The impact of caspase-12 on susceptibility to candidemia

Candida is one of the leading causes of sepsis, and an effective host immune response to Candida critically depends on the cytokines IL-1β and IL-18, which need caspase-1 cleavage to become bioactive. Caspase-12 has been suggested to inhibit caspase-1 activation and has been implicated as a susceptibility factor for bacterial sepsis. In populations of African descent, CASPASE-12 is either functional or non-functional. Here, we have assessed the frequencies of both CASPASE-12 alleles in an African-American Candida sepsis patients cohort compared to uninfected patients with similar predisposing factors. African-American Candida sepsis patients (n = 93) and non-infected African-American patients (n = 88) were genotyped for the CASPASE-12 genotype. Serum cytokine concentrations of IL-6, IL-8, and IFNγ were measured in the serum of infected patients. Statistical comparisons were performed in order to assess the effect of the CASPASE-12 genotype on susceptibility to candidemia and on serum cytokine concentrations. Our findings demonstrate that CASPASE-12 does not influence the susceptibility to Candida sepsis, nor has any effect on the serum cytokine concentrations in Candida sepsis patients during the course of infection. Although the functional CASPASE-12 allele has been suggested to increase susceptibility to bacterial sepsis, this could not be confirmed in our larger cohort of fungal sepsis patients

Host genetic signatures of susceptibility to fungal disease

Our relative inability to predict the development of fungal disease and its clinical outcome raises fundamental questions about its actual pathogenesis. Several clinical risk factors are described to predispose to fungal disease, particularly in immunocompromised and severely ill patients. However, these alone do not entirely explain why, under comparable clinical conditions, only some patients develop infection. Recent clinical and epidemiological studies have reported an expanding number of monogenic defects and common polymorphisms associated with fungal disease. By directly implicating genetic variation in the functional regulation of immune mediators and interacting pathways, these studies have provided critical insights into the human immunobiology of fungal disease. Most of the common genetic defects reported were described or suggested to impair fungal recognition by the innate immune system. Here, we review common genetic variation in pattern recognition receptors and its impact on the immune response against the two major fungal pathogens Candida albicans and Aspergillus fumigatus. In addition, we discuss potential strategies and opportunities for the clinical translation of genetic information in the field of medical mycology. These approaches are expected to transfigure current clinical practice by unleashing an unprecedented ability to personalize prophylaxis, therapy and monitoring for fungal disease.This work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), the Fundação para a Ciência e Tecnologia (FCT) (IF/00735/2014 to AC, and SFRH/BPD/96176/2013 to CC), the Institut Mérieux (Mérieux Research Grant 2017 to CC), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Research Grant 2017 to AC)

IRGM gene polymorphisms and risk of gastric cancer.

Item does not contain fulltextOBJECTIVE: The study aimed to assess the possible association of polymorphisms in the autophagy gene IRGM (rs13361189 and rs4958847) with the risk of gastric cancer. METHODS: A total of 102 patients with gastric adenocarcinoma, 52 with chronic gastritis and 351 healthy controls were included in this study. IRGM allelic variants were genotyped by quantitative real-time polymerase chain reaction. The association between polymorphisms and gastric cancer risk was estimated by odds ratios (OR) and 95% confidence interval (CI). RESULTS: A significant difference was found for rs4958847 A allele. Carriers of the A allele were protected against gastric cancer (OR = 0.58, 95% CI 0.35-0.97, P = 0.038). Moreover, the presence of this allele seems to play an important role in decreasing the risk for the intestinal type of gastric cancer (OR = 0.47, 95% CI 0.23-0.94, P = 0.03). In contrast, the rs13361189 IRGM polymorphism was not associated with susceptibility to gastric cancer. None of the targeted polymorphisms were associated with chronic gastritis. CONCLUSION: IRGM rs4958847 polymorphism influences susceptibility to gastric cancer, mainly for the intestinal type.1 juli 201

Role of autophagy genetic variants for the risk of Candida infections

Candida albicans can cause candidemia in neutropenic and critically ill patients, and oropharyngeal candidiasis in HIV-positive patients with low CD4(+) counts. However, not all patients at risk develop Candida infections, and the genetic background of the patient might play a role in the susceptibility to infection. Autophagy mediates pathogen clearance and modulation of inflammation. The aim of this study was to assess the effect of genetic variation in the ATG16L1 and IRGM autophagy genes on the susceptibility to candidemia and oropharyngeal candidiasis. We assessed whether genetic variation in the ATG16L1 and IRGM genes influences susceptibility to candidemia in a cohort of candidemia patients of both African and European origin. In addition, we assessed the effect of these polymorphisms for the susceptibility to oropharyngeal candidiasis in an HIV-positive cohort from Tanzania. Functional studies have been performed to assess the effect of the ATG16L1 and IRGM genetic variants on cytokine production both in vitro and in vivo. The results indicate that ATG16L1 variants modulate production of TNFα, but not other cytokines, while no effects were seen in the presence of IRGM polymorphisms. In addition, no significant associations between the SNPs in the ATG16L1 and IRGM genetic variants and the incidence of candidemia or oropharyngeal candidiasis were identified. In conclusion, despite moderate effects on the modulation of proinflammatory cytokine production, genetic variation in the autophagy genes ATG16L1 and IRGM has a minor impact on the susceptibility to both mucosal and systemic Candida infections

Genetic variation in the dectin-1/CARD9 recognition pathway and susceptibility to candidemia

Contains fulltext : 95924.pdf (publisher's version ) (Closed access)BACKGROUND: Candidemia is an important cause of morbidity and mortality in critically ill patients or patients undergoing invasive treatments. Dectin-1 is the main beta-glucan receptor, and patients with a complete deficiency of either dectin-1 or its adaptor molecule CARD9 display persistent mucosal infections with Candida albicans. The role of genetic variation of DECTIN-1 and CARD9 genes on the susceptibility to candidemia is unknown. METHODS: We assessed whether genetic variation in the genes encoding dectin-1 and CARD9 influence the susceptibility to candidemia and/or the clinical course of the infection in a large cohort of American and Dutch candidemia patients (n = 331) and noninfected matched controls (n = 351). Furthermore, functional studies have been performed to assess the effect of the DECTIN-1 and CARD9 genetic variants on cytokine production in vitro and in vivo in the infected patients. RESULTS: No significant association between the single-nucleotide polymorphisms DECTIN-1 Y238X and CARD9 S12N and the prevalence of candidemia was found, despite the association of the DECTIN-1 238X allele with impaired in vitro and in vivo cytokine production. CONCLUSIONS: Whereas the dectin-1/CARD9 signaling pathway is nonredundant in mucosal immunity to C. albicans, a partial deficiency of beta-glucan recognition has a minor impact on susceptibility to candidemia

Genetic basis for recurrent vulvo-vaginal candidiasis

Item does not contain fulltextVulvovaginal candidiasis (VVC) is a frequent disease affecting more than 75% of all women at least once in their lifetime. Up to 8% of them suffer from recurrent VVC (RVVC) characterized by at least three episodes each year. Several risk factors, such as antibiotic use, diabetes, or pregnancy, are known, but the vast majority of women with RVVC develop the infection without having any risk factor, implying that a genetic component most likely plays an important role in the susceptibility to RVVC. This review summarizes the immunogenetic alterations that lead to an increased susceptibility to vaginal infections with Candida albicans. Different mutations and polymorphisms in innate immune genes alter the mucosal immune response against fungi and are likely to have an important role in susceptibility to RVVC. A better understanding of the genetic and immunological mechanisms leading to RVVC is important for both the understanding of the pathophysiology of the disease and the design of novel therapeutic strategies