scholarly journals A loss-of-function mutation in IL-17F enhances susceptibility of mice to oropharyngeal candidiasis

2020 ◽  
Author(s):  
Chunsheng Zhou ◽  
Leticia Monin ◽  
Rachael Gordon ◽  
Felix E.Y. Aggor ◽  
Rami Bechara ◽  
...  
Keyword(s):  
Heterozygous Mutation ◽  
Chronic Mucocutaneous Candidiasis ◽  
Oropharyngeal Candidiasis ◽  
Loss Of Function ◽  
Mucocutaneous Candidiasis ◽  
Peptide Expression ◽  
The Individual ◽  
Antimicrobial Peptide Expression ◽  
Increased Susceptibility

AbstractOropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus C. albicans. IL-17 receptor signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this ‘experiment of nature’ by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9.The resulting Il17fS65L/S65L mice showed increased susceptibility to OPC, but only in homozygous, not heterozygous, mutant mice. The mutation was linked to impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi.

New and Inherited STAT1 Mutations in a Chinese Family with Chronic Mucocutaneous Candidiasis: A Case Report

2020 ◽  
Author(s):  
Xiaoheng XU ◽  
Wenxia MENG ◽  
Lu FENG ◽  
Wei GUO
Keyword(s):  
Human Gene ◽  
Genetic Diagnosis ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Chronic Mucocutaneous Candidiasis ◽  
Dna Binding Domain ◽  
Oral Medicine ◽  
Mucocutaneous Candidiasis ◽  
Mutation Database ◽  
First Time

A mild clinical Chronic Mucocutaneous Candidiasis (CMC) phenotype with STAT1 transcription factor mutation has been identified in a Chinese family. It is a rare variant in STAT1 (NM_0073315.3c.1175T>C Met392Thr). Specifically, it is a heterozygous mutation. To date, the pathogenicity of this variant in STAT1 (NM_0073315.3c.1175T>C Met392Thr) for CMC has not been reported in the Human Gene Mutation Database. Thus, this is the first report about STAT1 mutation found in CMC patients from Chinese ethnic group. This study also shows the mutation on the DNA-binding domain of STAT1 for the first time. The findings will broaden the spectrum of STAT1 mutations and facilitate genetic diagnosis by the oral medicine specialists.

scholarly journals Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

2011 ◽  
Vol 208 (8) ◽  
pp. 1635-1648 ◽  
Author(s):  
Luyan Liu ◽  
Satoshi Okada ◽  
Xiao-Fei Kong ◽  
Alexandra Y. Kreins ◽  
Sophie Cypowyj ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Coiled Coil ◽  
Cellular Responses ◽  
Chronic Mucocutaneous Candidiasis ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Mucocutaneous Candidiasis ◽  
Coiled Coil Domain ◽  
Whole Exome ◽  
Ifn Γ

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

scholarly journals Gene Silencing and Overexpression of Porcine Peptidoglycan Recognition Protein Long Isoforms: Involvement in β-Defensin-1 Expression

2005 ◽  
Vol 73 (11) ◽  
pp. 7133-7141 ◽  
Author(s):  
Yongming Sang ◽  
Balaji Ramanathan ◽  
Christopher R. Ross ◽  
Frank Blecha
Keyword(s):  
Antimicrobial Peptide ◽  
Intestinal Cells ◽  
Loss Of Function ◽  
Peptidoglycan Recognition Protein ◽  
Cdna Sequences ◽  
C Terminus ◽  
Peptide Expression ◽  
Recognition Protein ◽  
Activity Loss ◽  
Antimicrobial Peptide Expression

ABSTRACT Peptidoglycan recognition proteins (PGRPs) are a group of newly identified proteins with emerging functions in mammalian innate immunity. Here we report the identification and characterization of two long isoforms of porcine PGRP. Their complete cDNA sequences encode predicted peptides of 252 and 598 residues and are named pPGRP-L1 and pPGRP-L2, respectively. These porcine isoforms share identical PGRP domains at their C terminus, which are highly conserved with human and mouse orthologs. pPGRP-L1 is expressed constitutively in several tissues, including bone marrow, intestine, liver, spleen, kidney, and skin. pPGRP-L2 is highly expressed in the duodenum and liver, and expression in intestinal tissues is increased by Salmonella infection. In intestinal cells, expression of both pPGRP-L1 and pPGRP-L2 is increased by bacterial infection. Recombinant pPGRP-L1 and pPGRP-L2 have N-acetylmuramoyl-L-alanine amidase activity. Loss-of-function and gain-of-function experiments indicate that these two pPGRPs are involved in expression of the antimicrobial peptide β-defensin-1. Silencing of pPGRP-L2 in intestinal cells challenged with Listeria monocytogenes results in downregulation of β-defensin-1. Conversely, overexpression of pPGRP-L1 or pPGRP-L2 dramatically upregulates expression of β-defensin-1. Collectively, these findings suggest that porcine PGRPs are involved in antimicrobial peptide expression.

