Clonal Strain Persistence of Candida albicans Isolates from Chronic Mucocutaneous Candidiasis Patients

Funding: The study was supported by the MRC for a PhD studentship for AM and the Wellcome Trust for funding (086827, 075470, 097377 & 101873). Acknowledgments We thank Professor Frank Odds for MLST central database curation and useful discussions.Peer reviewedPublisher PD

STAT1 Hyperphosphorylation and Defective IL12R/IL23R Signaling Underlie Defective Immunity in Autosomal Dominant Chronic Mucocutaneous Candidiasis

We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency

MLST DSTs for 42 <i>C</i>. <i>albicans</i> isolates from 6 CMC patients and their antifungal susceptibilities.

<p>MLST DSTs for 42 <i>C</i>. <i>albicans</i> isolates from 6 CMC patients and their antifungal susceptibilities.</p

Patient clinical data.

<p>Flucon = fluconazole, itracon = itraconazole, amph sus = amphotericin suspension (10 mg/ml swirl and swallow 4x daily). All swabs were taken for routine Dg purposes. Ethical approval was obtained under the Newcastle Autoimmune Inflammatory Rheumatic Disease Research Biobank (NAIRB) Ref No NAIRB-DL-01 dx obtained from the Southwest 3 Research Ethics Committee (Ref. 10/H0106/30) to perform research on samples collected as part of the NAIRB by researchers based at Newcastle University. Pts 1–5 had primary CMC; whole exome sequencing confirmed gain-of-function STAT1 mutations in 3 while no mutation was identified in 2 patients; P4 had candida granuloma of soft palate. P6 had 2oCMC due to steroid inhalers (asthma). Swabs were processed in the Department of Microbiology, Newcastle upon Tyne Hospitals NHS Trust (NUTH): Mohammad Raza, Consultant Microbiologist (<a href="mailto:[email protected]" target="_blank">[email protected]</a>) and Claire Rennison, Senior BMS (now retired).</p

Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy

Background Accumulating evidence implicates TH17 cytokines in protection against Candida species infections, but the clinical relevance is not clear. Chronic mucocutaneous candidiasis (CMC) is a heterogeneous syndrome with the unifying feature of selective susceptibility to chronic candidiasis. Different subgroups with distinct clinical features are recognized, including autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), CMC with hypothyroidism, and isolated CMC. Understanding immune defects in patients with CMC will define cellular and molecular mechanisms crucial for protection against Candida species in human subjects. Objectives We sought to determine whether impaired TH17 responses underlie susceptibility to Candida species infections and whether the same defect is present in different CMC subgroups. Methods We assessed TH17 responses of PBMCs to Candida and non-Candida species stimuli by measuring IL-17, IL-22, IL-21, IL-6, IL-23, and IFN-γ cytokine production using cytokine arrays and intracellular cytokine-producing cell numbers and proliferation with flow cytometry. PBMCs from healthy subjects and unaffected family members served as controls. Results In patients with CMC with hypothyroidism, TH17 cells demonstrated decreased proliferation and IL-17 production in response to Candida species. In contrast, in patients with APECED, TH17 cell proliferation and IL-17 production were normal unless exposed to APECED plasma, which inhibited both functions in both APECED and normal PBMCs. Candida species–stimulated IL-22 production was impaired in all patients with CMC, whereas IL-6 and IL-23 responses were unaltered. Conclusion An impaired TH17 response to Candida species, although mediated by different mechanisms, was present in all CMC subgroups studied and might be a common factor predisposing to chronic candidiasis