Albicans In Mice Research Articles

Hypoxia protects the gut.

Antibiotic-induced loss of intestinal hypoxia boosts the growth of C. albicans in mice.

Transdermal administration of farnesol-ethosomes enhances the treatment of cutaneous candidiasis induced by Candida albicans in mice.

Cutaneous candidiasis attributed to Candida infection is a prevalent condition that impacts individuals of all age groups. As a type of microbial community, biofilms confer benefits to host infections and mitigate the clinical effects of antifungal treatments. In C. albicans, the yeast-to-hypha transition and biofilm formation are effectively suppressed by farnesol through its modulation of multiple signaling pathway. However, the characteristics of farnesol such as hydrophobicity, volatility, degradability, and instability in various conditions can impose limitations on its effectiveness. Nanotechnology holds the potential to enhance the efficiency and utilization of this molecule. Treatment of farnesol-ethosomes by transdermal administration demonstrated a very remarkable therapeutic effect against C. albicans in infection model of cutaneous candidiasis in mice. Many patients suffering fungal skin infection will benefit from this study.

Lactobacillus murinus: A key factor in suppression of enterogenous Candida albicans infections in Compound Agrimony enteritis capsules-treated mice.

Compound Agrimony (FuFangXianHeCao, FFXHC) Enteritis Capsules is an ethnomedicine that is derived from Yi Nationality Herbal Medicine for enteritis treatment. We found that FFXHC reduced the mortality outcomes in enterogenic Candida albicans infected mice models and increased the abundance of Lactobacillus murinus in the intestines. Lactobacillus murinus exhibited comparable therapeutic effects to those of FFXHC in enterogenic Candida albicans infected mice. This study provides novel perspectives into the pharmacological mechanisms of FFXHC. We investigated the mechanisms via which FFXHC inhibits C. albicans infections and its effects on L. murinus. Enterogenous C. albicans infection mice models were established and various parameters, including survival rate, weight change, number of colonies, treatment effects on intestinal mucosa, microecology, and immune cytokines evaluated. Susceptibility of C. albicans to L. murinus was evaluated in vitro. Treatment with FFXHC reduced the number of colonies, improved the health status, enhanced the survival rates, increased the abundance of L. murinus, reduced damage to the intestinal mucosa, and elevated occludin as well as claudin-1 levels. Interestingly, TNF-α, IFN-γ, IL-10, IL-22, and IL-17A levels were increased while IL-1β levels were suppressed in the intestinal mucosa without any change in peripheral blood cytokine levels. Moreover, FFXHC promoted L. murinus proliferation. This study also confirmed the incubation-dependent anti-C. albicans effects exerted by the metabolic supernatants of L. murinus. FFXHC effectively alleviated intestinal infections of C. albicans in mice and increased the abundance of L. murinus. Supplementation of L. murinus in food can achieve the effects that are comparable to those of FFXHC. Thus, L. murinus maybe essential in FFXHC-based treatment of intestinal C. albicans infections.

Antifungal potency of clove (Syzygium aromaticum) essential oil extract against induced systemic infection by Candida albicans in mice

Fungal infection is a serious health problem, involved with the life threatening mycosis and mortality. Emerging of resistance and limited antifungal drugs against most antifungal agents lead to the requirement for development of effective and alternate strategies to fight fungal infections. The aim of this study is to investigate the antifungal activity of clove oil extract against systemic induced infection In vivo by Candida albicans in mice. Fifty mice were used to induce systemic infection by injecting 1 ml of 1×106 C.albicans suspension intra-peritoneally for seven days consecutive, then sacrificed to observe the incidence of infection in internal organs (gross lesion) and measure the level of IL-6 and serum creatinine plus histopathological changes. The development of systemic infection with C. albicans (1 × 106 cells) was observed daily for 14 days which was accompanied with clinical signs of infection, including weight loss, depression, and ruffled appearance. IL-6 level showed no significant difference in all group before treatment and after inducing infection the level of IL-6 showed significant increase (P≤0.01) in control positive group while group treated with clove oil 5 mg/kg and 10 mg/kg showed significant decrease in the level compared with infected group and fluconazole treated group . Serum creatinine concentration was within the normal values in all groups (p>0.01) before the infection. There were an increase significantly (P≤0.01) in the level in all infected mice after 7 days of infection. The serum creatinine values of treated group with clove oil extract 5 mg/kg and 10 mg/kg showed decreased in the creatinine concentration . The present results demonstrated that the essential oil of clove extract rich with eugenol has great antifungal power. This extract can be suggested as antimicrobial and antifungal to treat candidemia and reduce the incidence of mortality rate due to systemic candidiasis.

