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Matthew Wagener, J Claire Hoving, Hlumani Ndlovu, Mohlopheni J Marakalala
One of the first steps toward mounting an effective immune response to Mycobacterium tuberculosis (Mtb) is recognition of the pathogen through pattern-recognition receptors (PRRs) expressed by innate immune cells. Activation of the PRR Dectin-1 by an unknown mycobacterial ligand triggers an intracellular signaling cascade involving numerous proteins, including spleen tyrosine kinase, protein kinase C-delta, and caspase recruitment domain family member 9, some of which have been shown to influence host immune response to TB infection...
2018: Frontiers in Immunology
Nikita H Trivedi, Jieh-Juen Yu, Chiung-Yu Hung, Richard P Doelger, Christopher S Navara, Lisa Y Armitige, Janakiram Seshu, Anthony P Sinai, James P Chambers, M Neal Guentzel, Bernard P Arulanandam
Macrophages are important innate immune cells that respond to microbial insults. In response to multi-bacterial infection, the macrophage activation state may change upon exposure to nascent mediators, which results in different bacterial killing mechanism(s). In this study, we utilized two respiratory bacterial pathogens, Mycobacterium bovis (Bacillus Calmette Guẻrin, BCG) and Francisella tularensis live vaccine strain (LVS) with different phagocyte evasion mechanisms, as model microbes to assess the influence of initial bacterial infection on the macrophage response to secondary infection...
January 1, 2018: Innate Immunity
Sitang Maknitikul, Natthanej Luplertlop, Urai Chaisri, Yaowapa Maneerat, Sumate Ampawong
Plasmodium falciparum, the most virulent malaria parasite species, causes severe symptoms especially acute lung injury (ALI), of which characterized by alveolar epithelium and endothelium destruction and accelerated to blood-gas-barrier breakdown. Parasitized erythrocytes, endothelial cells, monocytes, and cytokines are all involved in this mechanism, but hemozoin (HZ), the parasitic waste from heme detoxification, also mainly contributes. In addition, it is not clear why type II pneumocyte proliferation, alveolar restorative stage, is rare in malaria-associated ALI...
January 1, 2018: Experimental Biology and Medicine
Parisa Kalantari, Yoelkys Morales, Emily A Miller, Luis D Jaramillo, Holly E Ponichtera, Marcel A Wuethrich, Cheolho Cheong, Maria C Seminario, Joanne M Russo, Stephen C Bunnell, Miguel J Stadecker
The immunopathology caused by schistosome helminths varies greatly in humans and among mouse strains. A severe form of parasite egg-induced hepatic granulomatous inflammation, seen in CBA mice, is driven by Th17 cells stimulated by IL-1β and IL-23 produced by dendritic cells that express CD209a (SIGNR5), a C-type lectin receptor (CLR) related to human DC-SIGN. Here, we show that CD209a-deficient CBA mice display decreased Th17 responses and are protected from severe immunopathology. In vitro, CD209a augments the egg-induced IL-1β and IL-23 production initiated by the related CLRs Dectin-2 and Mincle...
January 30, 2018: Cell Reports
Xiaoming Zhong, Bin Chen, Liang Yang, Zhiwen Yang
CARD9 is a caspase recruitment domain-containing signaling protein that plays a critical role in innate and adaptive immunity. It has been widely demonstrated that CARD9 adaptor allows pattern recognition receptors to induce NF-κB and MAPK activation, which initiates a "downstream" inflammation cytokine cascade and provides effective protection against microbial invasion, especially fungal infection. Here our aim is to update existing paradigms and summarize the most recent findings on the CARD9 signaling pathway, revealing significant mechanistic insights into the pathogenesis of CARD9 deficiency...
January 19, 2018: Cell Death & Disease
Haiqi He, Ryan J Arsenault, Kenneth J Genovese, Casey Johnson, Michael H Kogut
Protein kinases act in coordination with phosphatases to control protein phosphorylation and regulate signaling pathways and cellular processes involved in nearly every functions of cell life. Salmonella are known to manipulate the host kinase network to gain entrance and survive inside host cells. The effect of Salmonella infection on the host kinase network has been studied in mammalian cells, but information is largely lacking in chicken immune cells. Our previous study indicated that chicken macrophage cells respond differentially to different Salmonella strains...
January 2018: Veterinary Immunology and Immunopathology
Yong Hyun Kim, Eui-Gil Jung, Kook-Il Han, Bharat Bhusan Patnaik, Hyun-Jung Kwon, Hyoun-Su Lee, Wan Jong Kim, Man-Deuk Han
The aim of this study was to determine, using murine RAW 264.7 macrophages, the immunomodulatory effect of extracellular β-glucan isolated from Pleurotus eryngii (PEBG) and its sulfated derivative (PEBG-S) on signaling molecules implicated in host innate immunity. β-Glucan was extracted and purified from the mycelial culture using optimal medium concentrations. It was then chemically converted to its sulfated form. Monosaccharide composition of β-glucan was characterized with p-aminobenzoic acid ethyl ester-derivatized sugars through highperformance liquid chromatography analysis...