scholarly journals COVID-19 Disease and Vitamin D: A Mini-Review

2020 ◽  
Vol 11 ◽  
Author(s):  
Mohamed Said Boulkrane ◽  
Victoria Ilina ◽  
Roman Melchakov ◽  
Julia Fedotova ◽  
Filippo Drago ◽  
...  
Keyword(s):  
Vitamin D ◽  
Potential Role ◽  
Viral Infections ◽  
Prevention Strategies ◽  
Risk Of Death ◽  
Peptide Expression ◽  
Immune Health ◽  
Novel Coronavirus ◽  
Antimicrobial Peptide Expression

Novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2, for which there is no effective treatment except employing prevention strategies, has already instituted significant number of deaths. In this review, we provide a scientific view on the potential role of vitamin D in SARS-CoV-2 virus/COVID-19 disease. Vitamin D is well-known to play a significant role in maintaining the immune health of an individual. Moreover, it induces antimicrobial peptide expression that can decrease viral replication and regulate the levels of pro-inflammatory/anti-inflammatory cytokines. Therefore, supplementation of vitamin D has the potential to reduce the incidence, severity and the risk of death from pneumonia resulting from the cytokine storm of many viral infections including COVID-19. We suggest that supplementation of subjects at high risk of COVID-19 with vitamin D (1.000 to 3.000 IU) to maintain its optimum serum concentrations may be of significant benefit for both in the prevention and treatment of the COVID-19.

scholarly journals A fine-tuned interplay of three A. thaliana UDP glucosyltransferases orchestrates salicylic acid homeostasis

2020 ◽  
Author(s):  
Sibylle Bauer ◽  
Elisabeth Georgii ◽  
Birgit Lange ◽  
Rafał P. Maksym ◽  
Robert Janowski ◽  
...  
Keyword(s):  
Salicylic Acid ◽  
Stress Responses ◽  
Dominant Role ◽  
Defense Responses ◽  
Loss Of Function ◽  
Combinatorial Set ◽  
Resistance To Infection ◽  
Stress Related Genes ◽  
The Individual

AbstractSalicylic acid (SA) is a central signaling molecule in development and defense, therefore its levels are tightly controlled. One control mechanism is conjugation with sugar moieties by UDP glucosyltransferases (UGTs). In Arabidopsis, UGT76B1, UGT74F1, and UGT74F2 are known to glucosylate SA. We show that these are the main SA UGTs in leaves, since only marginal levels of SA glucosides were found in a triple loss-of-function mutant. Analyzing transcriptomes, metabolite levels, and phenotypes of a full combinatorial set of loss-of-function mutants, we resolved the mutual relationships and the individual roles of these enzymes in SA homeostasis. The strongest gene expression changes were observed for the ugt76b1 ugt74f1 double mutant, which downregulated developmental genes and most pronouncedly upregulated cell death-related genes. Among the single mutants, ugt76b1 specifically exhibited increased production of reactive oxygen species, increased resistance to infection, and early senescence. Likewise, higher-order mutations confirmed the dominant role of UGT76B1 in controlling SA levels and thereby the expression of biotic stress response genes. Both UGT74F1 and UGT74F2 affected UGT76B1 expression. However, while UGT76B1 and UGT74F1 produced SA-2-O-β-glucoside, UGT74F2 did not contribute there substantially. Instead, UGT74F2 acted independently of UGT74F1, decreasing steady-state SA levels by producing salicyloyl glucose ester. Remarkably, this did not restrict defense responses. In contrast, UGT74F1 interacted with UGT76B1 in suppressing defense responses. Nevertheless, a benzothiadiazole-triggered defense scenario induced only UGT76B1, whereas UGT74F1 was linked to controlling abiotic stress responses. All three enzymes form a network that, in concert with other UGTs, regulates expression of developmental and stress-related genes.One sentence summaryThe salicylic acid glucosylating enzymes of Arabidopsis leaves are crucial for salicylic acid homeostasis and combinatorially impact defense responses and developmental processes.

scholarly journals Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

2021 ◽  
Vol 9 ◽  
Author(s):  
Elise M. N. Ferré ◽  
Monica M. Schmitt ◽  
Michail S. Lionakis
Keyword(s):  
Clinical Manifestations ◽  
Chronic Mucocutaneous Candidiasis ◽  
Loss Of Function ◽  
Primary Adrenal Insufficiency ◽  
Autoimmune Polyglandular Syndrome ◽  
Mucocutaneous Candidiasis ◽  
Targeted Screening ◽  
Autoimmune Polyendocrinopathy ◽  
Autoimmune Polyglandular Syndrome Type

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.

scholarly journals The Role of Th17-Related Cytokines in Atopic Dermatitis

2020 ◽  
Vol 21 (4) ◽  
pp. 1314 ◽  
Author(s):  
Makoto Sugaya
Keyword(s):  
Atopic Dermatitis ◽  
Skin Lesions ◽  
Barrier Dysfunction ◽  
T Helper 17 ◽  
Bowel Diseases ◽  
Th17 Cytokines ◽  
Peptide Expression ◽  
Inflammatory Bowel ◽  
Antimicrobial Peptide Expression