Antifungal Activity of Clove (Syzygium aromaticum) Essential Oil Extract against Induced Topical Skin Infection by Candida albicans in Mice in vivo

Antifungal Activity of Clove (Syzygium aromaticum) Essential Oil Extract against Induced Topical Skin Infection by Candida albicans in Mice in vivo

Mannan-Binding Lectin Regulates the Th17/Treg Axis Through JAK/STAT and TGF-β/SMAD Signaling Against Candida albicans Infection.

BackgroundMannan-binding lectin (MBL) is a key molecule in innate immunity and activates the lectin complement pathway, which plays an important role in resisting Candida albicans (C. albicans) infection. However, the underlying mechanism of this resistance to infection remains unclear.MethodsIn this study, we investigated how MBL regulates the differentiation of CD4+ T cells into T helper type 17 (Th17) and T regulatory (Treg) cells against C. albicans in mice, as well as the underlying mechanisms. We generated MBL double-knockout (KO) mice and infected them with C. albicans by intraperitoneal injection.ResultsCompared with that in wild-type (WT) mice, the percentage of Th17 cells increased in MBL-null mice, whereas Treg cells decreased, indicating that MBL might regulate the Th17/Treg balance. In addition, in MBL-null mice, the expression levels of interleukin (IL)-17A, IL-21, and the master transcription factor of Th17 cells, RORγt, significantly increased. Conversely, IL-10, IL-2, and the Treg-specific transcription factor, Foxp3, decreased. Moreover, we found that the levels of TGF-β and IL-6 upregulated in MBL-null mice. Mechanistically, we found that MBL regulated the TGF-β/SMAD pathway through the inhibition of p-SMAD2 and promotion of p-SMAD3, and mediated the JAK/STAT pathway through the inhibition of p-JAK2 and p-STAT3 and promotion of p-JAK3 and p-STAT5. MBL double-KO mice showed a more severe inflammatory response and significantly lower survival rates with C. albicans infection.ConclusionThese results suggest that MBL regulates the Th17/Treg cell balance to inhibit inflammatory responses, possibly via IL-6- and TGF-β-mediated JAK/STAT and TGF-β/SMAD signaling, and play an important role in anti-C. albicans infection.

Candida albicans triggers qualitative and temporal responses in gut bacteria

Interactions between commensal intestinal bacteria and fungi are collectively beneficial in maintaining the balance of the gut microflora and preventing gastrointestinal diseases. However, the contributions of specific bacterial species in response to fungal dysbiosis in the gut remain poorly defined. Here, to understand the dynamic changes, we established acute a challenge with Candida albicans in mice treated without antibiotics and analyzed the changes in the diversity of bacteria during the imbalance in intestinal C. albicans with high-throughput amplicon sequencing. Our results showed significant increases in species diversity after the first day of fungal challenge and the restoration of balance among the gut microflora on the third day of challenge. To explore the interactions between the intestinal bacteria and C. albicans, the antifungal activities of bacteria isolated from the mouse feces were also determined. Nineteen aerobic bacteria with antifungal activity were identified with whole 16S rRNA gene sequencing. These bacteria were isolated on the first day of challenge more than on the third day. These results suggested that the commensal intestinal bacteria may protect the host against fungal dysbiosis in the gut by altering their own species diversity. The interaction between bacteria and fungi in the gut may be the key to maintaining the dynamic balance of microorganisms in the context of environmental changes.