2017: International Journal of Medicinal Mushrooms
Moe Shiokawa, Sho Yamasaki, Shinobu Saijo
Host immune systems are constantly engaged with fungal pathogens which are common in environments as well as in healthy human skin and mucosa. C-type lectin receptors (CLRs) are expressed in myeloid cells and play central roles in host defenses against fungal infections by coordinating innate and adaptive immune systems. Upon ligand binding, CLRs stimulate cellular responses by inducing the production of cytokines and reactive oxygen species via the Syk/CARD9 signaling pathway, leading to fungal elimination...
November 20, 2017: Current Opinion in Microbiology
Juan Li, Donald C Vinh, Jean-Laurent Casanova, Anne Puel
It has been estimated that there are at least 1.5 million fungal species, mostly present in the environment, but only a few of these fungi cause human disease. Most fungal diseases are self-healing and benign, but some are chronic or life-threatening. Acquired and inherited defects of immunity, including breaches of mucocutaneous barriers and circulating leukocyte deficiencies, account for most severe modern-day mycoses. Other types of infection typically accompany these fungal infections. More rarely, severe fungal diseases can strike otherwise healthy individuals...
November 9, 2017: Current Opinion in Microbiology
Changwei Wu, Guisen Li, Li Wang
Background: Immunoglobulin A nephropathy (IgAN), the most common form of primary glomerular diseases worldwide, is a complex multifactorial disease. Previous genome wide association studies (GWAS) reported that variants CARD9 and VAV3 genes were associated with immunoregulation and susceptibility to IgAN. In this study, we further validated the associations and explored the interaction effect of rs4077515 and rs17019602 in IgAN patients. Results: There was no significant correlation between the two variants and IgAN (P > 0...
September 29, 2017: Oncotarget
Xiaowen Wang, Ruijun Zhang, Weiwei Wu, Yinggai Song, Zhe Wan, Wenling Han, Ruoyu Li
Phaeohyphomycosis is a group of severe infections caused by dematiaceous fungi. We previously identified CARD9 deficiencies in four Chinese patients with phaeohyphomycosis caused by Phialophora verrucosa. In this study, we sought to identify the genetic and immunological mechanisms underlying rare dematiaceous fungal infections in three otherwise healthy patients with phaeohyphomycosis caused by Exophiala spinifera, Ochroconis musae, and Corynespora cassiicola. CARD9 sequencing in these patients revealed one novel mutation (p...
October 25, 2017: Journal of Investigative Dermatology
Elizaveta S Leshchiner, Jason S Rush, Michael A Durney, Zhifang Cao, Vlado Dančík, Benjamin Chittick, Huixian Wu, Adam Petrone, Joshua A Bittker, Andrew Phillips, Jose R Perez, Alykhan F Shamji, Virendar K Kaushik, Mark J Daly, Daniel B Graham, Stuart L Schreiber, Ramnik J Xavier
Advances in human genetics have dramatically expanded our understanding of complex heritable diseases. Genome-wide association studies have identified an allelic series of CARD9 variants associated with increased risk of or protection from inflammatory bowel disease (IBD). The predisposing variant of CARD9 is associated with increased NF-κB-mediated cytokine production. Conversely, the protective variant lacks a functional C-terminal domain and is unable to recruit the E3 ubiquitin ligase TRIM62. Here, we used biochemical insights into CARD9 variant proteins to create a blueprint for IBD therapeutics and recapitulated the mechanism of the CARD9 protective variant using small molecules...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
Christina Gavino, Sibylle Mellinghoff, Oliver A Cornely, Marija Landekic, Catherine Le, Melanie Langelier, Makan Golizeh, Susanna Proske, Donald C Vinh
BACKGROUND: CARD9 deficiency (CANDF2; OMIM# 212050) is an autosomal-recessive monogenic inborn error of immunity conferring susceptibility to invasive fungal diseases, including the very distinct syndrome of spontaneous central nervous system candidiasis, in which opportunistic yeasts of the genus Candida infect the central nervous system (either brain parenchyma and/or meninges) in the absence of trauma, chemotherapy or underlying systemic disease. METHODS: We present a patient with spontaneous endophthalmitis of the right eye due to Candida albicans; further investigations revealed concomitant cerebral abscess...
October 6, 2017: Mycoses
Hong Liu, Zhenzhen Wang, Yi Li, Gongqi Yu, Xi'an Fu, Chuan Wang, Wenting Liu, Yongxiang Yu, Fangfang Bao, Astrid Irwanto, Jian Liu, Tongsheng Chu, Anand Kumar Andiappan, Sebastian Maurer-Stroh, Vachiranee Limviphuvadh, Honglei Wang, Zihao Mi, Yonghu Sun, Lele Sun, Ling Wang, Chaolong Wang, Jiabao You, Jinghui Li, Jia Nee Foo, Herty Liany, Wee Yang Meah, Guiye Niu, Zhenhua Yue, Qing Zhao, Na Wang, Meiwen Yu, Wenjun Yu, Xiujun Cheng, Chiea Chuen Khor, Kar Seng Sim, Tin Aung, Ningli Wang, Deyun Wang, Li Shi, Yong Ning, Zhongyi Zheng, Rongde Yang, Jinlan Li, Jun Yang, Liangbin Yan, Jianping Shen, Guocheng Zhang, Shumin Chen, Jianjun Liu, Furen Zhang
Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1...
