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Patnaik S, Durairajan SSK, Singh AK, Krishnamoorthi S, Iyaswamy A, Mandavi SP, Jeewon R, Williams LL. Role of Candida species in pathogenesis, immune regulation, and prognostic tools for managing ulcerative colitis and Crohn's disease. World J Gastroenterol 2024; 30:5212-5220. [PMID: 39735273 PMCID: PMC11612695 DOI: 10.3748/wjg.v30.i48.5212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/25/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024] Open
Abstract
The gut microbiome plays a key role in the pathogenesis and disease activity of inflammatory bowel disease (IBD). While research has focused on the bacterial microbiome, recent studies have shifted towards host genetics and host-fungal interactions. The mycobiota is a vital component of the gastrointestinal microbial community and plays a significant role in immune regulation. Among fungi, Candida species, particularly Candida albicans (C. albicans), have been extensively studied due to their dual role as gut commensals and invasive pathogens. Recent findings indicate that various strains of C. albicans exhibit considerable differences in virulence factors, impacting IBD's pathophysiology. Intestinal fungal dysbiosis and antifungal mucosal immunity may be associated to IBD, especially Crohn's disease (CD). This article discusses intestinal fungal dysbiosis and antifungal immunity in healthy individuals and CD patients. It discusses factors influencing the mycobiome's role in IBD pathogenesis and highlights significant contributions from the scientific community aimed at enhancing understanding of the mycobiome and encouraging further research and targeted intervention studies on specific fungal populations. Our article also provided insights into a recent study by Wu et al in the World Journal of Gastroenterology regarding the role of the gut microbiota in the pathogenesis of CD.
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Affiliation(s)
- Supriti Patnaik
- Molecular Mycology and Neurodegenerative Disease Research Laboratory, Department of Microbiology, Central University of Tamil Nadu, Thiruvarur 610005, India
| | - Siva Sundara Kumar Durairajan
- Molecular Mycology and Neurodegenerative Disease Research Laboratory, Department of Microbiology, Central University of Tamil Nadu, Thiruvarur 610005, India
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Abhay Kumar Singh
- Molecular Mycology and Neurodegenerative Disease Research Laboratory, Department of Microbiology, Central University of Tamil Nadu, Thiruvarur 610005, India
| | - Senthilkumar Krishnamoorthi
- Mr. & Mrs Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Ashok Iyaswamy
- Mr. & Mrs Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641021, India
| | - Shiva Prasad Mandavi
- Department of Chemistry, Central University of Tamil Nadu, Tiruvarur 610005, India
| | - Rajesh Jeewon
- Department of Health Sciences, Faculty of Medicine and Health Sciences, University of Mauritius, Reduit 80837, Mauritius
- Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Leonard L Williams
- Center for Excellence in Post Harvest Technologies, North Carolina Agricultural and Technical State University, The North Carolina Research Campus, Kannapolis, NC 28081, United States
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Paccoud O, Warris A, Puel A, Lanternier F. Inborn errors of immunity and invasive fungal infections: presentation and management. Curr Opin Infect Dis 2024; 37:464-473. [PMID: 39259685 DOI: 10.1097/qco.0000000000001062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
PURPOSE OF REVIEW We review the clinical presentations of invasive fungal infections in a selection of inborn errors of immunity. In addition, we review the particularities of their management, including antifungal therapy, prophylaxis, and immunomodulatory treatments. RECENT FINDINGS Patients with chronic granulomatous disease and with signal transducer and activator of transcription 3 (STAT3) deficiency are particularly prone to aspergillosis. Mold-active antifungal prophylaxis should be prescribed to all patients with chronic granulomatous disease, and in patients with STAT3 deficiency and underlying parenchymal lung disease. Invasive fungal infections are rare in patients with STAT1 gain-of-function mutations, while the clinical phenotype of caspase-associated recruitment domain-containing protein 9 deficiency encompasses a wide range of superficial and invasive fungal infections. Most patients with inborn errors of immunity and invasive fungal infections require prolonged durations of antifungals. Hematopoietic stem cell transplantation should be considered early for patients with chronic granulomatous disease, but results have been more mixed for other inborn errors of immunity with active invasive fungal infections. SUMMARY Inborn errors of immunity can confer increased susceptibility to a variety of invasive fungal infections, which can present with specific clinical and radiological features. Management of fungal infections in these patients is often challenging, and relies on a combination of antimicrobial prophylaxis, antifungal treatments, and immunomodulation.
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Affiliation(s)
- Olivier Paccoud
- Université Paris Cité, Department of Infectious Diseases and Tropical Medicine, Necker - Enfants Malades University Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), IHU Imagine, Paris, France
| | - Adilia Warris
- MRC Centre for Medical Mycology, University of Exeter, Exeter, UK; Department of Paediatric Infectious Diseases, Great Ormond Street Hospital London, London, UK
| | - Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, UMR 1163, INSERM, Necker - Enfants Malades University Hospital, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
- Université Paris Cité, Imagine Institute, Paris
| | - Fanny Lanternier
- Université Paris Cité, Department of Infectious Diseases and Tropical Medicine, Necker - Enfants Malades University Hospital, Assistance Publique - Hôpitaux de Paris (AP-HP), IHU Imagine, Paris, France
- Institut Pasteur, Université Paris Cité, National Reference Center for Invasive Mycoses and Antifungals, Mycology Translational Research Group, Mycology Department, France
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Lo YF, Wang SY, Wu YH, Ho MW, Yeh CF, Wu TY, Peng JJ, Lin YN, Ding JY, Shih HP, Lo CC, Chan YP, Rau CS, Kuo CY, Tu KH, Lei WT, Chen YC, Ku CL. The Pathogenic Role of Anti-Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in the Nocardiosis with the Central Nervous System Involvement. J Clin Immunol 2024; 44:176. [PMID: 39133333 DOI: 10.1007/s10875-024-01775-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 07/26/2024] [Indexed: 08/13/2024]
Abstract
PURPOSE Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are implicated in the pathogenesis of Cryptococcus gattii (C. gattii) infection and pulmonary alveolar proteinosis (PAP). Their presence has also been noted in nocardiosis cases, particularly those with disseminated disease. This study delineates a case series characterizing clinical features and specificity of anti-GM-CSF Abs in nocardiosis patients. METHODS In this study, eight patients were recruited to determine the presence or absence of anti-GM-CSF Abs. In addition to the detailed description of the clinical course, we thoroughly investigated the autoantibodies regarding the characteristics, isotypes, subclasses, titers, and neutralizing capacities by utilizing the plasma samples from patients. RESULTS Of eight patients, five tested positive for anti-GM-CSF Abs, all with central nervous system (CNS) involvement; patients negative for these antibodies did not develop CNS nocardiosis. Distinct from previously documented cases, none of our patients with anti-GM-CSF Abs exhibited PAP symptoms. The titer and neutralizing activity of anti-GM-CSF Abs in our cohort did not significantly deviate from those found in C. gattii cryptococcosis and PAP patients. Uniquely, one individual (Patient 3) showed a minimal titer and neutralizing action of anti-GM-CSF Abs, with no relation to disease severity. Moreover, IgM autoantibodies were notably present in all CNS nocardiosis cases investigated. CONCLUSION The presence of anti-GM-CSF Abs suggests an intrinsic immunodeficiency predisposing individuals toward CNS nocardiosis. The presence of anti-GM-CSF Abs helps to elucidate vulnerability to CNS nocardiosis, even with low titer of autoantibodies. Consequently, systematic screening for anti-GM-CSF Abs should be considered a crucial diagnostic step for nocardiosis patients.
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Affiliation(s)
- Yu-Fang Lo
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
| | - Shang-Yu Wang
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yi-Hui Wu
- Division of Infectious Diseases, Department of Internal Medicine, PingTung Christian Hospital and Future clinic, PingTung, Taiwan
| | - Mao-Wang Ho
- Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chun-Fu Yeh
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
- Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Centre, Taoyuan, Taiwan
| | - Tsai-Yi Wu
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
| | - Jhan-Jie Peng
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
| | - You-Ning Lin
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
- Center for Molecular and Clinical and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Jing-Ya Ding
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
- Center for Molecular and Clinical and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Han-Po Shih
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
- Center for Molecular and Clinical and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Chi Lo
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
- Center for Molecular and Clinical and Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Pei Chan
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
| | - Cheng-Shyuan Rau
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chen-Yen Kuo
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
- Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Kun-Hua Tu
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
- Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei-Te Lei
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan
- Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Hsinchu Mackay Memorial Hospital, Hsinchu City, Taiwan
- Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Hsinchu Municipal Mackay Children's Hospital, Hsinchu City, Taiwan
| | - Yi-Chun Chen
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist, Kaohsiung City, 833401, Taiwan.
| | - Cheng-Lung Ku
- Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd., Guishan Dist, Taoyuan City, 33302, Taiwan.
- Center for Molecular and Clinical and Immunology, Chang Gung University, Taoyuan, Taiwan.
- Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
- Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
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Cinicola BL, Uva A, Duse M, Zicari AM, Buonsenso D. Mucocutaneous Candidiasis: Insights Into the Diagnosis and Treatment. Pediatr Infect Dis J 2024; 43:694-703. [PMID: 38502882 PMCID: PMC11191067 DOI: 10.1097/inf.0000000000004321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/08/2024] [Indexed: 03/21/2024]
Abstract
Recent progress in the methods of genetic diagnosis of inborn errors of immunity has contributed to a better understanding of the pathogenesis of chronic mucocutaneous candidiasis (CMC) and potential therapeutic options. This review describes the latest advances in the understanding of the pathophysiology, diagnostic strategies, and management of chronic mucocutaneous candidiasis.
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Affiliation(s)
- Bianca Laura Cinicola
- From the Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Andrea Uva
- Pediatrics and Neonatology Unit, Maternal-Child Department, Santa Maria Goretti Hospital, Sapienza University of Rome, Latina, Italy
| | - Marzia Duse
- From the Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - Anna Maria Zicari
- From the Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - Danilo Buonsenso
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Center for Global Health Research and Studies, Università Cattolica del Sacro Cuore, Roma, Italia
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Tomomasa D, Lee BH, Hirata Y, Inoue Y, Majima H, Imanaka Y, Asano T, Katakami T, Lee J, Hijikata A, Worakitchanon W, Yang X, Wang X, Watanabe A, Kamei K, Kageyama Y, Seo GH, Fujimoto A, Casanova JL, Puel A, Morio T, Okada S, Kanegane H. Inherited CARD9 Deficiency Due to a Founder Effect in East Asia. J Clin Immunol 2024; 44:121. [PMID: 38758287 PMCID: PMC11736695 DOI: 10.1007/s10875-024-01724-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 04/25/2024] [Indexed: 05/18/2024]
Abstract
Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).
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Affiliation(s)
- Dan Tomomasa
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Beom Hee Lee
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, South Korea.
| | - Yuki Hirata
- Department of Opthalmology, Shonan Fujisawa Tokushukai Hospital, Kanagawa, Japan
| | - Yuzaburo Inoue
- Department of General Medical Science, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hidetaka Majima
- Medical Mycology Research Center, Chiba University, Chiba, Japan
| | - Yusuke Imanaka
- Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan
| | - Takaki Asano
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
- Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takashi Katakami
- Department of Neurology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan
| | - Jina Lee
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, South Korea
| | - Atsushi Hijikata
- School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Wittawin Worakitchanon
- Department of Human Genetics, School of International Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Xi Yang
- Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaowen Wang
- Department of Dermatology, Peking University First Hospital, Beijing, China
| | - Akira Watanabe
- Medical Mycology Research Center, Chiba University, Chiba, Japan
| | - Katsuhiko Kamei
- Medical Mycology Research Center, Chiba University, Chiba, Japan
| | - Yasufumi Kageyama
- Department of Neurology, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan
| | | | - Akihiro Fujimoto
- Department of Human Genetics, School of International Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, UMR 1163, INSERM, Necker Hospital for Sick Children, 75015, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA
- University Paris Cité, Imagine Institute, 75015, Paris, France
| | - Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, UMR 1163, INSERM, Necker Hospital for Sick Children, 75015, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA
- University Paris Cité, Imagine Institute, 75015, Paris, France
| | - Tomohiro Morio
- Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Satoshi Okada
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan.
