scholarly journals Yersinia type III secretion

2002 ◽  
Vol 158 (3) ◽  
pp. 401-408 ◽  
Author(s):  
Guy R. Cornelis
Keyword(s):  
Immune System ◽  
Yersinia Pestis ◽  
Yersinia Enterocolitica ◽  
Type Iii Secretion ◽  
Molecular Mechanisms ◽  
Yersinia Pseudotuberculosis ◽  
Signaling Cascades ◽  
Host Immune System ◽  
Insight Into ◽  
Pathogenic Yersinia

Pathogenic Yersinia spp (Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica) have evolved an exquisite method for delivering powerful effectors into cells of the host immune system where they inhibit signaling cascades and block the cells' response to infection. Understanding the molecular mechanisms of this system has provided insight into the processes of phagocytosis and inflammation.

scholarly journals Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

2016 ◽  
Vol 96 (3) ◽  
pp. 805-829 ◽  
Author(s):  
Andreas Wicki ◽  
Mario Mandalà ◽  
Daniela Massi ◽  
Daniela Taverna ◽  
Huifang Tang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Immune System ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Therapeutic Strategies ◽  
Host Immune System ◽  
Cancer Therapies ◽  
Acquired Drug Resistance ◽  
Physiological Signal

Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.

scholarly journals The YopD Translocator of Yersinia pseudotuberculosis Is a Multifunctional Protein Comprised of Discrete Domains

2004 ◽  
Vol 186 (13) ◽  
pp. 4110-4123 ◽  
Author(s):  
Jan Olsson ◽  
Petra J. Edqvist ◽  
Jeanette E. Bröms ◽  
Åke Forsberg ◽  
Hans Wolf-Watz ◽  
...  
Keyword(s):  
Pore Formation ◽  
Molecular Mechanisms ◽  
Yersinia Pseudotuberculosis ◽  
Regulatory Control ◽  
Multifunctional Protein ◽  
Target Cell Membrane ◽  
Discrete Domains ◽  
Key Steps ◽  
Mutagenesis Study ◽  
Insight Into

ABSTRACT To establish an infection, Yersinia pseudotuberculosis utilizes a plasmid-encoded type III translocon to microinject several anti-host Yop effectors into the cytosol of target eukaryotic cells. YopD has been implicated in several key steps during Yop effector translocation, including maintenance of yop regulatory control and pore formation in the target cell membrane through which effectors traverse. These functions are mediated, in part, by an interaction with the cognate chaperone, LcrH. To gain insight into the complex molecular mechanisms of YopD function, we performed a systematic mutagenesis study to search for discrete functional domains. We highlighted amino acids beyond the first three N-terminal residues that are dispensable for YopD secretion and confirmed that an interaction between YopD and LcrH is essential for maintenance of yop regulatory control. In addition, discrete domains within YopD that are essential for both pore formation and translocation of Yop effectors were identified. Significantly, other domains were found to be important for effector microinjection but not for pore formation. Therefore, YopD is clearly essential for several discrete steps during efficient Yop effector translocation. Recognition of this modular YopD domain structure provides important insights into the function of YopD.

scholarly journals Immune System Stimulation by Oncolytic Rodent Protoparvoviruses

Viruses ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 415 ◽  
Author(s):  
Assia Angelova ◽  
Jean Rommelaere
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Immune System ◽  
Tumor Microenvironment ◽  
Immune Suppression ◽  
Molecular Mechanisms ◽  
Clinical Development ◽  
Host Immune System ◽  
Tumor Cell Death ◽  
Immunogenic Tumor Cell

Rodent protoparvoviruses (PVs), parvovirus H-1 (H-1PV) in particular, are naturally endowed with oncolytic properties. While being historically described as agents that selectively replicate in and kill cancer cells, recent yet growing evidence demonstrates that these viruses are able to reverse tumor-driven immune suppression through induction of immunogenic tumor cell death, and the establishment of antitumorigenic, proinflammatory milieu within the tumor microenvironment. This review summarizes the most important preclinical proofs of the interplay and the cooperation between PVs and the host immune system. The molecular mechanisms of PV-induced immunostimulation are also discussed. Furthermore, initial encouraging in-human observations from clinical trials and compassionate virus uses are presented, and speak in favor of further H-1PV clinical development as partner drug in combined immunotherapeutic protocols.

scholarly journals Proteogenomic discovery of sORF-encoded peptides associated with bacterial virulence in Yersinia pestis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Shiyang Cao ◽  
Xinyue Liu ◽  
Yin Huang ◽  
Yanfeng Yan ◽  
Congli Zhou ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Type Iii Secretion ◽  
Molecular Mechanisms ◽  
Bioinformatic Analysis ◽  
Bacterial Virulence ◽  
Functional Assay ◽  
Reading Frame ◽  
Noncoding Regions ◽  
Small Open Reading Frame ◽  
Shed Light