Restoring glucose uptake rescues neutrophil dysfunction and protects against systemic fungal infection in mouse models of kidney disease.

Disseminated candidiasis caused by the fungus Candida albicans is a major clinical problem in individuals with kidney disease and accompanying uremia; disseminated candidiasis fatality is twice as common in patients with uremia as those with normal kidney function. Many antifungal drugs are nephrotoxic, making treatment of these patients particularly challenging. The underlying basis for this impaired capacity to control infections in uremic individuals is poorly understood. Here, we show in multiple models that uremic mice exhibit an increased susceptibility to systemic fungal infection. Uremia inhibits Glut1-mediated uptake of glucose in neutrophils by causing aberrant activation of GSK3β, resulting in reduced ROS generation and hence impaired killing of C. albicans in mice. Consequently, pharmacological inhibition of GSK3β restored glucose uptake and rescued ROS production and candidacidal function of neutrophils in uremic mice. Similarly, neutrophils isolated from patients with kidney disease and undergoing hemodialysis showed similar defect in the fungal killing activity, a phenotype rescued in the presence of a GSK3β inhibitor. These findings reveal a mechanism of neutrophil dysfunction during uremia and suggest a potentially translatable therapeutic avenue for treatment of disseminated candidiasis.

Evaluation of Susceptibility and Innate Immune Response to Candida albicans in Mice with Sub-health

Evaluation of Susceptibility and Innate Immune Response to Candida albicans in Mice with Sub-health

Gastrointestinal colonisation and systemic spread of Candida albicans in mice treated with antibiotics and prednisolone

Normally, Candida albicans is a commensal microbe that resides in the human oral cavity, gut and vagina. However, the fungus can cause mucosal and systemic infections in immunocompromised individuals. The mechanism by which local mucosal infections progress to systemic candidiasis is poorly understood. Here, a murine model of gastrointestinal (GI) candidiasis was developed by inoculation of the oral cavity, followed by treatment with tetracycline (TC) and prednisolone (PSL). Temporal progression from a local infection of the oral cavity to a systemic infection was then monitored. Histological analysis of tissues from mice treated with both TC and PSL revealed massive infiltration of the tongue and stomach by hyphae. PSL increased the fungal burden in the tongue, stomach and small intestine, and facilitated dissemination to the spleen, kidney and liver within 3 days post-infection. Treatment with both TC and PSL supressed interferon (IFN)-γ and interleukin (IL)-17 (cytokines that play key roles in host defence against fungal infection) levels in the tongue, which were induced by C. albicans infection. In addition, the mucosal layer of the small intestine of mice treated with both TC and PSL was almost destroyed by the fungal infection; this may be a critical event that allows passage of the fungus across the mucosa and into the systemic circulation. Thus, this mouse model is useful for studying mechanisms underlying progression of C. albicans from a local infection of the oral cavity to a systemic infection in immunocompromised individuals.

Red-Shifted Firefly Luciferase Optimized for Candida albicans In vivo Bioluminescence Imaging.

Candida albicans is a major fungal pathogen causing life-threatening diseases in immuno-compromised patients. The efficacy of current drugs to combat C. albicans infections is limited, as these infections have a 40–60% mortality rate. There is a real need for novel therapeutic approaches, but such advances require a detailed knowledge of C. albicans and its in vivo pathogenesis. Additionally, any novel antifungal drugs against C. albicans infections will need to be tested for their in vivo efficacy over time. Fungal pathogenesis and drug-mediated resolution studies can both be evaluated using non-invasive in vivo imaging technologies. In the work presented here, we used a codon-optimized firefly luciferase reporter system for detecting C. albicans in mice. We adapted the firefly luciferase in order to improve its maximum emission intensity in the red light range (600–700 nm) as well as to improve its thermostability in mice. All non-invasive in vivo imaging of experimental animals was performed with a multimodal imaging system able to detect luminescent reporters and capture both reflectance and X-ray images. The modified firefly luciferase expressed in C. albicans (Mut2) was found to significantly increase the sensitivity of bioluminescence imaging (BLI) in systemic infections as compared to unmodified luciferase (Mut0). The same modified bioluminescence reporter system was used in an oropharyngeal candidiasis model. In both animal models, fungal loads could be correlated to the intensity of emitted light. Antifungal treatment efficacies were also evaluated on the basis of BLI signal intensity. In conclusion, BLI with a red-shifted firefly luciferase was found to be a powerful tool for testing the fate of C. albicans in various mice infection models.