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Mizukami K, Dorsey-Oresto A, Raj K, Eringis A, Furrow E, Martin E, Yamanaka D, Kehl A, Kolicheski A, Jagannathan V, Leeb T, Lionakis MS, Giger U. Increased susceptibility to Mycobacterium avium complex infection in miniature Schnauzer dogs caused by a codon deletion in CARD9. Sci Rep 2024; 14:10346. [PMID: 38710903 PMCID: PMC11074286 DOI: 10.1038/s41598-024-61054-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 04/30/2024] [Indexed: 05/08/2024] Open
Abstract
Mammals are generally resistant to Mycobacterium avium complex (MAC) infections. We report here on a primary immunodeficiency disorder causing increased susceptibility to MAC infections in a canine breed. Adult Miniature Schnauzers developing progressive systemic MAC infections were related to a common founder, and pedigree analysis was consistent with an autosomal recessive trait. A genome-wide association study and homozygosity mapping using 8 infected, 9 non-infected relatives, and 160 control Miniature Schnauzers detected an associated region on chromosome 9. Whole genome sequencing of 2 MAC-infected dogs identified a codon deletion in the CARD9 gene (c.493_495del; p.Lys165del). Genotyping of Miniature Schnauzers revealed the presence of this mutant CARD9 allele worldwide, and all tested MAC-infected dogs were homozygous mutants. Peripheral blood mononuclear cells from a dog homozygous for the CARD9 variant exhibited a dysfunctional CARD9 protein with impaired TNF-α production upon stimulation with the fungal polysaccharide β-glucan that activates the CARD9-coupled C-type lectin receptor, Dectin-1. While CARD9-deficient knockout mice are susceptible to experimental challenges by fungi and mycobacteria, Miniature Schnauzer dogs with systemic MAC susceptibility represent the first spontaneous animal model of CARD9 deficiency, which will help to further elucidate host defense mechanisms against mycobacteria and fungi and assess potential therapies for animals and humans.
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Affiliation(s)
- Keijiro Mizukami
- Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- RIKEN Center for Integrative Medical Sciences, Laboratory for Genotyping Development, Yokohama, Kanagawa, Japan.
| | - Angella Dorsey-Oresto
- Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Karthik Raj
- Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Anna Eringis
- Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Eva Furrow
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA
| | - Errolyn Martin
- Wildlife Center of North Georgia, Inc., Acworth, GA, USA
| | - Daisuke Yamanaka
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
- Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | | | - Ana Kolicheski
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | - Vidhya Jagannathan
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Tosso Leeb
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Michail S Lionakis
- Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Urs Giger
- Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Vetsuisse Faculty, University of Zürich, Zurich, Switzerland.
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7
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Brandt M, Cao Z, Krishna C, Reedy JL, Gu X, Dutko RA, Oliver BA, Tusi BK, Park J, Richey L, Segerstolpe Å, Litwiler S, Creasey EA, Carey KL, Vyas JM, Graham DB, Xavier RJ. Translational genetics identifies a phosphorylation switch in CARD9 required for innate inflammatory responses. Cell Rep 2024; 43:113944. [PMID: 38489265 PMCID: PMC11008285 DOI: 10.1016/j.celrep.2024.113944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 02/07/2024] [Accepted: 02/24/2024] [Indexed: 03/17/2024] Open
Abstract
Population genetics continues to identify genetic variants associated with diseases of the immune system and offers a unique opportunity to discover mechanisms of immune regulation. Multiple genetic variants linked to severe fungal infections and autoimmunity are associated with caspase recruitment domain-containing protein 9 (CARD9). We leverage the CARD9 R101C missense variant to uncover a biochemical mechanism of CARD9 activation essential for antifungal responses. We demonstrate that R101C disrupts a critical signaling switch whereby phosphorylation of S104 releases CARD9 from an autoinhibited state to promote inflammatory responses in myeloid cells. Furthermore, we show that CARD9 R101C exerts dynamic effects on the skin cellular contexture during fungal infection, corrupting inflammatory signaling and cell-cell communication circuits. Card9 R101C mice fail to control dermatophyte infection in the skin, resulting in high fungal burden, yet show minimal signs of inflammation. Together, we demonstrate how translational genetics reveals molecular and cellular mechanisms of innate immune regulation.
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Affiliation(s)
- Marta Brandt
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Zhifang Cao
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Chirag Krishna
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Jennifer L Reedy
- Division of Infectious Disease, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Xiebin Gu
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Richard A Dutko
- Division of Infectious Disease, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Blayne A Oliver
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Betsabeh Khoramian Tusi
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Jihye Park
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Lauren Richey
- Tufts Comparative Medicine Services, Tufts University, Boston, MA 02111, USA
| | - Åsa Segerstolpe
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Scott Litwiler
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Elizabeth A Creasey
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | | | - Jatin M Vyas
- Division of Infectious Disease, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Daniel B Graham
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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8
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Ma N, Zhao Y, Tang M, Xia H, Li D, Lu G. Concurrent infection of Exophiala dermatitidis and Angiostrongylus cantonensis in central nervous system of a child with inherited CARD9 deficiency: A case report and literature review. J Mycol Med 2024; 34:101455. [PMID: 38042015 DOI: 10.1016/j.mycmed.2023.101455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 08/08/2023] [Accepted: 11/24/2023] [Indexed: 12/04/2023]
Abstract
Exophiala dermatitidis is a relatively common environmental black yeast with a worldwide distribution that rarely causes fungal infection. Here, we report a case of a 6-year-old girl with central nervous system (CNS) encephalitis caused by E. dermatitidis and Angiostrongylus cantonensis. E. dermatitidis was identified by both cerebrospinal fluid culture and metagenomic next-generation sequencing (mNGS). Angiostrongylus cantonensis infection was confirmed by an enzyme linked immunosorbent assay (ELISA). Whole exome sequencing showed that this previously healthy girl carried a homozygous CARD9 mutation for c.820dupG (p.D274Gfs*61) that underlies invasive fungal and parasite infections. We chose glucocortieoid pulse therapy and anti-infective therapy based on the initial results of laboratory examination and cranial MRI images. With the aggravation of the disease and the evidence of the subsequent etiologic test, the combination of antifungal antiparasitic treatments (voriconazole, fluorocytosine and amphotericin B) were actively used. Unfortunately, the girl finally died due to severe systemic infection. mNGS performs a potential value for diagnosing rare CNS infections, and autosomal recessive CARD9 deficiency should be considered in patient with fatal invasive fungal infections.
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Affiliation(s)
- Na Ma
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, 3rd section, South Renmin Road, Chengdu 610041, China
| | - Yufei Zhao
- The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, China
| | - Mingze Tang
- Department of Scientific Affairs, Hugobiotech Co., Ltd., No. 1 Disheng East Road, Beijing 100176, China
| | - Han Xia
- Department of Scientific Affairs, Hugobiotech Co., Ltd., No. 1 Disheng East Road, Beijing 100176, China.
| | - Deyuan Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, 3rd section, South Renmin Road, Chengdu 610041, China.
| | - Guoyan Lu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, No. 20, 3rd section, South Renmin Road, Chengdu 610041, China.
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9
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Vinh DC. From Mendel to mycoses: Immuno-genomic warfare at the human-fungus interface. Immunol Rev 2024; 322:28-52. [PMID: 38069482 DOI: 10.1111/imr.13295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/06/2023] [Accepted: 11/14/2023] [Indexed: 03/20/2024]
Abstract
Fungi are opportunists: They particularly require a defect of immunity to cause severe or disseminated disease. While often secondary to an apparent iatrogenic cause, fungal diseases do occur in the absence of one, albeit infrequently. These rare cases may be due to an underlying genetic immunodeficiency that can present variably in age of onset, severity, or other infections, and in the absence of a family history of disease. They may also be due to anti-cytokine autoantibodies. This review provides a background on how human genetics or autoantibodies underlie cases of susceptibility to severe or disseminated fungal disease. Subsequently, the lessons learned from these inborn errors of immunity marked by fungal disease (IEI-FD) provide a framework to begin to mechanistically decipher fungal syndromes, potentially paving the way for precision therapy of the mycoses.
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Affiliation(s)
- Donald C Vinh
- Infectious Diseases - Hematology/Oncology/Transplant Clinical Program, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute - McGill University Health Centre, Montreal, Quebec, Canada
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10
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Carlson SL, Mathew L, Savage M, Kok K, Lindsay JO, Munro CA, McCarthy NE. Mucosal Immunity to Gut Fungi in Health and Inflammatory Bowel Disease. J Fungi (Basel) 2023; 9:1105. [PMID: 37998910 PMCID: PMC10672531 DOI: 10.3390/jof9111105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 11/09/2023] [Accepted: 11/12/2023] [Indexed: 11/25/2023] Open
Abstract
The gut microbiome is a diverse microbial community composed of bacteria, viruses, and fungi that plays a major role in human health and disease. Dysregulation of these gut organisms in a genetically susceptible host is fundamental to the pathogenesis of inflammatory bowel disease (IBD). While bacterial dysbiosis has been a predominant focus of research for many years, there is growing recognition that fungal interactions with the host immune system are an important driver of gut inflammation. Candida albicans is likely the most studied fungus in the context of IBD, being a near universal gut commensal in humans and also a major barrier-invasive pathogen. There is emerging evidence that intra-strain variation in C. albicans virulence factors exerts a critical influence on IBD pathophysiology. In this review, we describe the immunological impacts of variations in C. lbicans colonisation, morphology, genetics, and proteomics in IBD, as well as the clinical and therapeutic implications.
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Affiliation(s)
- Sean L. Carlson
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
- Gastroenterology Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - Liya Mathew
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Michael Savage
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Klaartje Kok
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
- Gastroenterology Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - James O. Lindsay
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
- Gastroenterology Department, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK
| | - Carol A. Munro
- Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB24 3FX, UK
| | - Neil E. McCarthy
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London E1 2AT, UK
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11
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Roussel L, Pham-Huy A, Yu AC, Venkateswaran S, Perez A, Bourdel G, Sun Y, Villavicencio ST, Bernier S, Li Y, Kazimerczak-Brunet M, Alattar R, Déry MA, Shapiro AJ, Penner J, Vinh DC. A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis. J Clin Immunol 2023; 43:2011-2021. [PMID: 37695435 DOI: 10.1007/s10875-023-01580-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 08/30/2023] [Indexed: 09/12/2023]
Abstract
Autosomal recessive tyrosine kinase 2 (TYK2) deficiency is characterized by susceptibility to mycobacterial and viral infections. Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus. A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2. The deleterious effects of the TYK2 lesion were confirmed by immunoblotting; by evaluating functional responses to IFN-α/β, IL-10, and IL-23; and by assessing its scaffolding effect on the cell surface expression of cytokine receptor subunits. The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed. We characterize the first patient from Canada with a novel homozygous mutation in TYK2.
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Affiliation(s)
- Lucie Roussel
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Anne Pham-Huy
- Division of Infectious Diseases, Immunology and Allergy, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
| | - Andrea C Yu
- Division of Metabolics and Newborn Screening, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
| | - Sunita Venkateswaran
- Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
| | - Anna Perez
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Guillaume Bourdel
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Yichun Sun
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Stephanya Tellez Villavicencio
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Stéphane Bernier
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Yongbiao Li
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Makayla Kazimerczak-Brunet
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Rolan Alattar
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Marc-André Déry
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada
| | - Adam J Shapiro
- Division of Respirology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Justin Penner
- Division of Infectious Diseases, Immunology and Allergy, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
- Department of Pediatrics, Qikiqtani General Hospital, Iqaluit, NT, Canada
| | - Donald C Vinh
- Centre of Excellence for Genetic Research in Infection and Immunity, Research Institute, McGill University Health Centre, 1001 Decarie Blvd., Block E, Rm EM3-3230 (Mail Drop: EM3-3211), Montreal, QC, H4A 3J1, Canada.
- Division of Infectious Diseases, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
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12
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Xu X, Lu H, Li J, Duan J, Wang Z, Yang J, Gu S, Luo R, Liang S, Tang W, Zhang F, Hang J, Ge J, Lin X, Qu J, Jia X, Xu J. Heterozygous CARD9 mutation favors the development of allergic bronchopulmonary aspergillosis. Chin Med J (Engl) 2023; 136:1949-1958. [PMID: 37461235 PMCID: PMC10431571 DOI: 10.1097/cm9.0000000000002786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Indexed: 08/18/2023] Open
Abstract
BACKGROUND Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA. METHODS A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease. RESULTS The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production. CONCLUSION Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.
