Whatʼs New from Juntendo University, Tokyo Juntendo Medical Journal 2016. 62(4), 295-297

Peking University - Juntendo University Joint Symposium on Brain and Skin Diseases Rare Fungal Infections: What Should We Know?

RUOYU LI＊1) 2),XIAOWEN WANG＊1) 2)

＊1)Department of Dermatology, Peking University First Hospital, Beijing, China, ＊2)Research Center for Medical Mycology, Peking University, Beijing, China

Rare fungal infections sometimes are recalcitrant and life-threatening, which bring a big challenge to the clinical management. Recent studies of chronic mucocutaneous candidasis, deep and some dematiaceous fungal infections have led to many breakthroughs in our understanding of host defense against fungal infections. This review summarizes important findings, including the authorʼs recent work, of crucial mechanisms that predispose some rare cutaneous fungal infections, including Dectin-1 deficiency, CARD9 deficiency, and STAT1 gain-of-function mutations. Key words: CMC, Dectin-1, CARD9, STAT1, Th17 cells

Introduction involved in antifungal immunity, which shape different downstream signaling and adaptive Fungi are associated with a wide spectrum of immune responses, especially T helper responses 1). diseases in humans, with increasing morbidity and This review summarizes important findings, includ- mortality. Rare fungal infections, especially some ing our recent work, of crucial mechanisms that recalcitrant or life-threatening infections that occur predispose to some rare fungal infections, including in otherwise healthy hosts, pose serious challenges Dectin-1 deficiency, CARD9 deficiency, and STAT1 to our clinical work. Therefore, it is of great gain-of-function mutations. importance to elucidate the genetic and immunolog- ical mechanisms underlying the susceptibility to Dectin-1 deficiency these rare fungal infections. Studies from the past decade have led to many Dectin-1 is one of the CLRs families, which breakthroughs in our understanding of host defense express on myeloid cells and recognize fungal against fungal infections. The innate immune β-glucan, triggering phagocytosis and production of system is the first line of defense against pathogens inflammatory cytokines. Dectin-1 deficiency is a and broadly protects against invading microorgan- mild immunodeficiency that was described in a isms. Pattern-recognition receptors (PRRs) exist Dutch family with 3 affected sisters presenting with on innate cells to recognize conserved pathogen- recurrent vulvo-vaginal , chronic ony- associated molecular patterns (PAMPs) from fungi. chomycosis, or both 2). A homozygous nonsense Among those PRRs, Toll-like receptors (TLRs) and mutation (Y238X) in Dectin-1 resulted in the loss of C-type lectin receptors (CLRs) are the major PRRs a cysteine bond, which was predicted to disrupt

Corresponding author: Ruoyu Li Department of Dermatology, Peking University First Hospital 8 Xishiku St, Xicheng, Beijing 100034, China TEL: +8610-83573056 FAX: +8610-66155335 E-mail: [email protected] 〔Received May 12, 2016〕

Copyright © 2016 The Juntendo Medical Society. This is an open access article distributed under the terms of Creative Commons Attribution Li- cense (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original source is properly credited. doi: 10.14789/jmj.62.295