Secretory Aspartyl Proteinases Cause Vaginitis and Can Mediate Vaginitis Caused by Candida albicans in Mice.

ABSTRACTVaginal inflammation (vaginitis) is the most common disease caused by the human-pathogenic fungus Candida albicans. Secretory aspartyl proteinases (Sap) are major virulence traits of C. albicans that have been suggested to play a role in vaginitis. To dissect the mechanisms by which Sap play this role, Sap2, a dominantly expressed member of the Sap family and a putative constituent of an anti-Candida vaccine, was used. Injection of full-length Sap2 into the mouse vagina caused local neutrophil influx and accumulation of the inflammasome-dependent interleukin-1β (IL-1β) but not of inflammasome-independent tumor necrosis factor alpha. Sap2 could be replaced by other Sap, while no inflammation was induced by the vaccine antigen, the N-terminal-truncated, enzymatically inactive tSap2. Anti-Sap2 antibodies, in particular Fab from a human combinatorial antibody library, inhibited or abolished the inflammatory response, provided the antibodies were able, like the Sap inhibitor Pepstatin A, to inhibit Sap enzyme activity. The same antibodies and Pepstatin A also inhibited neutrophil influx and cytokine production stimulated by C. albicans intravaginal injection, and a mutant strain lacking SAP1, SAP2, and SAP3 was unable to cause vaginal inflammation. Sap2 induced expression of activated caspase-1 in murine and human vaginal epithelial cells. Caspase-1 inhibition downregulated IL-1β and IL-18 production by vaginal epithelial cells, and blockade of the IL-1β receptor strongly reduced neutrophil influx. Overall, the data suggest that some Sap, particularly Sap2, are proinflammatory proteins in vivo and can mediate the inflammasome-dependent, acute inflammatory response of vaginal epithelial cells to C. albicans. These findings support the notion that vaccine-induced or passively administered anti-Sap antibodies could contribute to control vaginitis.

Therapeutic efficacy of chitosan against invasive candidiasis in mice

The prevalence of antibiotic resistance has resulted in the need for new approaches to be developed to combat the previously easily treatable infections. This work aims to evaluate the antifungal and antioxidant effects of the chitosan, as a new alternative or complementary anti-fungal drug, alone or in combination with amphotericin B against a pathogenic Candida albicans in mice. Eighty neutropenic infected mice were randomly assigned into four main groups (20 mice/group). The 1st group was treated with saline, neutropenic infected (NI group) (IPC group, invasive pulmonary candidiasis), the 2nd group was treated with chitosan (ED50) (CE group), the 3rd group was treated with amphotericin B (150mg/kg) (AMB group) and the 4th group was treated with chitosan plus amphotericin B (CE+AMB group). Treatment was started at 24h after fungal inoculation and was administered for 3 consecutive days. All the previous treatments demonstrated notable growth inhibition against a C. albicans isolate as indicated by measuring the mean diameter of the inhibition zone. Compared with IPC group, CE, AMB, and AMB+CE-treated animals had 73%, 87%, and 90% reduction in fungal burden, respectively. Furthermore, treatment with CE and/or AMB for 24 and 72h significantly decreased MDA, SOD, CAT and NO levels and increased GSH and in the lung tissues as compared with the infected untreated group. In conclusion, CE treatment, with the combination of antifungal therapy, can alleviate oxidative stress and lung injury associated with IPC in neutropenic mice.