AbstractPlague caused by Yersinia pestis is one of the deadliest diseases. However, many molecular mechanisms of bacterial virulence remain unclear. This study engaged in the discovery of small open reading frame (sORF)-encoded peptides (SEPs) in Y. pestis. An integrated proteogenomic pipeline was established, and an atlas containing 76 SEPs was described. Bioinformatic analysis indicated that 20% of these SEPs were secreted or localized to the transmembrane and that 33% contained functional domains. Two SEPs, named SEPs-yp1 and -yp2 and encoded in noncoding regions, were selected by comparative peptidomics analysis under host-specific environments and high-salinity stress. They displayed important roles in the regulation of antiphagocytic capability in a thorough functional assay. Remarkable attenuation of virulence in mice was observed in the SEP-deleted mutants. Further global proteomic analysis indicated that SEPs-yp1 and -yp2 affected the bacterial metabolic pathways, and SEP-yp1 was associated with the bacterial virulence by modulating the expression of key virulence factors of the Yersinia type III secretion system. Our study provides a rich resource for research on Y. pestis and plague, and the findings on SEP-yp1 and SEP-yp2 shed light on the molecular mechanism of bacterial virulence.

scholarly journals Schistosomes alter expression of immunomodulatory gene products following in vivo praziquantel exposure

2020 ◽  
Author(s):  
Paul McCusker ◽  
Claudia M. Rohr ◽  
John D. Chan
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Host Immune System ◽  
Gene Products ◽  
Response To Chemotherapy ◽  
Kunitz Type ◽  
Insight Into ◽  
Immunomodulatory Gene

AbstractControl of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since the drug’s half-life is ∼2 hours, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate / humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy.Author SummaryThe disease schistosomiasis is caused by parasitic worms that live within the circulatory system. While this disease infects over 200 million people worldwide, treatment relies almost entirely on one drug, praziquantel, whose mechanism is poorly understood. In this study, we analyzed the effects of praziquantel treatment on the gene expression of parasites harvested from mice treated with praziquantel chemotherapy. Despite the rapid action of the drug on worms in vitro, we found that key outcomes in vivo (measurement of cell death and changes in gene expression) occurred relatively late (12+ hours after drug administration). We found that worms increased the expression of immunomodulatory gene products in response to praziquantel, including a Kunitz-type protease inhibitor that localized to the worm esophagus and may be secreted to the external host environment. These are an intriguing class of proteins, because they display anti-coagulant and immunomodulatory properties. Up-regulation of these gene products may reflect a parasite mechanism of immune-evasion in response to chemotherapy. This research provides insight into the mechanism of praziquantel by observing the effect of this drug on worms within the context of the host immune system.

scholarly journals Pseudogene accumulation might promote the adaptive microevolution of Yersinia pestis

2005 ◽  
Vol 54 (3) ◽  
pp. 259-268 ◽  
Author(s):  
Zongzhong Tong ◽  
Dongsheng Zhou ◽  
Yajun Song ◽  
Ling Zhang ◽  
Decui Pei ◽  
...  
Keyword(s):  
Phylogenetic Tree ◽  
Yersinia Pestis ◽  
Molecular Mechanisms ◽  
Yersinia Pseudotuberculosis ◽  
Screening Method ◽  
Wild Type ◽  
Natural Focus ◽  
Genome Sequences ◽  
Good Opportunity

Plague is a natural focus-based disease, and for better understanding of this disease it is crucial to determine the molecular mechanisms of its pathogen, Yersinia pestis, for adapting to different foci. Gene inactivation, loss and acquisition are the main mechanisms that contribute to a pathogen's fitness. Determination of the whole-genome sequences of three Y. pestis strains, CO92, KIM and 91001, provided a good opportunity to probe into its genome in minute detail. Many genetic variations were found between the three strains. The present work focused on adaptive microevolutionary analysis of Y. pestis from different natural plague foci in China based on pseudogene profiles. Twenty-four mutations that led to inactivation in the corresponding genes were analysed, and a PCR-based screening method was employed to investigate the distribution of these mutations among Y. pestis isolates from different foci and also among seven strains of Yersinia pseudotuberculosis. It was found that Y. pestis isolates from the same focus had identical mutation profiles, and 260 isolates of Y. pestis were divided into eight genotypes, while Y. pseudotuberculosis harboured wild-type alleles for all the mutations. The isolates of three known biovars were grouped into distinct branches in the phylogenetic tree, which supports the proposition that biovars mediaevalis and orientalis directly arose from biovar antiqua individually. The constructed phylogenetic tree suggests that the isolates from focus B should be the oldest lineage of Y. pestis in China except for isolates from foci L and M, which might be a special lineage of Y. pestis and originated differently to the others.

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