scholarly journals Legionnaires’ Disease: State of the Art Knowledge of Pathogenesis Mechanisms of Legionella

2020 ◽  
Vol 15 (1) ◽  
pp. 439-466 ◽  
Author(s):  
Sonia Mondino ◽  
Silke Schmidt ◽  
Monica Rolando ◽  
Pedro Escoll ◽  
Laura Gomez-Valero ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Severe Form ◽  
Effector Proteins ◽  
Future Research ◽  
Open Questions ◽  
Eukaryotic Origin ◽  
Legionella Species ◽  
Legionnaires Disease

Legionella species are environmental gram-negative bacteria able to cause a severe form of pneumonia in humans known as Legionnaires’ disease. Since the identification of Legionella pneumophila in 1977, four decades of research on Legionella biology and Legionnaires’ disease have brought important insights into the biology of the bacteria and the molecular mechanisms that these intracellular pathogens use to cause disease in humans. Nowadays, Legionella species constitute a remarkable model of bacterial adaptation, with a genus genome shaped by their close coevolution with amoebae and an ability to exploit many hosts and signaling pathways through the secretion of a myriad of effector proteins, many of which have a eukaryotic origin. This review aims to discuss current knowledge of Legionella infection mechanisms and future research directions to be taken that might answer the many remaining open questions. This research will without a doubt be a terrific scientific journey worth taking.

Creating a customized intracellular niche: subversion of host cell signaling byLegionellatype IV secretion system effectors

2015 ◽  
Vol 61 (9) ◽  
pp. 617-635 ◽  
Author(s):  
Ernest C. So ◽  
Corinna Mattheis ◽  
Edward W. Tate ◽  
Gad Frankel ◽  
Gunnar N. Schroeder
Keyword(s):  
Host Cell ◽  
Legionella Pneumophila ◽  
Current Knowledge ◽  
Secretion System ◽  
Effector Proteins ◽  
Cellular Processes ◽  
Type Iv ◽  
Open Questions ◽  
Exact Function ◽  
Wide Range

The Gram-negative facultative intracellular pathogen Legionella pneumophila infects a wide range of different protozoa in the environment and also human alveolar macrophages upon inhalation of contaminated aerosols. Inside its hosts, it creates a defined and unique compartment, termed the Legionella-containing vacuole (LCV), for survival and replication. To establish the LCV, L. pneumophila uses its Dot/Icm type IV secretion system (T4SS) to translocate more than 300 effector proteins into the host cell. Although it has become apparent in the past years that these effectors subvert a multitude of cellular processes and allow Legionella to take control of host cell vesicle trafficking, transcription, and translation, the exact function of the vast majority of effectors still remains unknown. This is partly due to high functional redundancy among the effectors, which renders conventional genetic approaches to elucidate their role ineffective. Here, we review the current knowledge about Legionella T4SS effectors, highlight open questions, and discuss new methods that promise to facilitate the characterization of T4SS effector functions in the future.

scholarly journals Legionella pneumophila LegC7 effector protein drives aberrant ER:endosome fusion in yeast

2020 ◽  
Author(s):  
Nathan K. Glueck ◽  
Kevin M. O’Brien ◽  
Vincent J. Starai
Keyword(s):  
Membrane Trafficking ◽  
Legionella Pneumophila ◽  
Molecular Mechanisms ◽  
Bacterial Pathogen ◽  
Severe Form ◽  
Effector Proteins ◽  
Effector Protein ◽  
Host Membrane ◽  
Membrane Tethering

AbstractLegionella pneumophila is a facultative intracellular bacterial pathogen, causing the severe form of pneumonia known as Legionnaires’ disease. Legionella actively alters host organelle trafficking through the activities of ‘effector’ proteins secreted via a TypeIVB secretion system, in order to construct the bacteria-laden Legionella-containing vacuole (LCV) and prevent lysosomal degradation. The LCV is derived from membrane derived from host ER, secretory vesicles, and phagosomes, although the precise molecular mechanisms that drive its synthesis remain poorly understood. In an effort to characterize the in vivo activity of the LegC7/YlfA SNARE-like effector protein from Legionella in the context of eukaryotic membrane trafficking in yeast, we find that LegC7 interacts with the Emp46p/Emp47p ER-to-Golgi glycoprotein cargo adapter complex, alters ER morphology, and induces aberrant ER:endosome fusion, as measured by visualization of ER cargo degradation, reconstitution of split-GFP proteins, and enhanced oxidation of the ER lumen. LegC7-dependent toxicity, disruption of ER morphology, and ER:endosome fusion events were dependent upon endosomal VPS class C tethering complexes and the endosomal t-SNARE, Pep12p. This work establishes a model in which LegC7 functions to recruit host ER material to the bacterial phagosome during infection by inducing membrane fusion, potentially through interaction with host membrane tethering complexes and/or cargo adapters.