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Affiliation(s)
- Xia Xu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai 200433, China
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Haiwen Lu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai 200433, China
| | - Jianxiong Li
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai 200433, China
| | - Jielin Duan
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Zhongwei Wang
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jiawei Yang
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai 200433, China
| | - Shuyi Gu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai 200433, China
| | - Rongguang Luo
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai 200433, China
| | - Shuo Liang
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai 200433, China
| | - Wei Tang
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Fengying Zhang
- Department of Respiratory and Critical Care Medicine, Shanghai Putuo District People's Hospital, Shanghai 200060, China
| | - Jingqing Hang
- Department of Respiratory and Critical Care Medicine, Shanghai Putuo District People's Hospital, Shanghai 200060, China
| | - Juan Ge
- Department of Respiratory and Critical Care Medicine, Nantong Hospital, Shanghai University, Nantong, Jiangsu 226007, China
| | - Xin Lin
- Institute for Immunology, Tsinghua University School of Medicine, Tsinghua-Peking Center for Life Sciences, Beijing 100083, China
| | - Jieming Qu
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Xinming Jia
- Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jinfu Xu
- Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Institute of Respiratory Medicine, School of Medicine, Tongji University, Shanghai 200433, China
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13
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Lionakis MS. Exploiting antifungal immunity in the clinical context. Semin Immunol 2023; 67:101752. [PMID: 37001464 PMCID: PMC10192293 DOI: 10.1016/j.smim.2023.101752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Indexed: 03/31/2023]
Abstract
The continuous expansion of immunocompromised patient populations at-risk for developing life-threatening opportunistic fungal infections in recent decades has helped develop a deeper understanding of antifungal host defenses, which has provided the foundation for eventually devising immune-based targeted interventions in the clinic. This review outlines how genetic variation in certain immune pathway-related genes may contribute to the observed clinical variability in the risk of acquisition and/or severity of fungal infections and how immunogenetic-based patient stratification may enable the eventual development of personalized strategies for antifungal prophylaxis and/or vaccination. Moreover, this review synthesizes the emerging cytokine-based, cell-based, and other immunotherapeutic strategies that have shown promise as adjunctive therapies for boosting or modulating tissue-specific antifungal immune responses in the context of opportunistic fungal infections.
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Affiliation(s)
- Michail S Lionakis
- From the Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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14
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Yang LJ, Wu W, Jiang WR, Zhu CL, Yao ZH. Upregulation of RasGRF1 ameliorates spatial cognitive dysfunction in mice after chronic cerebral hypoperfusion. Aging (Albany NY) 2023; 15:2999-3020. [PMID: 37053022 DOI: 10.18632/aging.204654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/31/2023] [Indexed: 04/14/2023]
Abstract
Chronic cerebral hypoperfusion (CCH)-mediated cognitive impairment is a serious problem worldwide. However, given its complexity, the underlying mechanisms by which CCH induces cognitive dysfunction remain unclear, resulting in a lack of effective treatments. In this study, we aimed to determine whether changes in the expression of RasGRF1, an important protein associated with cognition and synaptic plasticity, underlie the associated impairments in cognition after CCH. We found that RasGRF1 levels markedly decreased following CCH. Through prediction and validation studies, we observed that miRNA-323-3p was upregulated after CCH and could bind to the 3'-untranslated region of Rasgrf1 mRNA and regulate its expression in vitro. Moreover, the inhibition of miRNA-323-3p upregulated Rasgrf1 expression in the hippocampus after CCH, which was reversed by Rasgrf1 siRNA. This suggests that miRNA-323-3p is an important regulator of Rasgrf1. The Morris water maze and Y maze tests showed that miRNA-323-3p inhibition and Rasgrf1 upregulation improved spatial learning and memory, and electrophysiological measurements revealed deficits in long-term potentiation after CCH that were reversed by Rasgrf1 upregulation. Dendritic spine density and mature mushroom spine density were also improved after miRNA-323-3p inhibition and Rasgrf1 upregulation. Furthermore, Rasgrf1 upregulation by miRNA-323-3p inhibition improved dendritic spine density and mature mushroom spine density and ameliorated the deterioration of synapses and postsynaptic density. Overall, RasGRF1 regulation attenuated cognitive impairment, helped maintain structural and functional synaptic plasticity, and prevented synapse deterioration after CCH. These results suggest that Rasgrf1 downregulation by miRNA-323-3p plays an important role in cognitive impairment after CCH. Thus, RasGRF1 and miRNA-323-3p may represent potential therapeutic targets for cognitive impairment after CCH.
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Affiliation(s)
- Li-Jie Yang
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Wei Wu
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Wan-Rong Jiang
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Cheng-Liang Zhu
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zhao-Hui Yao
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan 430060, China
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15
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Of Mycelium and Men: Inherent Human Susceptibility to Fungal Diseases. Pathogens 2023; 12:pathogens12030456. [PMID: 36986378 PMCID: PMC10058615 DOI: 10.3390/pathogens12030456] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023] Open
Abstract
In medical mycology, the main context of disease is iatrogenic-based disease. However, historically, and occasionally, even today, fungal diseases affect humans with no obvious risk factors, sometimes in a spectacular fashion. The field of “inborn errors of immunity” (IEI) has deduced at least some of these previously enigmatic cases; accordingly, the discovery of single-gene disorders with penetrant clinical effects and their immunologic dissection have provided a framework with which to understand some of the key pathways mediating human susceptibility to mycoses. By extension, they have also enabled the identification of naturally occurring auto-antibodies to cytokines that phenocopy such susceptibility. This review provides a comprehensive update of IEI and autoantibodies that inherently predispose humans to various fungal diseases.
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16
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Inborn Errors of Immunity Causing Pediatric Susceptibility to Fungal Diseases. J Fungi (Basel) 2023; 9:jof9020149. [PMID: 36836264 PMCID: PMC9964687 DOI: 10.3390/jof9020149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/11/2023] [Accepted: 01/15/2023] [Indexed: 01/24/2023] Open
Abstract
Inborn errors of immunity are a heterogeneous group of genetically determined disorders that compromise the immune system, predisposing patients to infections, autoinflammatory/autoimmunity syndromes, atopy/allergies, lymphoproliferative disorders, and/or malignancies. An emerging manifestation is susceptibility to fungal disease, caused by yeasts or moulds, in a superficial or invasive fashion. In this review, we describe recent advances in the field of inborn errors of immunity associated with increased susceptibility to fungal disease.
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17
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Abstract
PURPOSE OF REVIEW This review provides readers with examples of refractory infections due to inborn errors of immunity, highlighting how they may be successfully treated by deducing and targeting the underlying immunodeficiency. RECENT FINDINGS The use of host-directed immunotherapy to treat infectious disease in inborn errors of immunity is currently limited but growing. Different strategies include depleting the cellular reservoir for pathogens with restricted cell-tropism; augmenting the diminished effector response; and restoring molecular equipoise. The immunotherapies illustrated are existing drugs that have been re-purposed and rationally used, depending on the molecular or cellular impact of the mutation. As more biologic response modifiers and molecular targeted therapies are developed for other indications, they open the avenues for their use in inborn errors of immunity. Conversely, as more molecular pathways underlying defective immune responses and refractory infections are elucidated, they lend themselves to tractability with these emerging therapies. SUMMARY Infections that fail appropriate antimicrobial therapy are a harbinger of underlying inborn errors of immunity. Dissecting the mechanism by which the immune system fails provides opportunities to target the host response and make it succeed.
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18
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Chen TK, Batra JS, Michalik DE, Casillas J, Patel R, Ruiz ME, Hara H, Patel B, Kadapakkam M, Ch'Ng J, Small CB, Zagaliotis P, Ragsdale CE, Leal LO, Roilides E, Walsh TJ. Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (rhu GM-CSF) as Adjuvant Therapy for Invasive Fungal Diseases. Open Forum Infect Dis 2022; 9:ofac535. [PMID: 36381625 PMCID: PMC9645583 DOI: 10.1093/ofid/ofac535] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/07/2022] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND Sargramostim (yeast-derived, glycosylated recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) augments innate and adaptive immune responses and accelerates hematopoietic recovery of chemotherapy-induced neutropenia. However, considerably less is known about its efficacy as adjunctive immunotherapy against invasive fungal diseases (IFDs). METHODS The clinical courses of 15 patients with pediatric malignancies and IFDs treated adjunctively with sargramostim at a single institution were analyzed in a retrospective cohort review. Further, a systematic review of published reports of rhu GM-CSF for IFDs was also conducted. RESULTS Among 65 cases, 15 were newly described pediatric patients and 50 were previously published cases of IFDs treated with rhu GM-CSF. Among the newly reported pediatric patients, IFDs were caused by Candida spp., Trichosporon sp., and molds (Aspergillus spp., Rhizopus sp., Lichtheimia sp., and Scedosporium sp). Twelve (80%) were neutropenic at baseline, and 12 (80%) were refractory to antifungal therapy. Among 12 evaluable patients, the overall response rate was 92% (8 [67%] complete responses, 3 [25%] partial responses, and 1 [8%] stable). Treatment is ongoing in the remaining 3 patients. Among 50 published cases (15 Candida spp., 13 Mucorales, 11 Aspergillus spp., 11 other organisms), 20 (40%) had baseline neutropenia and 36 (72%) were refractory to standard therapy before rhu GM-CSF administration. Consistent with responses in the newly reported patients, the overall response rate in the literature review was 82% (40 [80%] complete responses, 1 [2%] partial response, and 9 [18%] no response). CONCLUSIONS Sargramostim may be a potential adjunctive immunomodulator for selected patients with hematological malignancies and refractory IFDs.
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Affiliation(s)
- Tempe K Chen
- Department of Pediatric Infectious Diseases, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Department of Pediatrics, Division of Infectious Diseases, University of California Irvine School of Medicine, Irvine, California, USA
| | - Jagmohan S Batra
- Department of Pediatric Infectious Diseases, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Department of Pediatrics, Division of Infectious Diseases, University of California Irvine School of Medicine, Irvine, California, USA
| | - David E Michalik
- Department of Pediatric Infectious Diseases, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Department of Pediatrics, Division of Infectious Diseases, University of California Irvine School of Medicine, Irvine, California, USA
| | - Jacqueline Casillas
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Ramesh Patel
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Maritza E Ruiz
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Harneet Hara
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Bhavita Patel
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Meena Kadapakkam
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - James Ch'Ng
- Department of Pediatric Hematology/Oncology, MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, California, USA
- Division of Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA
| | - Catherine B Small
- Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, New York, New York, USA
| | - Panagiotis Zagaliotis
- Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, New York, New York, USA
- Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece
- Department of Pharmacology and Therapeutics, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Luis O Leal
- Partner Therapeutics, Inc., Lexington, Massachusetts, USA
| | - Emmanuel Roilides
- Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Thessaloniki, Greece
| | - Thomas J Walsh
- Transplantation-Oncology Infectious Diseases Program, Weill Cornell Medicine, New York, New York, USA
- Center for Innovative Therapeutics and Diagnostics, Richmond, Virginia, USA
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19
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Main human inborn errors of immunity leading to fungal infections. Clin Microbiol Infect 2022; 28:1435-1440. [PMID: 35863627 DOI: 10.1016/j.cmi.2022.06.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 01/23/2023]
Abstract
BACKGROUND The host molecular and genetic features are essential in providing susceptibility to a broad spectrum of fungal infections; most of these do not cause disease in healthy individuals because of mutual benefits with opportunistic fungi besides the host's capacity to control the infections. In contrast, patients with primary immunodeficiency (PID) can develop mild superficial to life-threatening invasive infections. In the last years, thanks to next-generation sequencing (NGS), several inborn-error variants have been discovered in genes encoding protein acting against fungal infections, contributing to better defining the role of innate and adaptive immunity cooperation during infection resolution. Candida fungal infection, that sometimes-striking healthy subjects, is responsible for the chronic mucocutaneous candidiasis (CMC) that is one of the principal clinical manifestations occurring in several rare PIDs associated with an inborn error of IL17-immunity. OBJECTIVE This review aimed to provide an overview of CMC-derived genetic defects, including IL17-deficiencies (IL17A, IL17F, IL17RA, IL17RC), STAT1 gain-of-function (GOF)- deficiency, STAT3-HIES and CARD9-deficiency. SOURCES We carried out detailed research work to identify interesting articles, commentaries, and reviews in the PubMed literature to ensure a correct and updated for this narrative review. CONTENT We propose an in-depth description and an update of genetic and cellular mechanisms underlying fungal infections, focusing on the IL17-mediated response, a report of clinical manifestations and describe therapeutic options. IMPLICATION This narrative review will help clinician to identify the correct management of patients based on molecular and cellular findings underlying pathogenic mechanisms of different IEIs. Moreover achieve the genetic diagnosis will be useful to offer genetic counselling intra- and inter-family and to ensure a personalized treatment of patients.
