue in part from the activity of Syk-coupled C-type lectin receptors and MyD88-coupled toll-like receptors in myeloid cells, including neutrophils, macrophages and dendritic cells (DCs). Given the multitude of cell types and receptors involved, elimination of a single pathway for fungal recognition in a cell type such as DCs, primarily known for their ability to prime T cell responses, would be expected to have little effect on innate resistance to fungal infection. Here we report that this is surprisingly not the case and that selective loss of Syk but not MyD88 in DCs abrogates innate resistance to acute systemic Candida albicans infection in mice. We show that Syk expression by DCs is necessary for IL-23p19 production in response to C. albicans, which is essential to transiently induce GM-CSF secretion by NK cells that are recruited to the site of fungal replication. NK cell-derived-GM-CSF in turn sustains the anti-microbial activity of neutrophils, the main fungicidal effectors. Thus, the activity of a single kinase in a single myeloid cell type orchestrates a complex series of molecular and cellular events that underlies innate resistance to fungal sepsis.

Pathogenesis and involvement of Interleukin-11 in response to Candida albicans in a murine intravenous challenge model

IntroductionSystemic candidiasis remains a significant cause of morbidity and mortality even in patients treated with antifungal agents, with Candida albicans remains the most causative agent. Differences in the virulence of Candida albicans strains used and mice species differ in their susceptibility to systemic infection. Hence, in this study, we characterized the pathogenesis of a clinical Candida albicans isolate from Malaysia in an immunocompetent balb/c mice model. ObjectiveTo evaluate the pathogenesis and involvement of interleukin-11 in response to Candida albicans in a murine intravenous challenge model. MethodsMice were challenged intravenously with Candida albicans via lateral tail vein and parameters such as mortality study, quantitative yeast culture, histopathology, were adopted to evaluate the pathogenesis of systemic Candida albicans infection. Besides that, transcript levels from kidney and brain on day 3 post infection were quantified via real time RT-PCR. Results & DiscussionMice infected systemically with Candida albicans resulted in high mortality. Kidney and brain have higher fungal recovery rates as compared to other organs and extensive yeast infiltration with moderate to severe inflammation were seen in kidney and brain tissues. Interleukin-11 was up-regulated in the brain and kidney. Involvement of interleukin-11 might reduce the host resistance against systemic Candida albicans infection as it involves in modulating and antagonizing the proinflammatory immune responses and maintenance of Th2 response which is detrimental during systemic candidiasis. ConclusionThis study demonstrated the pathological evidence of systemic infection caused by Candida albicans and involvement of IL-11 which could be of clinical relevance during systemic Candida albicans infection.