scholarly journals Molecular Mechanisms of Insulin Resistance in Polycystic Ovary Syndrome: Unraveling the Conundrum in Skeletal Muscle?

2019 ◽  
Vol 104 (11) ◽  
pp. 5372-5381 ◽  
Author(s):  
Nigel K Stepto ◽  
Alba Moreno-Asso ◽  
Luke C McIlvenna ◽  
Kirsty A Walters ◽  
Raymond J Rodgers
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Polycystic Ovary Syndrome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Polycystic Ovary ◽  
Evidence Synthesis ◽  
Basic Research ◽  
Future Research ◽  
Ovary Syndrome

Abstract Context Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting 8% to 13% of women across the lifespan. PCOS affects reproductive, metabolic, and mental health, generating a considerable health burden. Advances in treatment of women with PCOS has been hampered by evolving diagnostic criteria and poor recognition by clinicians. This has resulted in limited clinical and basic research. In this study, we provide insights into the current and future research on the metabolic features of PCOS, specifically as they relate to PCOS-specific insulin resistance (IR), that may affect the most metabolically active tissue, skeletal muscle. Current Knowledge PCOS is a highly heritable condition, yet it is phenotypically heterogeneous in both reproductive and metabolic features. Human studies thus far have not identified molecular mechanisms of PCOS-specific IR in skeletal muscle. However, recent research has provided new insights that implicate energy-sensing pathways regulated via epigenomic and resultant transcriptomic changes. Animal models, while in existence, have been underused in exploring molecular mechanisms of IR in PCOS and specifically in skeletal muscle. Future Directions Based on the latest evidence synthesis and technologies, researchers exploring molecular mechanisms of IR in PCOS, specifically in muscle, will likely need to generate new hypothesis to be tested in human and animal studies. Conclusion Investigations to elucidate the molecular mechanisms driving IR in PCOS are in their early stages, yet remarkable advances have been made in skeletal muscle. Overall, investigations have thus far created more questions than answers, which provide new opportunities to study complex endocrine conditions.

The DEAH helicase DHX36 and its role in G-quadruplex-dependent processes

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Philipp Schult ◽  
Katrin Paeschke
Keyword(s):  
Current Knowledge ◽  
Future Research ◽  
Transcriptional Level ◽  
Cellular Functions ◽  
Multiple Functions ◽  
Open Questions ◽  
G Quadruplex ◽  
Cellular Pathways ◽  
Nucleic Acid Structures ◽  
Dependent Processes

AbstractDHX36 is a member of the DExD/H box helicase family, which comprises a large number of proteins involved in various cellular functions. Recently, the function of DHX36 in the regulation of G-quadruplexes (G4s) was demonstrated. G4s are alternative nucleic acid structures, which influence many cellular pathways on a transcriptional and post-transcriptional level. In this review we provide an overview of the current knowledge about DHX36 structure, substrate specificity, and mechanism of action based on the available models and crystal structures. Moreover, we outline its multiple functions in cellular homeostasis, immunity, and disease. Finally, we discuss the open questions and provide potential directions for future research.

The Legionella pneumophila effector RavY contributes to a replication-permissive vacuolar environment during infection

2021 ◽  
Author(s):  
Luying Liu ◽  
Craig R. Roy
Keyword(s):  
Legionella Pneumophila ◽  
Effector Proteins ◽  
Type Iv Secretion ◽  
Host Cells ◽  
Effector Protein ◽  
Intracellular Replication ◽  
Phagocytic Cells ◽  
Host Molecules ◽  
Type Iv ◽  
Legionnaires Disease