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correct protein folding. As a consequence, cell- mutations 7). We showed patients with marked surface expression of the mutated receptor and the decreased Th17 cells and impaired cytokine capability to bind β-glucan or was responses against P. verrucosa. Our study linked, lost. Both monocytes and macrophages from for the first time, CARD9 deficiencies with suscepti- patients showed poor in vitro production of IL-6, bility to opportunistic filamentous fungi. Later on, IL-17, and TNF-α on stimulation with β-glucan, idiopathic deep dermatophytosis and invasive C. albicans yeast, or hyphae elements. Later, Y238X exophiala infections have also been reported in AR was shown as a polymorphism with a heterozygos- CARD9-deficient patients, underscoring the impor- ity frequency of up to 40% in some populations. This tance of CARD9- dependent pattern recognition early stop codon SNPhas further been shown to be signaling in both mucocutaneous and invasive associated with increased Candida colonization in a antifungal host defense. cohort of patients with HSCT 3), but not with systemic candidiasis, in a case- control study of STAT1 mutations patients with candidemia 4). Signal transducer and activator of transcription 1 CARD9 deficiency (STAT1), one of the 7 transcription factors of the STAT family, is the major signaling molecule Caspase recruitment domain-containing protein downstream of the type I and type II interferon 9 (CARD9) is a key adaptor molecule expressed in (IFN) receptors. When IFN-γ binds to its receptor, myeloid cells downstream of the pattern recogni- it causes the dimerization of the two receptor tion receptors (PRRs) that recognize fungal cell subunits and phosphorylation of Janus kinase wall components and subsequently activate spleen (JAK) 1 and JAK2. The activated JAKs phospho- tyrosine kinase (Syk). After phosphorylation, rylate IFN-γR1, followed by recruitment and CARD9 binds B-cell lymphoma 10 (BCL10) and activation of STAT1. By forming a homodimer, mucosa-associated lymphoid tissue lymphoma STAT1 translocates to the nucleus and triggers translocation gene 1 (MALT1) to form the CBM the transcription of IFN-γ-inducible genes, which complex, resulting in nuclear factor kappa B plays a pivotal role in the defense against intra- (NF-κB) activation and innate antifungal immun- cellular pathogens. ity, thereby triggering the differentiation of naive T Heterozygous missense mutations in STAT1 cells into T-helper (Th) 17 cells. were first reported in 2011 in 14 patients with Chronic mucocutaneous candidasis (CMC) is a autosomal dominant CMC from 5 families 8), and 12 primary immunodeficiency that generally manifests different heterozygous STAT1 coiled-coil domain itself as recurrent or persistent oral thrush, and (CCD) missense mutations in 47 patients from 20 . In 2009, a homozygous loss-of- families 9). All the mutations were shown to be function nonsense mutation in CARD9 was gain-of-function, leading to accumulation of phos- reported in 4 patients from a large consanguineous phorylated STAT1 in the nucleus. Persistently family with CMC 5). The Q295X mutation resulted in activated STAT1 may shift the immune response a premature stop codon in the coiled-coil domain of from STAT3-mediated Th17 cells generation, CARD9 and in the lack of CARD9 expression. which is crucial for the antifungal defense of skin Patients showed reduced TNF-α production and and mucosa, towards STAT1-dependent Th17 low numbers of IL-17 producing T cells. Recently, inhibiting responses. Due to the high frequency of AR CARD9 deficiencies were also discovered in mutations, all patients suspected of CMC are patients with Candida meningoencephalitis 6). Apart suggested to first sequence for STAT1 mutations from the reduced numbers of Th17 lymphocytes, nowadays. Up till now, more than 123 CMC patients CARD9-deficient neutrophils showed a selective with 32 different STAT1 variants have been C. albicans killing defect 6). reported in the literature. The majority of In 2014, we reported 4 Chinese patients with GOF-STAT1 mutations are confirmed to be in the subcutaneous phaeohyphomycosis caused by CCD, with 22 variants in 98 patients reported, verrucosa, a black , with CARD9 whereas 10 variants involving 25 patients in the

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DNA-binding domain (DBD) were also described. References We also ascertained seven patients of Han ethnic groups in China with different clinical manifesta- 1) Romani L: Immunity to fungal infections. Nat Rev tions of CMC harboring novel and recurrent Immunol, 2011; 11: 275-288. 2) Ferwerda B, Ferwerda G, Plantinga TS, et al: Human STAT1 mutations recently. dectin-1 deficiency and mucocutaneous fungal infec- In 2013, we reported a case of a 7-year-old girl tions. N Engl J Med, 2009; 361: 1760-1767. with cutaneous fusariosis recalcitrant to therapy. 3) Plantinga TS, van der Velden WJ, Ferwerda B, et al: Early stop polymorphism in human DECTIN-1 is By using exome sequencing for this patient, we associated with increased candida colonization in identified a de novo missense mutation in the hematopoietic stem cell transplant recipients. Clin Infect STAT1 gene 10). This is the first link of primary Dis, 2009; 49: 724-732. 4) Rosentul DC, Plantinga TS, Oosting M, et al: Genetic cutaneous opportunistic fungal infections due to variation in the dectin-1/CARD9 recognition pathway Fusarium solani with the STAT1 mutation. GOF and susceptibility to candidemia. J Infect Dis, 2011; 204: mutation of STAT1 is also associated with a spec- 1138-1145. 5) Glocker EO, Hennigs A, Nabavi M, et al: A homozygous trum of other fungal infections, such as dissemi- CARD9 mutation in a family with susceptibility to fungal nated and , infections. N Engl J Med, 2009; 361: 1727-1735. Penicillium marneffei infections, and disseminated 6) Drewniak A, Gazendam RP, Tool AT, et al: Invasive fungal infection and impaired neutrophil killing in , highlighting the pivotal role of human CARD9 deficiency. Blood, 2013; 121: 2385-2392. STAT1 in fungal infections. 7) Wang X, Wang W, Lin Z, et al: CARD9 mutations linked to subcutaneous phaeohyphomycosis and TH17 cell deficiencies. J Allergy Clin Immunol, 2014; 133: 905-908 Conclusion e3. 8) van de Veerdonk FL, Plantinga TS, Hoischen A, et al: Rare fungal infections, especially those with early STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med, 2011; 365: onset and recalcitrant feature, are rare but impor- 54-61. tant, which have hugely promoted our understand- 9) Puel A, Cypowyj S, Bustamante J, et al: Chronic ing of immunological pathways involved in human mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science, 2011; 332: antifungal immunity. Of course, there are still a 65-68. large number of questions yet to be deciphered. We 10) Wang X, Lin Z, Gao L, et al: 2013; Exome sequencing believe that collaborations from the field of derma- reveals a signal transducer and activator of transcription 1 (STAT1) mutation in a child with recalcitrant tology, microbiology, genetics, immunology and cutaneous fusariosis. J Allergy Clin Immunol, 2013; 131: systems biology will provide new insight into it, to 1242-1243. develop the novel and personalized immunothera- peutic strategies in the near future.

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