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Fiona Moghaddas, Ping Zeng, Yuxia Zhang, Heike Schützle, Sebastian Brenner, Sigrun R Hofmann, Reinhard Berner, Yuanbo Zhao, Bingtai Lu, Xiaoyun Chen, Li Zhang, Suyun Cheng, Stefan Winkler, Kai Lehmberg, Scott W Canna, Peter E Czabotar, Ian P Wicks, Dominic De Nardo, Christian M Hedrich, Huasong Zeng, Seth L Masters
BACKGROUND: Monogenic autoinflammatory disorders are characterised by dysregulation of the innate immune system, for example by gain-of-function mutations in inflammasome forming proteins such as NLRC4. OBJECTIVE: Here we investigate the mechanism by which a novel mutation in the leucine rich repeat (LRR) domain of NLRC4 (c.G1965C, p.W655C) contributes to autoinflammatory disease. METHODS: We studied two unrelated patients with early onset macrophage activation syndrome (MAS) harboring the same de novo mutation in NLRC4...
May 17, 2018: Journal of Allergy and Clinical Immunology
Jianhe Wang, Jing Wang, Lian-Hui Zhang
Pseudomonas aeruginosa is known to cause life-threatening infections. The previous studies showed that the type III secretion system (T3SS) of this pathogen is a key virulence determinant, which is activated by polyamines signals spermidine (Spd) and spermine (Spm) from mammalian host. To test the potential of blocking host-pathogen communication in disease control, in this study we developed a high potency mouse monoclonal antibody (Mab 4E4, IgG1 sub-isotype) by using Spm-protein conjugate as an immunogen...
May 14, 2018: Microbial Biotechnology
Yong Zhang, Yan Liu, Tingting Wang, Xuming Deng, Xiao Chu
The type III secretion system (T3SS) is a key virulence mechanism of many Gram-negative bacterial pathogens. Upon contact between bacteria and host cells, T3SS transfers a series of effectors from the bacterial cytosol to host cells. It is widely known that a mutation in T3SS does not impair bacterial growth, thereby avoiding any subsequent development of resistance. Thus, T3SS is expected to be a candidate therapeutic target. While developing the T3SS screening method, we discovered that sanguinarine chloride, a natural compound, could decrease the production of the SPI-1 type III secretion system main virulence proteins SipA and SipB and prevent the invasion of HeLa cells by Salmonella enterica serovar Typhimurium without affecting the growth of Salmonella...
July 2018: Biochemistry and Biophysics Reports
Jingyi Yang, Yue Zhao, Peng Li, Yi Yang, Ejuan Zhang, Maohua Zhong, Yaoming Li, Dihan Zhou, Yuan Cao, Mengji Lu, Feng Shao, Huimin Yan
The NLR apoptosis inhibitory proteins (NAIPs) function as specific cytosolic receptors for bacterial ligands to form the NAIP-NLRC4 inflammasome for anti-bacterial defenses. In mice, NAIP5/6 and NAIP2 recognize bacteria flagellin and the rod protein of the type III secretion system (T3SS), respectively. However, molecular mechanism for specific ligand pattern-recognition by the NAIPs is largely unknown. Here, through extensive domain swapping and truncation analyses, three structural domains, the pre-BIR, BIR1, and HD1, in NAIP2 and NAIP5 are identified, that are important for specific recognition of their respective ligand(s)...
2018: Cell Discovery
Sarp Bamyaci, Sofie Ekestubbe, Roland Nordfelth, Saskia F Erttmann, Tomas Edgren, Åke Forsberg
Type III Secretion Systems (T3SSs) are used by various Gram-negative pathogens to subvert the host defense by a host cell contact-dependent mechanism to secrete and translocate virulence effectors. While the effectors differ between pathogens and determine the pathogenic life style, the overall mechanism of secretion and translocation is conserved. T3SSs are regulated at multiple levels and some secreted substrates have also been shown to function in regulation. In Yersinia , one of the substrates, YopN, has long been known to function in the host cell contact-dependent regulation of the T3SS...