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20
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Song P, Peng G, Yue H, Ogawa T, Ikeda S, Okumura K, Ogawa H, Niyonsaba F. Candidalysin, a Virulence Factor of Candida albicans, Stimulates Mast Cells by Mediating Cross-Talk Between Signaling Pathways Activated by the Dectin-1 Receptor and MAPKs. J Clin Immunol 2022; 42:1009-1025. [PMID: 35420364 DOI: 10.1007/s10875-022-01267-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 04/04/2022] [Indexed: 11/27/2022]
Abstract
PURPOSE Although mast cells (MCs) modulate the activity of effector cells during Candida albicans infection, their role in the pathogenesis of candidiasis remains unclear. Candidalysin, a C. albicans-derived peptide toxin, is a crucial factor in fungal infections. We aimed to investigate the effect of candidalysin on MC activation and the underlying molecular mechanism. METHODS Serum from candidalysin-immunized mice was used to measure candidalysin expression in patients infected with C. albicans. MC degranulation and migration were evaluated by β-hexosaminidase release assay and chemotaxis assay, respectively. EIA and ELISA were used to evaluate the production of eicosanoids and cytokines/chemokines, respectively. The production of nitric oxide (NO) was measured with a DAF-FM diacetate kit, while reactive oxygen species (ROS) production was analyzed by flow cytometry. MAPK activation was evaluated by Western blotting. RESULTS We detected high candidalysin expression in the lesions of patients infected with C. albicans, and the MC number was increased in these lesions. LL-37 colocalized with MCs in the lesions of candidiasis patients. Candidalysin-enhanced MC accumulation in mice and treating LAD2 and HMC-1 cells with candidalysin induced their degranulation, migration, and production of pro- and anti-inflammatory cytokines/chemokines, eicosanoids, ROS, NO, and LL-37. Interestingly, C. albicans strains lacking candidalysin failed to induce MC activation. Moreover, candidalysin increased dectin-1 expression, and the inhibition of dectin-1 decreased MC activation. Downstream dectin-1 signaling involved the MAPK pathways. CONCLUSION The finding that candidalysin causes cutaneous MC activation may improve our understanding of the role of MCs in the pathology of cutaneous C. albicans infection.
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Affiliation(s)
- Pu Song
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shannxi, China
| | - Ge Peng
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hainan Yue
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takasuke Ogawa
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigaku Ikeda
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ko Okumura
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideoki Ogawa
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - François Niyonsaba
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
- Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan.
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21
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Liu X, Jiang B, Hao H, Liu Z. CARD9 Signaling, Inflammation, and Diseases. Front Immunol 2022; 13:880879. [PMID: 35432375 PMCID: PMC9005907 DOI: 10.3389/fimmu.2022.880879] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/07/2022] [Indexed: 12/15/2022] Open
Abstract
Caspase-recruitment domain 9 (CARD9) protein is expressed in many cells especially in immune cells, and is critically involved in the function of the innate and adaptive immune systems through extensive interactions between CARD9 and other signaling molecules including NF-κB and MAPK. CARD9-mediated signaling plays a central role in regulating inflammatory responses and oxidative stress through the productions of important cytokines and chemokines. Abnormalities of CARD9 and CARD9 signaling or CARD9 mutations or polymorphism are associated with a variety of pathological conditions including infections, inflammation, and autoimmune disorders. This review focuses on the function of CARD9 and CARD9-mediated signaling pathways, as well as interactions with other important signaling molecules in different cell types and the relations to specific disease conditions including inflammatory diseases, infections, tumorigenesis, and cardiovascular pathologies.
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Affiliation(s)
- Xuanyou Liu
- Center for Precision Medicine and Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO, United States
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO, United States
| | - Bimei Jiang
- Department of Pathophysiology, Central South University, Changsha, China
| | - Hong Hao
- Center for Precision Medicine and Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO, United States
| | - Zhenguo Liu
- Center for Precision Medicine and Division of Cardiovascular Medicine, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO, United States
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22
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Garcia-Solis B, Van Den Rym A, Pérez-Caraballo JJ, Al-Ayoubi A, Alazami AM, Lorenzo L, Cubillos-Zapata C, López-Collazo E, Pérez-Martínez A, Allende LM, Markle J, Fernández-Arquero M, Sánchez-Ramón S, Recio MJ, Casanova JL, Mohammed R, Martinez-Barricarte R, Pérez de Diego R. Clinical and Immunological Features of Human BCL10 Deficiency. Front Immunol 2021; 12:786572. [PMID: 34868072 PMCID: PMC8633570 DOI: 10.3389/fimmu.2021.786572] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 10/25/2021] [Indexed: 12/27/2022] Open
Abstract
The CARD-BCL10-MALT1 (CBM) complex is critical for the proper assembly of human immune responses. The clinical and immunological consequences of deficiencies in some of its components such as CARD9, CARD11, and MALT1 have been elucidated in detail. However, the scarcity of BCL10 deficient patients has prevented gaining detailed knowledge about this genetic disease. Only two patients with BCL10 deficiency have been reported to date. Here we provide an in-depth description of an additional patient with autosomal recessive complete BCL10 deficiency caused by a nonsense mutation that leads to a loss of expression (K63X). Using mass cytometry coupled with unsupervised clustering and machine learning computational methods, we obtained a thorough characterization of the consequences of BCL10 deficiency in different populations of leukocytes. We showed that in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and TFH cells. The patient had recurrent respiratory infections since early childhood, and showed a family history of lethal severe infectious diseases. Fortunately, hematopoietic stem-cell transplantation (HSCT) cured her. Overall, this report highlights the importance of early genetic diagnosis for the management of BCL10 deficient patients and HSCT as the recommended treatment to cure this disease.
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Affiliation(s)
- Blanca Garcia-Solis
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.,Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.,Interdepartmental Group of Immunodeficiencies, Madrid, Spain
| | - Ana Van Den Rym
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.,Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.,Interdepartmental Group of Immunodeficiencies, Madrid, Spain
| | - Jareb J Pérez-Caraballo
- Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States.,Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Abdulwahab Al-Ayoubi
- Department of Pediatrics, King Saud Medical City Children's Hospital, Riyadh, Saudi Arabia
| | - Anas M Alazami
- Translational Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Lazaro Lorenzo
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
| | - Carolina Cubillos-Zapata
- Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.,Center for Biomedical Research Network, CIBEres, Madrid, Spain
| | - Eduardo López-Collazo
- Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain
| | - Antonio Pérez-Martínez
- Translational Research in Paediatric Oncology, Haematopoietic Stem Cell Transplantation, Cell Therapy, Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, La Paz University Hospital, Madrid, Spain.,Department of Paediatric Haemato-Oncology and Stem Cell Transplantation, La Paz University Hospital, Madrid, Spain
| | - Luis M Allende
- Department of Immunology, 12 de Octubre Hospital, Research Insitute imas12, Complutense University, Madrid, Spain
| | - Janet Markle
- Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States.,Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Miguel Fernández-Arquero
- Interdepartmental Group of Immunodeficiencies, Madrid, Spain.,Clinical Immunology Department, San Carlos Clinical Hospital, Madrid, Spain
| | - Silvia Sánchez-Ramón
- Interdepartmental Group of Immunodeficiencies, Madrid, Spain.,Clinical Immunology Department, San Carlos Clinical Hospital, Madrid, Spain
| | - Maria J Recio
- Interdepartmental Group of Immunodeficiencies, Madrid, Spain.,Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States.,Imagine Institute, University Paris Descartes, Paris, France.,Howard Hughes Medical Institute, New York, NY, United States
| | - Reem Mohammed
- Department of Pediatrics, Division of Allergy & Immunology King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Rubén Martinez-Barricarte
- Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States.,Division of Molecular Pathogenesis, Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Rebeca Pérez de Diego
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.,Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain.,Interdepartmental Group of Immunodeficiencies, Madrid, Spain
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23
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CARD9 Expression Pattern, Gene Dosage, and Immunodeficiency Phenotype Revisited. J Clin Immunol 2021; 42:336-349. [PMID: 34791587 PMCID: PMC10108093 DOI: 10.1007/s10875-021-01173-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 10/13/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND CARD9 deficiency is an autosomal recessive primary immunodeficiency underlying increased susceptibility to fungal infection primarily presenting as invasive CNS Candida and/or cutaneous/invasive dermatophyte infections. More recently, a rare heterozygous dominant negative CARD9 variant c.1434 + 1G > C was reported to be protective from inflammatory bowel disease. OBJECTIVE We studied two siblings carrying homozygous CARD9 variants (c.1434 + 1G > C) and born to heterozygous asymptomatic parents. One sibling was asymptomatic and the other presented with candida esophagitis, upper respiratory infections, hypogammaglobulinemia, and low class-switched memory B cells. METHODS AND RESULTS The CARD9 c.1434 + 1G > C variant generated two mutant transcripts confirmed by mRNA and protein expression: an out-of-frame c.1358-1434 deletion/ ~ 55 kDa protein (CARD9Δex.11) and an in-frame c.1417-1434 deletion/ ~ 61 kDa protein (CARD9Δ18 nt.). Neither transcript was able to form a complete/functional CBM complex, which includes TRIM62. Based on the index patient's CVID-like phenotype, CARD9 expression was tested and detected in lymphocytes and monocytes from humans and mice. The functional impact of different CARD9 mutations and gene dosage conditions was evaluated in heterozygous and homozygous c.1434 + 1 G > C members of the index family, and in WT (two WT alleles), haploinsufficiency (one WT, one null allele), and null (two null alleles) individuals. CARD9 gene dosage impacted lymphocyte and monocyte functions including cytokine generation, MAPK activation, T-helper commitment, transcription, plasmablast differentiation, and immunoglobulin production in a differential manner. CONCLUSIONS CARD9 exon 11 integrity is critical to CBM complex function. CARD9 is expressed and affects particular T and B cell functions in a gene dosage-dependent manner, which in turn may contribute to the phenotype of CARD9 deficiency.
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24
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Lazarus HM, Ragsdale CE, Gale RP, Lyman GH. Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time? Front Immunol 2021; 12:706186. [PMID: 34484202 PMCID: PMC8416151 DOI: 10.3389/fimmu.2021.706186] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/26/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Sargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer via the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans. OBJECTIVE Assess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings. METHODS AND RESULTS We systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies. CONCLUSIONS Sargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.
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Affiliation(s)
- Hillard M. Lazarus
- Department of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | | | - Robert Peter Gale
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Gary H. Lyman
- Public Health Sciences and Clinical Research Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
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25
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Raffa PEAZ, Vencio RCC, Ponce ACC, Malamud BP, Vencio IC, Pacheco CC, Costa FD, Franceschini PR, Medeiros RTR, Aguiar PHP. Spinal intramedullary abscess due to Candida albicans in an immunocompetent patient: A rare case report. Surg Neurol Int 2021; 12:275. [PMID: 34221606 PMCID: PMC8247672 DOI: 10.25259/sni_435_2021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 05/18/2021] [Indexed: 11/19/2022] Open
Abstract
Background: A spinal intramedullary abscess is a rare clinical entity in which patients classically present with a subacute myelopathy and progressive paraplegia, sensory deficits, and/or bowel and bladder dysfunction. We report the second case of spinal intramedullary abscess caused by Candida albicans to ever be published and the first case of its kind to be surgically managed. Case Description: A 44-year-old female presented with severe lumbar pain associated with paraparesis, incontinence, and paraplegia. She reported multiple hospital admissions and had a history of seizures, having already undergone treatment for neurotuberculosis and fungal infection of the central nervous system unsuccessfully. Nevertheless, no laboratory evidence of immunosuppression was identified on further investigation. Magnetic resonance imaging showed a D10-D11, well-circumscribed, intramedullary mass within the conus, which was hypointense on T1-weighted imaging and hyperintense on T2/STIR weighted. The patient underwent surgery for removal and biopsy of the lesion, which provided the diagnosis of an intramedullary abscess caused by C. albicans, a very rare condition with only one case reported in literature so far. Conclusion: C. albicans intramedullary abscess is a very rare clinical entity, especially in immunocompetent patients. We highlight C. albicans as an important etiology that must be considered in differential diagnosis. Critical evaluation of every case, early diagnosis, timely referral and surgical management of the abscess is essential to improve neurological outcome.