T helper-17 (Th17) cells, which mainly produce IL-17, are associated with development of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, and psoriasis. IL-17 and related cytokines are therapeutic targets of these diseases. In atopic dermatitis (AD), Th2 cytokines such as IL-4 and IL-13 are regarded to be the main player of the disease; however, Th17 cytokines are also expressed in AD skin lesions. Expression of IL-22 rather than IL-17 is predominant in AD skin, which is contrary to cytokine expression in psoriasis skin. Relatively low IL-17 expression in AD skin can induce relatively low antimicrobial peptide expression, which may be a reason why bacterial infection is frequently seen in AD patients. Failure of clinical trials for investigating the efficacy of anti-IL-12/23 p40 in AD has suggested that IL-17 expressed in skin lesions should not be the main player but a bystander responding to barrier dysfunction.

scholarly journals Parkin is recruited selectively to impaired mitochondria and promotes their autophagy

2008 ◽  
Vol 183 (5) ◽  
pp. 795-803 ◽  
Author(s):  
Derek Narendra ◽  
Atsushi Tanaka ◽  
Der-Fen Suen ◽  
Richard J. Youle
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mammalian Cells ◽  
Loss Of Function ◽  
Gene Coding ◽  
Selective Elimination ◽  
Mitochondrial Toxins ◽  
Early Onset Parkinson’S Disease ◽  
Increased Susceptibility

Loss-of-function mutations in Park2, the gene coding for the ubiquitin ligase Parkin, are a significant cause of early onset Parkinson's disease. Although the role of Parkin in neuron maintenance is unknown, recent work has linked Parkin to the regulation of mitochondria. Its loss is associated with swollen mitochondria and muscle degeneration in Drosophila melanogaster, as well as mitochondrial dysfunction and increased susceptibility to mitochondrial toxins in other species. Here, we show that Parkin is selectively recruited to dysfunctional mitochondria with low membrane potential in mammalian cells. After recruitment, Parkin mediates the engulfment of mitochondria by autophagosomes and the selective elimination of impaired mitochondria. These results show that Parkin promotes autophagy of damaged mitochondria and implicate a failure to eliminate dysfunctional mitochondria in the pathogenesis of Parkinson's disease.

Abstract 21: Leptin-Induced Arterial Pressure Increase: Key Role of the PI3K Pathway

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Shannon M Harlan ◽  
Donald A Morgan ◽  
Kamal Rahmouni
Keyword(s):  
Arterial Pressure ◽  
Leptin Receptor ◽  
Intraperitoneal Administration ◽  
Pi3k Pathway ◽  
Heterozygous Mutation ◽  
Pi3k Signaling ◽  
Loss Of Function ◽  
Lipid Phosphatase ◽  
The Brain

Leptin is an adipocyte-derived hormone that acts in the brain to decrease food intake and increases energy expenditure. Leptin also raises arterial pressure by increasing sympathetic nerve activity (SNA). We previously implicated PI3K as a downstream pathway in leptin receptor (ObRb) signaling that mediates the renal SNA effects of leptin. We used genetic approaches to test the hypothesis that bidirectional changes in PI3K activity (gain vs. loss of function) will be associated with contrasting changes in renal SNA and arterial pressure responses to leptin. PI3K signaling was enhanced in leptin-sensitive neurons in Pten ΔObRb mice in which the lipid phosphatase Pten was ablated in cells that express ObRb, leading to accumulating PIP3 in these cells. For loss of function, we used p110α D933A/WT mice which carry a heterozygous mutation in the p110α subunit of PI3K specifically disrupting this pathway. Consistent with our previous findings, the increase in renal SNA caused by intracerebralventricular (ICV) injection of leptin (2 μg) was exaggerated and blunted in Pten ΔObRb mice (286±41%) and p110α D933A/WT mice (-40±6%), respectively, relative to littermate controls (70±4%). These effects were specific to leptin, as the renal SNA response to ICV MTII (melanocortin receptors agonist) was comparable (P=0.3) between controls (196±36%), Pten ΔObRb mice (159±98%) and p110α D933A/WT mice (194±36%). Interestingly, the Pten ΔObRb mice had significantly (P<0.01) higher baseline radiotelemetric mean arterial pressure (MAP, 137±4 mmHg) as compared to littermate controls (107±2 mmHg). In contrast, despite being hyperleptinemic the p110α D933A/WT mice had normal (P=0.34) baseline MAP (112±1 mmHg) as compared to controls (113±2 mmHg). We further measured the arterial pressure response to leptin treatment. Intraperitoneal administration of leptin (60 μg) raised MAP in control mice by 13±5 mmHg and this response was significantly (P<0.05) enhanced in the Pten ΔObRb mice (+35±14 mmHg). Conversely, the p110α D933A/WT mice had a significantly blunted (P<0.05) MAP response to leptin (-3±4 mmHg). Our data demonstrate the importance of PI3K signaling in leptin receptor-containing neurons for the regulation of arterial pressure and in mediating leptin effects.

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