May 14, 2018: Infection and Immunity
Huaqin Ruan, Meijuan Hu, Jingyu Chen, Xue Li, Ting Li, Yongxiu Lai, En Tao Wang, Jun Gu
The distribution of rhcRST and rhcJ-C1 fragments located in different loci of the type III secretion system (T3SS) gene cluster in the peanut-nodulating bradyrhizobia isolated from Guangdong Province, China was investigated by PCR-based sequencing. T3SS was detected in approximately one-third of the peanut bradyrhizobial strains and the T3SS-harboring strains belonging to different Bradyrhizobium genomic species. Diverse T3SS groups corresponding to different symbiotic gene types were defined among the 23 T3SS-harboring strains...
April 8, 2018: Systematic and Applied Microbiology
Wei Liu, Yuanyuan Jiang, Jing Sun, Shizhong Geng, Zhiming Pan, Richard A Prinz, Chengming Wang, Jun Sun, Xinan Jiao, Xiulong Xu
Autophagy is a conserved cellular process that functions as a first-line defense to restrict the growth of invading parasitic bacteria. As an intracellular pathogen, Salmonella (S) Typhimurium invades host cells through two Type III secretion systems (T3SS) and resides in the Salmonella-containing vacuole (SCV). When the SCV membrane is perforated and ruptured by T3SS-1, a small portion of the Salmonella egresses from the SCV and replicates rapidly in the nutrient-rich cytosol. Cytosolic Salmonella and those residing in the membrane-damaged SCV are tagged by ubiquitination and marked for autophagy through the ubiquitin-binding adaptor proteins such as p62, NDP52, and optineurin...
May 11, 2018: Cell Death & Disease
Juan D Hernandez-Doria, Vanessa Sperandio
Bacteriophage-encoded genetic elements control bacterial biological functions. Enterohemorrhagic Escherichia coli (EHEC) strains harbor lambda-phages encoding the Shiga-toxin (Stx), which is expressed during the phage lytic cycle and associated with exacerbated disease. Phages also reside dormant within bacterial chromosomes through their lysogenic cycle, but how this impacts EHEC virulence remains unknown. We find that during lysogeny the phage transcription factor Cro activates the EHEC type III secretion system (T3SS)...
May 9, 2018: Cell Host & Microbe
Christina Kloth, Bastian Schirmer, Antje Munder, Tane Stelzer, Justin Rothschuh, Roland Seifert
The effector protein Exotoxin Y (ExoY) produced by Pseudomonas aeruginosa is injected via the type III secretion system (T3SS) into host cells. ExoY acts as nucleotidyl cyclase promoting the intracellular accumulation of cyclic nucleotides. To what extent nucleotidyl cyclase activity contributes to the pathogenicity of ExoY and which mechanisms participate in the manifestation of lung infection is still unclear. Here, we used an acute airway infection model in mice to address the role of ExoY in lung infection...
May 4, 2018: Toxins
Qiong Xing, Ke Shi, Athina Portaliou, Paolo Rossi, Anastassios Economou, Charalampos G Kalodimos
The flagellum and the injectisome enable bacterial locomotion and pathogenesis, respectively. These nanomachines assemble and function using a type III secretion system (T3SS). Exported proteins are delivered to the export apparatus by dedicated cytoplasmic chaperones for their transport through the membrane. The structural and mechanistic basis of this process is poorly understood. Here we report the structures of two ternary complexes among flagellar chaperones (FliT and FliS), protein substrates (the filament-capping FliD and flagellin FliC), and the export gate platform protein FlhA...