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Affiliation(s)
| | | | | | | | - Isabela Caiado Vencio
- Department of Medicine, School of Medicine of Pontifical Catholic University of São Paulo, Sorocaba, São Paulo, Brazil
| | | | | | - Paulo Roberto Franceschini
- Department of Neurology and Neurosurgery, University of Caxias do Sul, Caxias do Sul, Rio Grande do Sul, Brazil
| | | | - Paulo Henrique Pires Aguiar
- Department of Medicine, Division of Neurology, Catholic Pontifical University of São Paulo, Sorocaba, São Paulo, Brazil
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26
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Cunningham ET, Pichi F, Mahajan VB, Rosenbaum JT, Zierhut M. Genetics of Uveitis. Ocul Immunol Inflamm 2021; 29:215-218. [PMID: 33950774 DOI: 10.1080/09273948.2021.1910430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Emmett T Cunningham
- The Department of Ophthalmology, California Pacific Medical Center, San Francisco, California, USA.,The Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, USA.,The Francis I. Proctor Foundation, UCSF School of Medicine, San Francisco, California, USA
| | - Francesco Pichi
- Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates.,Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Vinit B Mahajan
- Omics Laboratory, Stanford University, Palo Alto, California, USA.,The Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA.,Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA
| | - James T Rosenbaum
- The Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon, USA.,The Department of Medicine, Oregon Health and Science University, Portland, Oregon, USA.,Legacy Devers Eye Institute, Portland, Oregon, USA
| | - Manfred Zierhut
- Centre for Ophthalmology, University Tuebingen, Tuebingen, Germany
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27
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In Vivo and In Vitro Impairments in T Helper Cell and Neutrophil Responses against Mucor irregularis in Card9 Knockout Mice. Infect Immun 2021; 89:IAI.00040-21. [PMID: 33649049 DOI: 10.1128/iai.00040-21] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 12/24/2022] Open
Abstract
Mucor irregularis is a frequently found fungus in Asia, especially China, and it causes primary cutaneous mucormycosis with a high rate of disfigurement. Caspase recruitment domain-containing protein 9 (Card9) is an essential adaptor molecule downstream of C-type lectin receptors. It mediates the activation of nuclear factor kappa B (NF-κB), regulates T helper 1 (Th1) and Th17 differentiation, and plays an important role in fungal immune surveillance. CARD9 deficiency correlates with the increased susceptibility to many fungal infections, including cutaneous mucormycosis caused by M. irregularis However, the underlying immunological mechanisms were not elucidated. Our study established a murine model of subcutaneous M. irregularis infection, and we isolated immune cells, including bone marrow-derived macrophages, bone marrow-derived dendritic cells, naive T cells, and neutrophils, from wild-type (WT) and Card9 knockout (Card9-/- ) mice to examine the antifungal effect of Card9 on M. irregularis in vivo and in vitro Card9-/- mice exhibited increased susceptibility to M. irregularis infection. Impaired local cytokine and chemokine production, NF-κB (p65) activation, and Th1/17 cell differentiation and partially impaired neutrophil-dependent antifungal immunity were observed in Card9-/- mice. This work enriches our knowledge of the relationship between CARD9 deficiency and mucormycosis.
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28
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Li S, Shao J, Lou G, Wu C, Liu Y, Zheng M. MiR-144-3p-mediated dysregulation of EIF4G2 contributes to the development of hepatocellular carcinoma through the ERK pathway. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:53. [PMID: 33526055 PMCID: PMC7852102 DOI: 10.1186/s13046-021-01853-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/21/2021] [Indexed: 12/13/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common cancers with high incidence and mortality. However, the underlying mechanisms of HCC still remain unclear. Eukaryotic translation initiation factors (eIFs) have a substantial effect on tumor development. In this study, we were aimed to investigate the role of eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) in HCC. Methods Western blot (WB) of 30 paired HCC tissues and tissue microarrays (TMAs) conducted by immunohistochemistry (IHC) in 89 paired HCC samples were performed to assess EIF4G2 expression. Clone formation, real-time cell analysis (RTCA), wound healing and transwell assays were adopted to evaluate the role of EIF4G2 on HCC cell proliferation, migration and invasion abilities. The function of EIF4G2 in HCC tumor growth was assessed in a xenograft nude mouse model in vivo. The regulation of EIF4G2 by miR-144-3p was performed by luciferase reporter assay and WB. Results The EIF4G2 protein was clearly upregulated in HCC tissues, and high EIF4G2 expression was closely related to HCC prognosis. EIF4G2 silencing could inhibit HCC cell growth and metastasis in vitro, and suppress tumorigenesis in vivo by repressing the ERK signaling pathway. The results of luciferase reporter assays, WB and IHC staining verified that EIF4G2 was negatively regulated by miR-144. And re-expression of EIF4G2 could partially reverse the inhibiting effect of miR-144 in HCC. Conclusion In summary, our study revealed the role of EIF4G2 in HCC development via the activation of the ERK pathway. We also found that EIF4G2 could be negatively regulated by the tumor suppressor miR-144. Our investigations indicated that EIF4G2 might be a promising therapeutic target in HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01853-6.
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Affiliation(s)
- Shuangshuang Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, China
| | - Jiajia Shao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, China
| | - Guohua Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, China
| | - Chao Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, China
| | - Yanning Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, China.
| | - Min Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, China.
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29
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Ji C, Yang Z, Zhong X, Xia J. The role and mechanism of CARD9 gene polymorphism in diseases. Biomed J 2020; 44:560-566. [PMID: 34690098 PMCID: PMC8640546 DOI: 10.1016/j.bj.2020.12.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/02/2020] [Accepted: 12/22/2020] [Indexed: 01/03/2023] Open
Abstract
CARD9 is a cytosolic adaptor in myeloid cells, has a critical role in inflammatory disorders, and provides a protective function against microbial pathogen, especially fungal infection. Recently, CARD9 polymorphisms are of interest, showing a positive correlation with the elevated risk of fungal infection, inflammatory bowel disease, and other autoimmune diseases. Mechanistically, CARD9 polymorphisms impair the activation of RelB, a subunit of non-canonical NF-κB, which lead to the reduced cytokine and chemokine production by innate immune cells. In addition, CARD9 polymorphisms show a defective neutrophil accumulation in infectious sites. Furthermore, CARD9 polymorphisms could alter the composition of the gut microbiome. In this review, we summarize the latest findings of CARD9 polymorphisms with respect to inflammatory diseases.
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Affiliation(s)
- Changxue Ji
- Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Preparatory Stage), Shanghai, China
| | - Zhiwen Yang
- Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Preparatory Stage), Shanghai, China
| | | | - Jindong Xia
- Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Preparatory Stage), Shanghai, China.
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30
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Zhang Y, Huang C, Song Y, Ma Y, Wan Z, Zhu X, Wang X, Li R. Primary Cutaneous Aspergillosis in a Patient with CARD9 Deficiency and Aspergillus Susceptibility of Card9 Knockout Mice. J Clin Immunol 2020; 41:427-440. [PMID: 33180249 DOI: 10.1007/s10875-020-00909-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 11/03/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE We describe a case of primary cutaneous aspergillosis caused by Aspergillus fumigatus, and elucidate the underlying genetic and immunological mechanisms. MATERIALS AND METHODS Routine clinical and laboratory investigations were performed. Whole-exome sequencing of the patient's DNA suggested the presence of a CARD9 mutation, which was confirmed by Sanger sequencing. Innate and adaptive immunological responses of patient-derived CARD9-deficient cells were evaluated with ELISA and flow cytometry. Cutaneous and pulmonary aspergillosis models were established in Card9 knockout (KO) mice, which were compared with wild-type and immunosuppressed mice, to explore the pathogenesis and Aspergillus susceptibility. RESULTS A 45-year-old man presented with a 37-year history of skin lesions on his face. A diagnosis of primary cutaneous aspergillosis was made through histopathology, immunohistochemistry, and tissue culture. Sanger sequencing of CARD9 showed a homozygous frame-shift mutation (c.819_820insG, p.D274fsX60), which led to the lack of CARD9 expression. Peripheral blood mononuclear cells from the patient showed selective impairment of proinflammatory cytokines, and Th1-, Th17-, and Th22-associated responses upon fungus-specific stimulation. The cutaneous aspergillosis model established in Card9 KO mice presented with persistent infection, with fungal germs and short hyphae in tissue, consistent with the patient's lesions. Skin lesions in immunosuppressed mice were more severe, and led to death. Unlike our patient, Card9 KO mice were relatively susceptible to pulmonary aspergillosis, with reasons to be investigated. CONCLUSIONS This is, to our knowledge, the first report that links cutaneous aspergillosis to CARD9 mutation. This work enriches both the phenotypic spectrum of CARD9 deficiencies and the genetic background of cutaneous aspergillosis.
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Affiliation(s)
- Yi Zhang
- Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.,Research Center for Medical Mycology, Peking University, Beijing, China.,Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.,National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Chen Huang
- Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.,Research Center for Medical Mycology, Peking University, Beijing, China.,Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.,National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Yinggai Song
- Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.,Research Center for Medical Mycology, Peking University, Beijing, China.,Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.,National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Yubo Ma
- Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.,Research Center for Medical Mycology, Peking University, Beijing, China.,Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.,National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Zhe Wan
- Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.,Research Center for Medical Mycology, Peking University, Beijing, China.,Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.,National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Xuejun Zhu
- Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.,Research Center for Medical Mycology, Peking University, Beijing, China.,Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China.,National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Xiaowen Wang
- Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China. .,Research Center for Medical Mycology, Peking University, Beijing, China. .,Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China. .,National Clinical Research Center for Skin and Immune Diseases, Beijing, China.
| | - Ruoyu Li
- Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China. .,Research Center for Medical Mycology, Peking University, Beijing, China. .,Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, China. .,National Clinical Research Center for Skin and Immune Diseases, Beijing, China.
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31
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CARD9 Deficiency in a Chinese Man with Cutaneous Mucormycosis, Recurrent Deep Dermatophytosis and a Review of the Literature. Mycopathologia 2020; 185:1041-1050. [PMID: 32865705 DOI: 10.1007/s11046-020-00487-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/18/2020] [Indexed: 12/26/2022]
Abstract
Deficiency of caspase recruitment domain-containing protein 9 (CARD9) is an autosomal recessive primary immunodeficiency disorder, which typically predisposes immunocompetent individuals to single fungal infections and multiple fungal infections are very rare. We study an otherwise healthy 48-year-old man, who had been admitted to our hospital diagnosed with deep dermatophytosis caused by Trichophyton rubrum for three times at 29, 33 and 48 years old, respectively. At the age of 39 years, he suffered from cutaneous mucormycosis due to Mucor irregularis. Moreover, he had a long history of superficial fungal diseases and occasional oral candidiasis. Whole-exome sequencing revealed two compound heterozygous splicing variants in CARD9 gene, c. 184 + 5 G > T and c. 951G > A, confirmed by Sanger sequencing. Patients with recurrent fungal infections especially invasive fungal infections in the absence of known immunodeficiencies should be tested for CARD9 mutations.
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32
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Primary immunodeficiencies and invasive fungal infection: when to suspect and how to diagnose and manage. Curr Opin Infect Dis 2020; 32:531-537. [PMID: 31567735 DOI: 10.1097/qco.0000000000000593] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
PURPOSE OF REVIEW Invasive fungal infections (IFIs) most often occur secondary to acquired immunodeficiency states such as transplantation, AIDS or immune-modulatory treatment for neoplastic and autoimmune disorders. Apart from these acquired conditions, several primary immunodeficiency disorders (PIDs) can present with IFIs in the absence of iatrogenic immunosuppression. This review highlights recent advances in our understanding of PIDs that cause IFIs, which may help clinicians in the diagnosis and management of such infections. RECENT FINDINGS A growing number of PIDs that cause varying combinations of invasive infections by commensal Candida, inhaled molds (primarily Aspergillus), Cryptococcus, Pneumocystis, endemic dimorphic fungi, dermatophytes, and/or agents of phaeohyphomycosis has uncovered the organ- and fungus-specific requirements for effective antifungal host defense in humans. Employing certain diagnostic algorithms tailored to the infecting fungus can facilitate the genetic diagnosis of the underlying PID, which has implications for the optimal management of affected patients. SUMMARY Heightened clinical suspicion is required for the diagnosis of underlying genetic defects in patients who develop IFIs in the absence of acquired immunodeficiency. Early initiation of antifungal therapy followed by long-term secondary prophylaxis is typically needed to achieve remission, but hematopoietic stem-cell transplantation may sometimes be necessary to promote immune restoration and infection control.