Comparison between bioluminescence imaging technique and CFU count for the study of oropharyngeal candidiasis in mice.

We recently described a bioluminescence in vivo imaging technique, representing a powerful tool to test the real-time progression of oropharyngeal candidiasis, hence potentially useful to evaluate the efficacy of antifungal therapies. In this study, the in vivo imaging technique was compared with CFU measurement of target organs (tongue, esophagus and stomach) for monitoring and quantifying oropharyngeal candidiasis. We have correlated these two analytical methods at different times post-infection using engineered, luminescent Candida albicans in mice rendered susceptible to oral candidiasis by cortisone-acetate. Scatter plots, Pearson correlation and Student's t test were used to compare the methods. We observed that the bioluminescence in vivo imaging technique was more reliable than CFU counts in detecting early infection of, and its extent in, the oral cavity of the mouse. This was also evident following the introduction of a variable such as treatment with fluconazole. The results described in this study could validate the bioluminescence in vivo imaging technique as a method to monitor and quantify oropharyngeal candidiasis and to assess early discovery of active compounds in vivo.

IL-17 and infections

IL-17 immunity has been shown to be essential for mucocutaneous protection against Candida albicans in mice and humans. However, mice with defective IL-17 immunity display broader susceptibility, as they are also prone to infections with diverse infectious agents at various sites. Humans with genetic defects affecting their IL-17 immunity usually suffer from chronic mucocutaneous candidiasis (CMC): recurrent or persistent infections of the skin, nails, and mucosae with C. albicans, with or without other clinical signs. Most patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) due to STAT3 deficiency or AD STAT1 gain-of-function display impaired IL-17-producing T-cell development, and CMC is one of their principal clinical manifestations. Similarly, patients with autosomal recessive (AR) autoimmune polyendocrine syndrome type 1 (APS-1) caused by AIRE deficiency have high levels of neutralizing autoantibodies against IL-17A, IL-17F and/or IL-22 and present CMC as their only infectious disease. Finally, CMC is the main clinical phenotype observed in patients with inborn errors specifically affecting IL-17 immunity. Indeed, patients with AD IL-17F deficiency or AR IL-17RA or ACT1 deficiency display CMC and, to a lesser extent, superficial staphylococcal diseases. Candida infection was recently reported in psoriasis patients treated with anti-IL-17A antibodies. Careful monitoring for CMC is thus important during anti-IL-17 treatment.

Synthesis of Laminarin Fragments and Evaluation of a β-(1,3) Glucan Hexasaccaride-CRM197 Conjugate as Vaccine Candidate against Candida albicans

Laminarin-CRM197 glycoconjugates were previously demonstrated to be immunogenic and confer protection against Candida albicans in mice. Laminarin consists of β-(1,3) glucan repeating units, with sporadic β-(1,6) branches. A set of short glucans was used to study the effect of the β-(1,6) branch on the antigenicity of linear β-(1,3) glucans. A linear β-(1,3) glucan hexasaccharide was selected as the best fragment able to inhibit the binding between laminarin and antilaminarin antibodies. The hexamer was then conjugated to CRM197 and induced, in mice, significant titers of specific antilaminarin antibodies comparable with those raised by the Lam-CRM197 conjugate.

Genetic control of susceptibility to infection with Candida albicans in mice.