May 2, 2018: Nature Communications
Jingru Wang, Xiaolong Shao, Yingchao Zhang, Yanan Zhu, Pan Yang, Jian Yuan, Tingting Wang, Chunyan Yin, Wei Wang, Sheng Chen, Haihua Liang, Xin Deng
The type III secretion system (T3SS) is the main machinery for Pseudomonas syringae and other Gram-negative bacteria to invade plant cells. HrpR and HrpS form a hetero-hexamer, which activates the expression of HrpL that induces all T3SS genes by binding to a 'hrp box' in promoters. However, the individual molecular mechanism of HrpR or HrpS has not been fully understood. Through chromatin immunoprecipitation coupled to high-throughput DNA sequencing (ChIP-seq), we found that HrpR, HrpS, and HrpL had 4, 47, and 31 targets on the genome, respectively...
May 2, 2018: Molecular Plant-microbe Interactions: MPMI
Abby R Kroken, Camille K Chen, David J Evans, Timothy L Yahr, Suzanne M J Fleiszig
Pseudomonas aeruginosa is internalized into multiple types of epithelial cell in vitro and in vivo and yet is often regarded as an exclusively extracellular pathogen. Paradoxically, ExoS, a type three secretion system (T3SS) effector, has antiphagocytic activities but is required for intracellular survival of P. aeruginosa and its occupation of bleb niches in epithelial cells. Here, we addressed mechanisms for this dichotomy using invasive (ExoS-expressing) P. aeruginosa and corresponding effector-null isogenic T3SS mutants, effector-null mutants of cytotoxic P...
May 1, 2018: MBio
Chen Xu, Bao-Zhong Zhang, Qiubin Lin, Jian Deng, Bin Yu, Smriti Arya, Kwok-Yung Yuen, Jian-Dong Huang
BACKGROUND: Staphylococcus aureus (S. aureus) causes a wide range of infectious diseases in human and animals. The emergence of antibiotic-resistant strains demands novel strategies for prophylactic vaccine development. In this study, live attenuated S. enterica subsp. enterica serotype Typhimurium (S. Typhimurium) vaccine against S. aureus infection was developed, in which Salmonella Pathogenesis Island-1 Type 3 Secretion System (SPI-1 T3SS) was employed to deliver SaEsxA and SaEsxB, two of ESAT-6-like (Early Secreted Antigenic Target-6) virulence factors of S...
April 25, 2018: BMC Infectious Diseases
Sheo Shankar Pandey, Pradeep Kumar Patnana, Yasobanta Padhi, Subhadeep Chatterjee
Expression of hrp (hypersensitive reaction and pathogenicity) genes inside the host is crucial for virulence of phytopathogenic bacteria. The hrp genes encode components of type3 secretion system (T3SS), HR elicitors and several regulators, which are involved in the co-ordinated expression of hrp genes in the host environment and in hrp inducing chemically defined medium. However, little is known about specific host or environmental factors which may play a role in the induction of hrp gene expression. In this study, we show that iron-limiting condition elicits induced expression of hrp genes, including type3 secretion system (T3SS) and effectors (T3E)...
April 24, 2018: Environmental Microbiology Reports
Michael L Barta, Shoichi Tachiyama, Meenakumari Muthuramalingam, Olivia Arizmendi, Cecilia E Villanueva, Kasra X Ramyar, Brian V Geisbrecht, Scott Lovell, Kevin P Battaile, Wendy L Picking, William D Picking
Bacterial type III secretion systems (T3SS) are used to inject proteins into mammalian cells to subvert cellular functions. The Shigella T3SS apparatus (T3SA) is comprised of a basal body, cytoplasmic sorting platform and exposed needle with needle "tip complex" (TC). TC maturation occurs when the translocator protein IpaB is recruited to the needle tip where both IpaD and IpaB control secretion induction. IpaB insertion into the host membrane is the first step of translocon pore formation and secretion induction...
April 19, 2018: Protein Science: a Publication of the Protein Society
Heather B Case, Nicholas E Dickenson
Shigella rely entirely on the action of a single type three secretion system (T3SS) to support cellular invasion of colonic epithelial cells and to circumvent host immune responses. The ATPase Spa47 resides at the base of the Shigella needle-like type three secretion apparatus (T3SA), supporting protein secretion through the apparatus and providing a likely means for native virulence regulation by Shigella and a much needed target for non-antibiotic therapeutics to treat Shigella infections. Here, we show that MxiN is a differential regulator of Spa47 and that its regulatory impact is determined by the oligomeric state of the Spa47 ATPase, with which it interacts...