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33
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Song Y, Du M, Menezes da Silva N, Yang E, Vicente VA, Sybren de Hoog G, Li R. Comparative Analysis of Clinical and Environmental Strains of Exophiala spinifera by Long-Reads Sequencing and RNAseq Reveal Adaptive Strategies. Front Microbiol 2020; 11:1880. [PMID: 32849462 PMCID: PMC7412599 DOI: 10.3389/fmicb.2020.01880] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 07/16/2020] [Indexed: 12/19/2022] Open
Abstract
Exophiala spinifera, a capsule-producing black yeast, is overrepresented as agent of disseminated infection in humans with inherited dysfunction of the CARD9 gene. In a review of published caspase recruitment domain-containing protein 9 (CARD9) deficiency cases, black fungi were linked to mutations other than those prevalent in yeast and dermatophyte cases, and were found to respond to a larger panel of cytokines. Here, we sequenced and annotated the genomes of BMU 08022 from a patient with CARD9 deficiency and two environmental strains, BMU 00051 and BMU 00047. We performed genomic and transcriptomic analysis for these isolates including published black yeasts genomes, using a combination of long-read (PACBIO) and short-read (Illumina) sequencing technologies with a hybrid assembly strategy. We identified the virulence factors, fitness, and the major genetic and gene expression differences between the strains with RNAseq technology. Genome assembly reached sub-chromosome level with between 12,043 and 12,130 predicted genes. The number of indels identified in the clinical strain was higher than observed in environmental strains. We identify a relatively large core genome of 9,887 genes. Moreover, substantial syntenic rearrangements of scaffolds I and III in the CARD9-related isolate were detected. Seventeen gene clusters were involved in the production of secondary metabolites. PKS-cluster 17 was consistently found to be absent in the clinical strain. Comparative transcriptome analysis demonstrated that 16 single-copy genes were significantly differentially expressed upon incubation in brain-heart infusion broth vs. Sabouraud glucose broth. Most of the single-copy genes upregulated with Brain Heart Infusion (BHI) were transporters. There were 48 unique genes differentially expressed exclusively to the clinical strain in two different media, including genes from various metabolic processes and transcriptional regulation. Up-regulated genes in the clinical strain with Gene Ontology (GO) enrichment are mainly involved in transmembrane transport, biosynthetic process and metabolic process. This study has provided novel insights into understanding of strain-differences in intrinsic virulence of the species and indicated that intraspecific variability may be related to habitat choice. This indicates that strains of E. spinifera are differentially prone to cause infection in susceptible patient populations, and provides clues for future studies exploring the mechanisms of pathogenic and adaptive strategies of black yeasts in immunodeficient patients.
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Affiliation(s)
- Yinggai Song
- Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.,Research Center for Medical Mycology, Peking University, Beijing, China.,National Clinical Research Center for Skin and Immune Diseases, Beijing, China
| | - Minghao Du
- Peking University Health Science Center, Beijing, China
| | - Nickolas Menezes da Silva
- Microbiology, Parasitology and Pathology Post-Graduation Program, Department of Pathology, Federal University of Paraná, Curitiba, Brazil.,Center of Expertise in Mycology of Radboud University Medical Center, Canisius Wilhelmina Hospital, Nijmegen, Netherlands
| | - Ence Yang
- Peking University Health Science Center, Beijing, China
| | - Vania A Vicente
- Microbiology, Parasitology and Pathology Post-Graduation Program, Department of Pathology, Federal University of Paraná, Curitiba, Brazil
| | - G Sybren de Hoog
- Research Center for Medical Mycology, Peking University, Beijing, China.,Microbiology, Parasitology and Pathology Post-Graduation Program, Department of Pathology, Federal University of Paraná, Curitiba, Brazil.,Center of Expertise in Mycology of Radboud University Medical Center, Canisius Wilhelmina Hospital, Nijmegen, Netherlands
| | - Ruoyu Li
- Department of Dermatology and Venerology, Peking University First Hospital, Beijing, China.,Research Center for Medical Mycology, Peking University, Beijing, China.,National Clinical Research Center for Skin and Immune Diseases, Beijing, China
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34
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Puel A. Human inborn errors of immunity underlying superficial or invasive candidiasis. Hum Genet 2020; 139:1011-1022. [PMID: 32124012 DOI: 10.1007/s00439-020-02141-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 02/18/2020] [Indexed: 12/24/2022]
Abstract
Candida species, including C. albicans in particular, can cause superficial or invasive disease, often in patients with known acquired immunodeficiencies or iatrogenic conditions. The molecular and cellular basis of these infections in patients with such risk factors remained largely elusive, until the study of inborn errors of immunity clarified the basis of the corresponding inherited and "idiopathic" infections. Superficial candidiasis, also known as chronic mucocutaneous candidiasis (CMC), can be caused by inborn errors of IL-17 immunity. Invasive candidiasis can be caused by inborn errors of CARD9 immunity. In this chapter, we review both groups of inborn errors of immunity, and discuss the contribution of these studies to the deciphering of the critical mechanisms of anti-Candida immunity in patients with other conditions.
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Affiliation(s)
- Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Necker Branch, 75015, Paris, France. .,Imagine Institute, Paris University, 75015, Paris, France. .,St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, Rockefeller Branch, New York, NY, 10065, USA.
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35
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Erman B, Fırtına S, Aksoy BA, Aydogdu S, Genç GE, Doğan Ö, Bozkurt C, Fışgın T, Çipe FE. Invasive Saprochaete capitata Infection in a Patient with Autosomal Recessive CARD9 Deficiency and a Review of the Literature. J Clin Immunol 2020; 40:466-474. [PMID: 32020378 DOI: 10.1007/s10875-020-00759-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 01/22/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Autosomal recessive (AR) CARD9 deficiency is an inherited immune disorder which results in impaired innate immunity against various fungi. Superficial and invasive fungal infections, mainly caused by Candida or Trichophyton species, are the hallmark of CARD9 deficiency. Together with the increasing number of CARD9-deficient patients reported, different pathogenic fungal species have been described such as Phialophora, Exophiala, Corynespora, Aureobasidium, and Ochroconis. Saprochaete capitata is an opportunistic infectious agent in immunocompromised patients and is a common cause of invasive fungal disease in patients with hematological malignancies. In this study, we investigated the causative genetic defect in a patient with S. capitata fungal infection which disseminated to lymph nodes and common bile duct. METHODS The identification of the isolated yeast strain was made by direct microscopic examination and confirmed by internal transcribed spacer (ITS) sequencing. We applied whole exome sequencing to search for the disease-causing mutation. Sanger sequencing was used to validate the mutation in the patient and his parents. RESULTS S. capitata was isolated from the biopsy specimen as the causative microorganism responsible for the invasive fungal disease in the patient. Whole exome sequencing revealed a homozygous c.883C > T, (p.Q295*) mutation in CARD9, confirmed by Sanger sequencing. CONCLUSIONS This is the first report of invasive Saprochaete infection associated with autosomal recessive (AR) CARD9 deficiency in the literature and thereby further extends the spectrum of fungal diseases seen in these patients.
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Affiliation(s)
- Baran Erman
- Department of Molecular Biology and Genetics, Istinye University, Istanbul, Turkey.
- Institute of Child Health, Hacettepe University, 06100, Ankara, Turkey.
| | - Sinem Fırtına
- Department of Molecular Biology and Genetics, Istinye University, Istanbul, Turkey
| | - Başak Adaklı Aksoy
- Department of Pediatrics, Istinye University Faculty of Medicine, Istanbul, Turkey
| | - Selime Aydogdu
- Department of Hematology-Oncology, Medical Park Hospital, Istanbul, Turkey
| | - Gonca Erköse Genç
- Department of Medical Microbiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Öner Doğan
- Department of Pathology, Medical School of Koc University, Istanbul, Turkey
| | - Ceyhun Bozkurt
- Department of Pediatrics, Istinye University Faculty of Medicine, Istanbul, Turkey
| | - Tunç Fışgın
- Department of Pediatrics, Altınbaş University Faculty of Medicine, Istanbul, Turkey
| | - Funda Erol Çipe
- Department of Pediatrics, Istinye University Faculty of Medicine, Istanbul, Turkey
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36
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Van Den Rym A, Taur P, Martinez-Barricarte R, Lorenzo L, Puel A, Gonzalez-Navarro P, Pandrowala A, Gowri V, Safa A, Toledano V, Cubillos-Zapata C, López-Collazo E, Vela M, Pérez-Martínez A, Sánchez-Ramón S, Recio MJ, Casanova JL, Desai MM, Perez de Diego R. Human BCL10 Deficiency due to Homozygosity for a Rare Allele. J Clin Immunol 2020; 40:388-398. [PMID: 32008135 DOI: 10.1007/s10875-020-00760-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 01/23/2020] [Indexed: 12/30/2022]
Abstract
In 2014, a child with broad combined immunodeficiency (CID) who was homozygous for a private BCL10 allele was reported to have complete inherited human BCL10 deficiency. In the present study, we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986). The mutant allele was a loss-of-expression and loss-of-function allele. As with the previously reported patient, this patient had complete BCL10 deficiency. The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis. Cellular and immunological phenotypes were similar to those of the previous patient. TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected. Autosomal-recessive BCL10 deficiency should therefore be considered in children with CID.
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Affiliation(s)
- Ana Van Den Rym
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain
- Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain
- Interdepartmental Group of Immunodeficiencies, Madrid, Spain
| | - Prasad Taur
- Division of Immunology, Bai Jerbai Wadia Hospital for Children, Parel, Mumbai, 400012, India
| | - Rubén Martinez-Barricarte
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA
| | - Lazaro Lorenzo
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France
| | - Anne Puel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France
- Imagine Institute, University Paris Descartes, 75015, Paris, France
| | - Pablo Gonzalez-Navarro
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain
- Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain
- Interdepartmental Group of Immunodeficiencies, Madrid, Spain
| | - Ambreen Pandrowala
- Division of Immunology, Bai Jerbai Wadia Hospital for Children, Parel, Mumbai, 400012, India
| | - Vijaya Gowri
- Division of Immunology, Bai Jerbai Wadia Hospital for Children, Parel, Mumbai, 400012, India
| | - Amin Safa
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain
- Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain
- Interdepartmental Group of Immunodeficiencies, Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, 28040, Madrid, Spain
| | - Victor Toledano
- Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain
| | - Carolina Cubillos-Zapata
- Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain
- Center for Biomedical Research Network, CIBEres, Madrid, Spain
| | - Eduardo López-Collazo
- Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain
| | - Maria Vela
- Translational Research in Paediatric Oncology, Haematopoietic Stem Cell Transplantation, Cell Therapy, INGEMM-IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Antonio Pérez-Martínez
- Translational Research in Paediatric Oncology, Haematopoietic Stem Cell Transplantation, Cell Therapy, INGEMM-IdiPAZ, La Paz University Hospital, Madrid, Spain
- Department of Paediatric Haemato-oncology and Stem Cell Transplantation, La Paz University Hospital, Madrid, Spain
| | - Silvia Sánchez-Ramón
- Interdepartmental Group of Immunodeficiencies, Madrid, Spain
- Clinical Immunology Department, San Carlos Clinical Hospital, 28040, Madrid, Spain
| | - Maria J Recio
- Interdepartmental Group of Immunodeficiencies, Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, 28040, Madrid, Spain
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, 10065, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, 75015, Paris, France
- Imagine Institute, University Paris Descartes, 75015, Paris, France
- Paediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), 75015, Paris, France
- Howard Hughes Medical Institute, New York, NY, 10065, USA
| | - Mukesh M Desai
- Division of Immunology, Bai Jerbai Wadia Hospital for Children, Parel, Mumbai, 400012, India
| | - Rebeca Perez de Diego
- Laboratory of Immunogenetics of Human Diseases, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain.
- Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, 28046, Madrid, Spain.
- Interdepartmental Group of Immunodeficiencies, Madrid, Spain.