Candida albicans is an opportunistic pathogen that causes acute disseminated infections in immunocompromised hosts, representing an important cause of morbidity and mortality in these patients. To study the genetic control of susceptibility to disseminated C. albicans in mice, we phenotyped a group of 23 phylogenetically distant inbred strains for susceptibility to infection as measured by extent of fungal replication in the kidney 48 hours following infection. Susceptibility was strongly associated with the loss-of-function mutant complement component 5 (C5/Hc) allele, which is known to be inherited by approximately 40% of inbred strains. Our survey identified 2 discordant strains, AKR/J (C5-deficient, resistant) and SM/J (C5-sufficient, susceptible), suggesting that additional genetic effects may control response to systemic candidiasis in these strains. Haplotype association mapping in the 23 strains using high density SNP maps revealed several putative loci regulating the extent of C. albicans replication, amongst which the most significant were C5 (P value = 2.43×10−11) and a novel effect on distal chromosome 11 (P value = 7.63×10−9). Compared to other C5-deficient strains, infected AKR/J strain displays a reduced fungal burden in the brain, heart and kidney, and increased survival, concomitant with uniquely high levels of serum IFNγ. C5-independent genetic effects were further investigated by linkage analysis in an [A/JxAKR/J]F2 cross (n = 158) where the mutant Hc allele is fixed. These studies identified a chromosome 11 locus (Carg4, Candida albicans resistance gene 4; LOD = 4.59), and a chromosome 8 locus (Carg3; LOD = 3.95), both initially detected by haplotype association mapping. Alleles at both loci were inherited in a co-dominant manner. Our results verify the important effect of C5-deficiency in inbred mouse strains, and further identify two novel loci, Carg3 and Carg4, which regulate resistance to C. albicans infection in a C5-independent manner.

Gut colonization byCandida albicansaggravates inflammation in the gut and extra-gut tissues in mice

We examined whether Candida albicans gut colonization aggravates immune diseases in mice. Chronic and latent C. albicans gut colonization was established by the intragastric inoculation of C. albicans in mice fed as part of a purified diet. Allergic diarrhea was induced by repetitive intragastric administration of ovalbumin in sensitized BALB/c mice. Contact hypersensitivity was evaluated by measuring ear swelling after topical application of 2, 4-dinitrofluorobenzene in NC/Nga mice. Arthritis was induced by intradermal injection of bovine type-II collagen emulsified with complete Freund's adjuvant in DBA/1J mice. C. albicans gut colonization increased the incidence of allergic diarrhea, which was accompanied by gut hyperpermeability, as well as increased infiltration of inflammatory cells in the colon. Contact hypersensitivity was also exacerbated by C. albicans gut colonization, as demonstrated by increased swelling, myeloperoxidase activity, and proinflammatory cytokines in ear auricles. Furthermore, C. albicans gut colonization promoted limb joint inflammation in collagen-induced arthritis, in an animal model of rheumatoid arthritis. These findings suggest that C. albicans gut colonization in mice aggravates inflammation in allergic and autoimmune diseases, not only in the gut but also in the extra-gut tissues and underscores the necessity of investigating the pathogenic role of C. albicans gut colonization in immune diseases in humans.

Einfluß von Pinocembrin auf den Verlauf der experimentellen Candida-lnfektion der Maus

Pinocembrin (5,7-dihydroxy-flavanon)--a component of the bee product propolis--was tested for its in vivo activity against Candida albicans in mice. It was shown that the intravenous infection of AB-Jena mice with 2.5 X 10(5) Candida albicans cells was a very suitable model. Despite of treatment with pinocembrin at daily doses of 100 mg/kg body weight the animals as well as the controls died between the 6th and 24th day after beginning. On the other hand the animals treated with 5 mg/kg amphotericin B survived the test-period of 30 days. The question of effectiveness of pinocembrin in vivo should be cleared up in further pharmacokinetic investigations.

P1950 In vivo efficacy of the triazole BAL8557 against disseminated Candida albicans in mice assessed by survival and tissue bur-den in temporarily and persistently neutropenic mice treated with 1 -7 doses of drug over a dose range of 20 -80%of Emax

P1950 In vivo efficacy of the triazole BAL8557 against disseminated Candida albicans in mice assessed by survival and tissue bur-den in temporarily and persistently neutropenic mice treated with 1 -7 doses of drug over a dose range of 20 -80%of Emax