December 2017: Journal of Investigative Dermatology
Huafeng Wang, Taek-Jin Lee, Scott J Fites, Richard Merkhofer, Robert Zarnowski, Tristan Brandhorst, Kevin Galles, Bruce Klein, Marcel Wüthrich
The development of vaccines against fungi and other intracellular microbes is impeded in part by a lack of suitable adjuvants. While most current vaccines against infectious diseases preferentially induce production of antibodies, cellular immunity is essential for the resolution of fungal infections. Microbes such as fungi and Mycobacterium tuberculosis require Th17 and Th1 cells for resistance, and engage the C-type lectin receptors including Dectin-2. Herein, we discovered a novel Dectin-2 ligand, the glycoprotein Blastomyces Eng2 (Bl-Eng2)...
August 2017: PLoS Pathogens
Bruno Lamas, Marie-Laure Michel, Nadine Waldschmitt, Hang-Phuong Pham, Vassiliki Zacharioudaki, Louise Dupraz, Myriam Delacre, Jane M Natividad, Gregory Da Costa, Julien Planchais, Bruno Sovran, Chantal Bridonneau, Adrien Six, Philippe Langella, Mathias L Richard, Mathias Chamaillard, Harry Sokol
OBJECTIVE: In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 (CARD9), a key innate immunity gene, is required to shape a normal gut microbiota. Card9(-/-) mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohaemorrhagic Escherichia coli. Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and microbiota-independent mechanisms...
August 8, 2017: Gut
Jin Hee Park, Jae Young Choi, Mir Faisal Mustafa, Hyun Ho Park
The caspase-associated recruitment domain (CARD)‑containing protein 9 (CARD9) signalosome is composed of CARD9, B‑cell CLL/lymphoma 10 (BCL10) and mucosa‑associated lymphoid tissue lymphoma translocation protein 1 (MALT1). The CARD9 signalosome has been reported to exert critical functions in the immunoreceptor tyrosine‑based activation motif‑coupled receptor‑mediated activation of myeloid cells, through nuclear factor‑κB pathways during innate immunity processes. During CARD9 signalosome assembly, BCL10 has been revealed to function as an adaptor protein and to interact with CARD9 via CARD‑CARD interactions; BCL10 also interacts with MALT1 via its C‑terminal Ser/Thr‑rich region and the first immunoglobulin domain of MALT1...
October 2017: Molecular Medicine Reports
B R Brown, E J Lee, P E Snow, E E Vance, Y Iwakura, N Ohno, N Miura, X Lin, G D Brown, C A Wells, J R Smith, R R Caspi, H L Rosenzweig
Uveitis (intraocular inflammation) is a leading cause of loss of vision. Although its aetiology is largely speculative, it is thought to arise from complex genetic-environmental interactions that break immune tolerance to generate eye-specific autoreactive T cells. Experimental autoimmune uveitis (EAU), induced by immunization with the ocular antigen, interphotoreceptor retinoid binding protein (IRBP), in combination with mycobacteria-containing complete Freund's adjuvant (CFA), has many clinical and histopathological features of human posterior uveitis...
December 2017: Clinical and Experimental Immunology
K Murata, Y Motomura, T Tanaka, S Kanno, T Yano, M Onimaru, A Shimoyama, H Nishio, Y Sakai, M Oh-Hora, H Hara, K Fukase, H Takada, S Masuda, S Ohga, S Yamasaki, T Hara
Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9)(-/-) and myeloid differentiation primary response gene 88 (MyD88)(-/-) mice...
October 2017: Clinical and Experimental Immunology
Emi Kanno, Kazuyoshi Kawakami, Hiromasa Tanno, Aiko Suzuki, Noriko Sato, Airi Masaki, Ayano Imamura, Naoyuki Takagi, Takayuki Miura, Hideki Yamamoto, Keiko Ishii, Hiromitsu Hara, Yoshimichi Imai, Ryoko Maruyama, Masahiro Tachi
The inflammatory response after skin injury involves the secretion of a variety of cytokines and growth factors that are necessary for tissue repair. Caspase recruitment domain-containing protein 9 (CARD9) is an essential signalling adaptor molecule for NF-κB activation upon triggering through C-type lectin receptors (CLRs), which are expressed in macrophages and dendritic cells. However, the role of CARD9 in inflammatory responses at the wound site has not been elucidated. In this study, we analysed the role of CARD9 in the healing process of skin wounds...
November 2017: Experimental Dermatology
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