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Inherited CARD9 Deficiency in a Patient with Both Exophiala spinifera and Aspergillus nomius Severe Infections. J Clin Immunol 2020; 40:359-366. [PMID: 31940125 DOI: 10.1007/s10875-019-00740-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 12/30/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Caspase-associated recruitment domain-9 (CARD9) deficiency is an inborn error of immunity that typically predisposes otherwise healthy patients to single fungal infections and the occurrence of multiple invasive fungal infections is rare. It has been described as the first known condition that predisposes to extrapulmonary Aspergillus infection with preserved lungs. We present a patient that expands the clinical variability of CARD9 deficiency. MATERIALS AND METHODS Genetic analysis was performed by Sanger sequencing. Neutrophils and mononuclear phagocyte response to fungal stimulation were evaluated through luminol-enhanced chemiluminescence and whole blood production of the proinflammatory mediator interleukin (IL)-6, respectively. RESULTS We report a 56-year-old Argentinean woman, whose invasive Exophiala spinifera infection at the age of 32 years was unexplained and reported in year 2004. At the age of 49 years, she presented with chronic pulmonary disease due to Aspergillus nomius. After partial improvement following treatment with caspofungin and posaconazole, right pulmonary bilobectomy was performed. Despite administration of multiple courses of antifungals, sustained clinical remission could not be achieved. We recently found that the patient's blood showed an impaired production of IL-6 when stimulated with zymosan. We also found that she is homozygous for a previously reported CARD9 loss-of-function mutation (Q289*). CONCLUSIONS This is the first report of a patient with inherited CARD9 deficiency and chronic invasive pulmonary aspergillosis (IPA) due to A. nomius. Inherited CARD9 deficiency should be considered in otherwise healthy children and adults with one or more invasive fungal diseases.
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38
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Complete clinical remission of invasive Candida infection with CARD9 deficiency after G-CSF treatment. Comp Immunol Microbiol Infect Dis 2020; 70:101417. [PMID: 32113042 DOI: 10.1016/j.cimid.2020.101417] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 12/19/2019] [Accepted: 01/03/2020] [Indexed: 01/09/2023]
Abstract
Caspase-associated recruitment domain-containing protein 9 (CARD9) deficiency is an autosomal-recessive primary immunodeficiency characterized by susceptibility to recurrent Candida infections, and its diagnosis and treatment is challenging. The present study aims to investigate the genetic characteristic and treatment strategy of a Chinese pediatric patient with CARD9 deficiency. In the present study, whole-exome sequencing (WES) was performed to screen the causal variants in a Chinese pediatric patient who exhibited an invasive Candida infection in the abdominal cavity and central nervous system. After the disease-causing gene being confirmed, the patient was treated with a combination of G-CSF and antifungal agents. DNA sequencing revealed a homozygous insertion mutation (c.819-820insG) in exon 6 of the CARD9 gene, which led to downstream amino acids conversion on codon 274 (p.D274fsX60). Th17 cell populations and cytokine levels showed decreased levels. The treatment regimen successfully resolved the patient's symptoms, and he remained symptom-free after more than 1 year of follow-up. This study described an invasive Candida infection in a pediatric patient and WES identified an insertion variant of the CARD9 gene. A combination of G-CSF and antifungal agents was highly effective in treating the invasive fungal infection accompanied by CARD9-induced immunodeficiency.
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Physiological and Pathological Functions of CARD9 Signaling in the Innate Immune System. Curr Top Microbiol Immunol 2020; 429:177-203. [PMID: 32415389 DOI: 10.1007/82_2020_211] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Caspase recruitment domain protein 9 (CARD9) forms essential signaling complexes in the innate immune system that integrate cues from C-type lectin receptors and specific intracellular pattern recognition receptors. These CARD9-mediated signals are pivotal for host defense against fungi, and they mediate immunity against certain bacteria, viruses and parasites. Furthermore, CARD9-regulated pathways are involved in sterile inflammatory responses critical for immune homeostasis and can control pro- and antitumor immunity in cancer microenvironments. Consequently, multiple genetic alterations of human CARD9 are connected to primary immunodeficiencies or prevalent inflammatory disorders in patients. This review will summarize our current understanding of CARD9 signaling in the innate immune system, its physiological and pathological functions and their implications for human immune-mediated diseases.
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Argersinger DP, Natkha VP, Shepard MJ, Thomas AA, Oler AJ, Williamson PR, Chittiboina P, Heiss JD. Intradural cauda equina Candida abscess presenting with hydrocephalus: case report. J Neurosurg Spine 2019; 31:890-893. [PMID: 31470401 PMCID: PMC7339489 DOI: 10.3171/2019.6.spine19271] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 06/25/2019] [Indexed: 11/06/2022]
Abstract
Central nervous system (CNS) candida infections are often associated with a poor prognosis. Typically, CNS candidiasis presents as meningitis or microabscesses. Here, the authors report a patient with a challenging presentation of a CNS Candida infection as a discrete, large cauda equina abscess. The patient initially presented with ventriculomegaly due to fourth ventricular outflow obstruction and a cauda equina mass. The patient was treated with a ventriculoperitoneal shunt and underwent a lumbar laminectomy for exploration of the lumbar lesion. An intradural abscess was encountered during surgery. Fungal wet mount revealed fungal elements and polymerase chain reaction confirmed the presence of Candida albicans. The patient did not have any known predisposition to fungal infections; therefore, the authors performed whole-exome sequencing using peripheral blood mononuclear cell DNA. They found heterozygous missense variants in the following genes: colony-stimulating factor 2 (CSF2) and Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1)-genes that have been specifically associated with protection from CNS candidiasis via caspase recruitment domain-containing protein 9 (CARD9) signaling, and phospholipase C gamma 2 (PLCG2)-a lectin receptor involved in candidiasis. The authors' experience suggests that C. albicans can present as a cauda equina abscess. Hydrocephalus, a result of diffuse arachnoiditis, is a potential complication from intradural fungal abscesses.
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Affiliation(s)
- Davis P. Argersinger
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
| | - Vitaliy P. Natkha
- Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, Texas
| | - Matthew J. Shepard
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Alissa A. Thomas
- University of Vermont Medical Center, Department of Neurological Sciences, Burlington, Vermont
| | - Andrew J. Oler
- Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
| | - Peter R. Williamson
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
| | - Prashant Chittiboina
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
- Neurosurgery Unit for Pituitary and Inheritable Disorders, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
| | - John D. Heiss
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
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Abstract
Purpose of review Fungal infections cause significant mortality in patients with acquired immunodeficiencies including AIDS, hematological malignancies, transplantation, and receipt of corticosteroids, biologics or small-molecule kinase inhibitors that impair key immune pathways. The contribution of several such pathways in antifungal immunity has been uncovered by inherited immunodeficiencies featuring profound fungal susceptibility. Furthermore, the risk of fungal infection in patients with acquired immunodeficiencies may be modulated by single nucleotide polymorphisms (SNPs) in immune-related genes. This review outlines key features underlying human genetic fungal predisposition. Recent findings The discovery of monogenic disorders that cause fungal disease and the characterization of immune-related gene SNPs that may regulate fungal susceptibility have provided important insights into how genetic variation affects development and outcome of fungal infections in humans. Summary Recognition of individualized genetic fungal susceptibility traits in humans should help devise precision-medicine strategies for risk assessment, prognostication and treatment of patients with opportunistic fungal infections.
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Nazarian RM, Lilly E, Gavino C, Hamilos DL, Felsenstein D, Vinh DC, Googe PB. Novel
CARD9
mutation in a patient with chronic invasive dermatophyte infection (tinea profunda). J Cutan Pathol 2019; 47:166-170. [DOI: 10.1111/cup.13574] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 07/10/2019] [Accepted: 08/16/2019] [Indexed: 12/01/2022]
Affiliation(s)
- Rosalynn M. Nazarian
- Department of PathologyMassachusetts General Hospital and Harvard Medical School Boston Massachusetts
| | - Evelyn Lilly
- Department of DermatologyMassachusetts General Hospital and Harvard Medical School Boston Massachusetts
| | - Christina Gavino
- Department of Medicine, McGill University Health Center, and Infectious Disease Susceptibility ProgramResearch Institute‐McGill University Health Centre Montreal Quebec Canada
| | - Daniel L. Hamilos
- Department of MedicineDivision of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School Boston Massachusetts
| | - Donna Felsenstein
- Department of MedicineInfectious Disease Unit, Massachusetts General Hospital and Harvard Medical School Boston Massachusetts
| | - Donald C. Vinh
- Department of Medicine, McGill University Health Center, and Infectious Disease Susceptibility ProgramResearch Institute‐McGill University Health Centre Montreal Quebec Canada
| | - Paul B. Googe
- Department of DermatologyUniversity of North Carolina at Chapel Hill Chapel Hill North Carolina
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Roussel L, Landekic M, Golizeh M, Gavino C, Zhong MC, Chen J, Faubert D, Blanchet-Cohen A, Dansereau L, Parent MA, Marin S, Luo J, Le C, Ford BR, Langelier M, King IL, Divangahi M, Foulkes WD, Veillette A, Vinh DC. Loss of human ICOSL results in combined immunodeficiency. J Exp Med 2019; 215:3151-3164. [PMID: 30498080 PMCID: PMC6279397 DOI: 10.1084/jem.20180668] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 09/21/2018] [Accepted: 11/06/2018] [Indexed: 12/30/2022] Open
Abstract
Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (ICOSLG; c.657C>G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSLN219K also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency.
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Affiliation(s)
- Lucie Roussel
- Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada
| | - Marija Landekic
- Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada
| | - Makan Golizeh
- Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada
| | - Christina Gavino
- Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada
| | - Ming-Chao Zhong
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada
| | - Jun Chen
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada
| | - Denis Faubert
- Proteomics Discovery Platform, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada
| | - Alexis Blanchet-Cohen
- Bioinformatics, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada
| | - Luc Dansereau
- Department of Internal Medicine, Hôpital de l'Archipel, Centre intégré de santé et de services sociaux des Îles, Les Îles-de-la-Madeleine, Québec, Canada
| | - Marc-Antoine Parent
- Department of Family Medicine, Centre intégé de santé et de services sociaux des Îles, Les Îles-de-la-Madeleine, Québec, Canada
| | - Sonia Marin
- Hôpital de l'Archipel, Centre intégré de santé et de services sociaux des Îles, Les Îles-de-la-Madeleine, Québec, Canada
| | - Julia Luo
- Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada
| | - Catherine Le
- Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada
| | - Brinley R Ford
- Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada
| | - Mélanie Langelier
- Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada
| | - Irah L King
- Meakins-Christie Laboratories, Research Institute-McGill University Health Centre, Montréal, Québec, Canada.,Department of Medicine, McGill University, Montréal, Québec, Canada
| | - Maziar Divangahi
- Meakins-Christie Laboratories, Research Institute-McGill University Health Centre, Montréal, Québec, Canada.,Department of Medicine, McGill University, Montréal, Québec, Canada.,Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
| | - William D Foulkes
- Department of Medical Genetics, Research Institute-McGill University Health Centre, Montréal, Québec, Canada.,Department of Human Genetics, McGill University, Montréal, Québec, Canada
| | - André Veillette
- Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada.,Department of Medicine, McGill University, Montréal, Québec, Canada.,Department of Medicine, University of Montréal, Montréal, Québec, Canada
| | - Donald C Vinh
- Infectious Disease Susceptibility Program, McGill University Health Centre and Research Institute-McGill University Health Centre, Montréal, Québec, Canada .,Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada.,Department of Human Genetics, McGill University, Montréal, Québec, Canada.,Department of Medicine, McGill University, Montréal, Québec, Canada
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Guo Y, Zhu Z, Gao J, Zhang C, Zhang X, Dang E, Li W, Qiao H, Liao W, Wang G, Ma C, Fu M. The Phytopathogenic Fungus Pallidocercospora crystallina-Caused Localized Subcutaneous Phaeohyphomycosis in a Patient with a Homozygous Missense CARD9 Mutation. J Clin Immunol 2019; 39:713-725. [PMID: 31414217 DOI: 10.1007/s10875-019-00679-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 07/29/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE In the past decade, an increasing number of otherwise healthy individuals suffered from invasive fungal infections due to inherited CARD9 mutations. Herein, we present a patient with a homozygous CARD9 mutation who was suffering from localized subcutaneous phaeohyphomycosis caused by the phytopathogenic fungus Pallidocercospora crystallina which has not been reported to cause infections in humans. METHODS The medical history of our patient was collected. P. crystallina was isolated from the biopsied tissue. To characterize this novel pathogen, the morphology was analyzed, whole-genome sequencing was performed, and the in vivo immune response was explored in mice. Whole-exome sequencing was carried out with samples from the patient's family. Finally, the expression and function of mutated CARD9 were investigated. RESULTS A dark red plaque was on the patient's left cheek for 16 years and was diagnosed as phaeohyphomycosis due to a P. crystallina infection. Whole-genome sequencing suggested that that this strain had a lower pathogenicity. The in vivo immune response in immunocompetent or immunocompromised mice indicated that P. crystallina could be eradicated within a few weeks. Whole-exome sequencing revealed ahomozygous missense mutation in CARD9 (c.1118G>C p.R373P). The mRNA and protein expression levels were similar among cells carrying homozygous (C/C), heterozygous (G/C), and wild-type (G/G) CARD9 alleles. Compared to PBMCs or neutrophils with heterozygous or wild-type CARD9 alleles, however, PBMCs or neutrophils with homozygous CARD9 alleles showed impaired anti-P. crystallina effects. CONCLUSION Localized subcutaneous phaeohyphomycosis caused by P. crystallina was reported in a patient with a homozygous CARD9 mutation. Physicians should be aware of the possibility of a CARD9 mutation in seemingly healthy patients with unexplainable phaeohyphomycosis.