April 3, 2018: Biochemistry
Yongxin Jin, Ying Liu, Zhenpeng Li, Katherine Santostefano, Jing Shi, Xinwen Zhang, Donghai Wu, Zhihui Cheng, Weihui Wu, Naohiro Terada, Shouguang Jin, Fang Bai
Virus-mediated expression of defined transcription factor (TF) genes can effectively induce cellular reprogramming. However, sustained expression of the TFs often hinders pluripotent stem cell (PSC) differentiation into specific cell types, as each TF exerts its effect on PSCs for a defined period of time during differentiation. Here, we applied a bacterial type III secretion system (T3SS)-based protein delivery tool to directly translocate TFs in the form of protein into human PSCs. This transient protein delivery technique showed high delivery efficiency for hPSCs, and it avoids potential genetic alterations caused by the introduction of transgenes...
2018: PloS One
Rajendra Karki, Ein Lee, David Place, Parimal Samir, Jayadev Mavuluri, Bhesh Raj Sharma, Arjun Balakrishnan, R K Subbarao Malireddi, Rechel Geiger, Qifan Zhu, Geoffrey Neale, Thirumala-Devi Kanneganti
Inflammasome activation is critical for host defenses against various microbial infections. Activation of the NLRC4 inflammasome requires detection of flagellin or type III secretion system (T3SS) components by NLR family apoptosis inhibitory proteins (NAIPs); yet how this pathway is regulated is unknown. Here, we found that interferon regulatory factor 8 (IRF8) is required for optimal activation of the NLRC4 inflammasome in bone-marrow-derived macrophages infected with Salmonella Typhimurium, Burkholderia thailandensis, or Pseudomonas aeruginosa but is dispensable for activation of the canonical and non-canonical NLRP3, AIM2, and Pyrin inflammasomes...
March 16, 2018: Cell
Fei Ye, Fanli Yang, Ruijie Yu, Xi Lin, Jianxun Qi, Zhujun Chen, Yu Cao, Yuquan Wei, George F Gao, Guangwen Lu
The T3SS chaperone CesT is recently shown to interact with the post-transcriptional regulator CsrA to modulate post-attachment signaling in enteropathogenic and enterohemorrhagic Escherichia coli. The molecular basis of the CesT/CsrA binding, however, remains elusive. Here, we show that CesT and CsrA both created two ligand binding sites in their homodimers, forming irregular multimeric complexes in solution. Through construction of a recombinant CsrA-dimer (Re-CsrA) that contains a single CesT binding site, the atomic binding features between CesT and CsrA are delineated via the structure of the CesT/Re-CsrA complex...
March 22, 2018: Nature Communications
Doreen Baumann, Helen Salia, Lilo Greune, Stephanie Norkowski, Britta Körner, Zina M Uckeley, Gad Frankel, Marianne Guenot, Christian Rüter, M Alexander Schmidt
Enteropathogenic Escherichia coli (EPEC) subvert host cell signaling pathways by injecting effector proteins via a Type 3 Secretion System (T3SS). The T3SS-dependent EspB protein is a multi-functional effector protein, which contributes to adherence and translocator pore formation and after injection exhibits several intracellular activities. In addition, EspB is also secreted into the environment. Effects of secreted EspB have not been reported thus far. As a surrogate for secreted EspB we employed recombinant EspB (rEspB) derived from the prototype EPEC strain E2348/69 and investigated the interactions of the purified protein with different human epithelial and immune cells including monocytic THP-1 cells, macrophages, dendritic cells, U-937, epithelial T84, Caco-2, and HeLa cells...
March 12, 2018: International Journal of Medical Microbiology: IJMM
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