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Affiliation(s)
- Yanyang Guo
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Zhenlai Zhu
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Jixin Gao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Chen Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Xiujun Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Erle Dang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Wei Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China.,Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Hongjiang Qiao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Wenjun Liao
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Gang Wang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Cuiling Ma
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China
| | - Meng Fu
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, 127 Changlexi Road, Xi'an, 710032, Shaanxi, People's Republic of China.
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45
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Hematopoietic Stem Cell Transplantation in CARD9 Deficiency: Knight in Shining Armor? J Clin Immunol 2019; 39:459-461. [DOI: 10.1007/s10875-019-00660-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 06/11/2019] [Indexed: 10/26/2022]
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46
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Chang CC, Levitz SM. Fungal immunology in clinical practice: Magical realism or practical reality? Med Mycol 2019; 57:S294-S306. [PMID: 31292656 PMCID: PMC7137463 DOI: 10.1093/mmy/myy165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 12/21/2018] [Accepted: 01/28/2019] [Indexed: 12/15/2022] Open
Abstract
Invasive fungal infections (IFIs) occur predominantly in immunocompromised individuals but can also be seen in previously well persons. The human innate immune system recognizes key components of the fungal cell wall as foreign resulting in a myriad of signaling cascades. This triggers release of antifungal molecules as well as adaptive immune responses, which kill or at least contain the invading fungi. However, these defences may fail in hosts with primary or secondary immunodeficiencies resulting in IFIs. Knowledge of a patient's immune status enables the clinician to predict the fungal infections most likely to occur. Moreover, the occurrence of an opportunistic mycosis in a patient without known immunocompromise usually should prompt a search for an occult immune defect. A rapidly expanding number of primary and secondary immunodeficiencies associated with mycoses has been identified. An investigative approach to determining the nature of these immunodeficiencies is suggested to help guide clinicians encountering patients with IFI. Finally, promising adjunctive immunotherapy measures are currently being investigated in IFI.
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Affiliation(s)
- Christina C Chang
- Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
| | - Stuart M Levitz
- Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, United States
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47
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Vinh DC. The molecular immunology of human susceptibility to fungal diseases: lessons from single gene defects of immunity. Expert Rev Clin Immunol 2019; 15:461-486. [PMID: 30773066 DOI: 10.1080/1744666x.2019.1584038] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Fungal diseases are a threat to human health. Therapies targeting the fungus continue to lead to disappointing results. Strategies targeting the host response represent unexplored opportunities for innovative treatments. To do so rationally requires the identification and neat delineation of critical mechanistic pathways that underpin human antifungal immunity. The study of humans with single-gene defects of the immune system, i.e. inborn errors of immunity (IEIs), provides a foundation for these paradigms. Areas covered: A systematic literature search in PubMed, Scopus, and abstracts of international congresses was performed to review the history of genetic resistance/susceptibility to fungi and identify IEIs associated with fungal diseases. Immunologic mechanisms from relevant IEIs were integrated with current definitions and understandings of mycoses to establish a framework to map out critical immunobiological pathways of human antifungal immunity. Expert opinion: Specific immune responses non-redundantly govern susceptibility to their corresponding mycoses. Defining these molecular pathways will guide the development of host-directed immunotherapies that precisely target distinct fungal diseases. These findings will pave the way for novel strategies in the treatment of these devastating infections.
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Affiliation(s)
- Donald C Vinh
- a Department of Medicine (Division of Infectious Diseases; Division of Allergy & Clinical Immunology), Department of Medical Microbiology, Department of Human Genetics , McGill University Health Centre - Research Institute , Montreal , QC , Canada
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48
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Ruland J, Hartjes L. CARD–BCL-10–MALT1 signalling in protective and pathological immunity. Nat Rev Immunol 2018; 19:118-134. [DOI: 10.1038/s41577-018-0087-2] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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49
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Vaezi A, Fakhim H, Abtahian Z, Khodavaisy S, Geramishoar M, Alizadeh A, Meis JF, Badali H. Frequency and Geographic Distribution of CARD9 Mutations in Patients With Severe Fungal Infections. Front Microbiol 2018; 9:2434. [PMID: 30369919 PMCID: PMC6195074 DOI: 10.3389/fmicb.2018.02434] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 09/24/2018] [Indexed: 12/12/2022] Open
Abstract
Autosomal recessive deficiency in the caspase recruitment domain containing protein 9 (CARD9) results in susceptibility to fungal infections. In the last decade, infections associated with CARD9 deficiency are more reported due to the advent of genome sequencing. The aim of this study was to evaluate the frequency, geographic distribution and nature of mutations in patients with CARD9 deficiency. We identified 60 patients with 24 mutations and different fungal infections. The presence of the homozygous (HMZ) p.Q295X (c.883C > T) and HMZ p.Q289X (c.865C > T) mutations were associated with an elevated risk of candidiasis (OR: 1.6; 95% CI: 1.18–2.15; p = 0.004) and dermatophytosis (OR: 1.85; 95% CI: 1.47–2.37; p < 0.001), respectively. The geographical distribution differed, showing that the main mutations in African patients were different Asian patients; HMZ p.Q289X (c.865C > T) and HMZ p.Q295X (c.865C > T) accounted for 75% and 37.9% of the African and Asian cases, respectively. The spectrum of CARD9 mutations in Asian patients was higher than in African. Asia is the most populous continent in the world and may have a greater genetic burden resulting in more patients with severe fungal infections. The presence of a high diversity of mutations revealing 24 distinct variations among 60 patients emphasize that the unique genetic alteration in CARD9 gene may be associated with certain geographical areas.
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Affiliation(s)
- Afsane Vaezi
- Department of Medical Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hamed Fakhim
- Department of Medical Parasitology and Mycology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Zahra Abtahian
- Infectious Disease and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sadegh Khodavaisy
- Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Geramishoar
- Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahad Alizadeh
- Department of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, Academic Center for Education, Culture and Research, Tehran, Iran
| | - Jacques F Meis
- Department of Medical Microbiology and Infectious Diseases, ECMM Excellence Center for Medical Mycology, Canisius-Wilhelmina Hospital, Nijmegen, Netherlands.,Centre of Expertise in Mycology Radboudumc/CWZ, Nijmegen, Netherlands
| | - Hamid Badali
- Department of Medical Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Invasive Fungi Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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50
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Arango-Franco CA, Moncada-Vélez M, Beltrán CP, Berrío I, Mogollón C, Restrepo A, Trujillo M, Osorio SD, Castro L, Gómez LV, Muñoz AM, Molina V, Del Río Cobaleda DY, Ruiz AC, Garcés C, Alzate JF, Cabarcas F, Orrego JC, Casanova JL, Bustamante J, Puel A, Arias AA, Franco JL. Early-Onset Invasive Infection Due to Corynespora cassiicola Associated with Compound Heterozygous CARD9 Mutations in a Colombian Patient. J Clin Immunol 2018; 38:794-803. [PMID: 30264381 DOI: 10.1007/s10875-018-0549-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 09/11/2018] [Indexed: 12/28/2022]
Abstract
PURPOSE CARD9 deficiency is an inborn error of immunity that predisposes otherwise healthy humans to mucocutaneous and invasive fungal infections, mostly caused by Candida, but also by dermatophytes, Aspergillus, and other fungi. Phaeohyphomycosis are an emerging group of fungal infections caused by dematiaceous fungi (phaeohyphomycetes) and are being increasingly identified in patients with CARD9 deficiency. The Corynespora genus belongs to phaeohyphomycetes and only one adult patient with CARD9 deficiency has been reported to suffer from invasive disease caused by C. cassiicola. We identified a Colombian child with an early-onset, deep, and destructive mucocutaneous infection due to C. cassiicola and we searched for mutations in CARD9. METHODS We reviewed the medical records and immunological findings in the patient. Microbiologic tests and biopsies were performed. Whole-exome sequencing (WES) was made and Sanger sequencing was used to confirm the CARD9 mutations in the patient and her family. Finally, CARD9 protein expression was evaluated in peripheral blood mononuclear cells (PBMC) by western blotting. RESULTS The patient was affected by a large, indurated, foul-smelling, and verrucous ulcerated lesion on the left side of the face with extensive necrosis and crusting, due to a C. cassiicola infectious disease. WES led to the identification of compound heterozygous mutations in the patient consisting of the previously reported p.Q289* nonsense (c.865C > T, exon 6) mutation, and a novel deletion (c.23_29del; p.Asp8Alafs10*) leading to a frameshift and a premature stop codon in exon 2. CARD9 protein expression was absent in peripheral blood mononuclear cells from the patient. CONCLUSION We describe here compound heterozygous loss-of-expression mutations in CARD9 leading to severe deep and destructive mucocutaneous phaeohyphomycosis due to C. cassiicola in a Colombian child.
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Affiliation(s)
- Carlos A Arango-Franco
- Grupo de Inmunodeficiencias Primarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia.,Escuela de Microbiología, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia
| | - Marcela Moncada-Vélez
- Grupo de Inmunodeficiencias Primarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia
| | - Claudia Patricia Beltrán
- Departamento de Pediatría, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia
| | - Indira Berrío
- Medical and Experimental Mycology Group, Corporación para Investigaciones Biológicas (CIB), Medellín, Colombia.,Hospital General de Medellín "Luz Castro de Gutiérrez" ESE, Medellín, Colombia
| | - Cristian Mogollón
- Infectología, Hospital Universitario Fernando Troconnis, Santa Marta, Colombia
| | | | | | - Sara Daniela Osorio
- Grupo de Inmunodeficiencias Primarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia.,Escuela de Microbiología, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia
| | - Lorena Castro
- Grupo de Inmunodeficiencias Primarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia.,Escuela de Microbiología, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia
| | - Lina Vanessa Gómez
- Hospital Pablo Tobón Uribe, Medellín, Colombia.,Servicio de Dermatología, Universidad Pontificia Bolivariana, Medellín, Colombia
| | - Ana María Muñoz
- Servicio de Dermatología, Universidad Pontificia Bolivariana, Medellín, Colombia
| | - Verónica Molina
- Hospital Pablo Tobón Uribe, Medellín, Colombia.,Servicio de Dermatología, Universidad Pontificia Bolivariana, Medellín, Colombia
| | | | | | - Carlos Garcés
- Departamento de Pediatría, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia.,Hospital Pablo Tobón Uribe, Medellín, Colombia
| | - Juan Fernando Alzate
- Centro Nacional de Secuenciación Genómica CNSG, Facultad de Medicina, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia
| | - Felipe Cabarcas
- Centro Nacional de Secuenciación Genómica CNSG, Facultad de Medicina, Universidad de Antioquia UdeA, Calle 70 No 52-21, Medellín, Colombia.,Grupo SISTEMIC, Facultad de Ingeniería, Universidad de Antioquia UdeA , Calle 70 No 52-21, Medellín, Colombia
| | - Julio Cesar Orrego
- Grupo de Inmunodeficiencias Primarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Paris, EU, France.,Imagine Institute, Paris Descartes University, Paris, EU, France.,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.,Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.,Howard Hughes Medical Institute, New York, NY, USA
| | - Jacinta Bustamante
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Paris, EU, France.,Imagine Institute, Paris Descartes University, Paris, EU, France.,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.,Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, EU, France
| | - Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM-U1163, Paris, EU, France.,Imagine Institute, Paris Descartes University, Paris, EU, France.,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
| | - Andrés Augusto Arias
- Grupo de Inmunodeficiencias Primarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia. .,Escuela de Microbiología, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia.
| | - José Luis Franco
- Grupo de Inmunodeficiencias Primarias, Universidad de Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia
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