Legionella pneumophila is the causative agent of Legionnaires’ Disease and is capable replicating inside phagocytic cells such as mammalian macrophages. The Dot/Icm type IV secretion system is a L. pneumophila virulence factor that is essential for successful intracellular replication. During infection, L. pneumophila builds a replication permissive vacuole by recruiting multiple host molecules and hijacking host cellular signaling pathways, a process mediated by the coordinated functions of multiple Dot/Icm effector proteins. RavY is a predicted Dot/Icm effector protein found to be important for optimal L. pneumophila replication inside host cells. Here, we demonstrate that RavY is a Dot/Icm-translocated effector protein that is dispensable for axenic replication of L. pneumophila , but critical for optimal intracellular replication of the bacteria. RavY is not required for avoidance of endosomal maturation, nor does RavY contribute to the recruitment of host molecules found on replication-permissive vacuoles, such as ubiquitin, RAB1a, and RTN4. Vacuoles containing L. pneumophila ravY mutants promote intracellular survival but limit replication. The replication defect of the L. pneumophila ravY mutant was complemented when the mutant was in the same vacuole as wild type L. pneumophila . Thus, RavY is an effector that is essential for promoting intracellular replication of L. pneumophila once the specialized vacuole has been established.

Mechanisms linking energy balance and reproduction: impact of prenatal environment

2016 ◽  
Vol 25 (1) ◽  
Author(s):  
Erin M. Rhinehart
Keyword(s):  
Energy Balance ◽  
Metabolic Regulation ◽  
Developmental Plasticity ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Reproductive Fitness ◽  
Future Research ◽  
Energy Availability ◽  
Prenatal Environment ◽  
Regulation Of Reproduction

AbstractThe burgeoning field of metabolic reproduction regulation has been gaining momentum due to highly frequent discoveries of new neuroendocrine factors regulating both energy balance and reproduction. Universally throughout the animal kingdom, energy deficits inhibit the reproductive axis, which demonstrates that reproduction is acutely sensitive to fuel availability. Entrainment of reproductive efforts with energy availability is especially critical for females because they expend large amounts of energy on gestation and lactation. Research has identified an assortment of both central and peripheral factors involved in the metabolic regulation of reproduction. From an evolutionary perspective, these mechanisms likely evolved to optimize reproductive fitness in an environment with an unpredictable food supply and regular bouts of famine. To be effective, however, the mechanisms responsible for the metabolic regulation of reproduction must also retain developmental plasticity to allow organisms to adapt their reproductive strategies to their particular niche. In particular, the prenatal environment has emerged as a critical developmental window for programming the mechanisms responsible for the metabolic control of reproduction. This review will discuss the current knowledge about hormonal and molecular mechanisms that entrain reproduction with prevailing energy availability. In addition, it will provide an evolutionary, human life-history framework to assist in the interpretation of findings on gestational programming of the female reproductive function, with a focus on pubertal timing as an example. Future research should aim to shed light on mechanisms underlying the prenatal modulation of the adaptation to an environment with unstable resources in a way that optimizes reproductive fitness.

scholarly journals MAP Kinase Pathways in the YeastSaccharomyces cerevisiae

1998 ◽  
Vol 62 (4) ◽  
pp. 1264-1300 ◽  
Author(s):  
Michael C. Gustin ◽  
Jacobus Albertyn ◽  
Matthew Alexander ◽  
Kenneth Davenport
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Future Research ◽  
Mapk Pathways ◽  
Mapk Cascades

SUMMARY A cascade of three protein kinases known as a mitogen-activated protein kinase (MAPK) cascade is commonly found as part of the signaling pathways in eukaryotic cells. Almost two decades of genetic and biochemical experimentation plus the recently completed DNA sequence of the Saccharomyces cerevisiae genome have revealed just five functionally distinct MAPK cascades in this yeast. Sexual conjugation, cell growth, and adaptation to stress, for example, all require MAPK-mediated cellular responses. A primary function of these cascades appears to be the regulation of gene expression in response to extracellular signals or as part of specific developmental processes. In addition, the MAPK cascades often appear to regulate the cell cycle and vice versa. Despite the success of the gene hunter era in revealing these pathways, there are still many significant gaps in our knowledge of the molecular mechanisms for activation of these cascades and how the cascades regulate cell function. For example, comparison of different yeast signaling pathways reveals a surprising variety of different types of upstream signaling proteins that function to activate a MAPK cascade, yet how the upstream proteins actually activate the cascade remains unclear. We also know that the yeast MAPK pathways regulate each other and interact with other signaling pathways to produce a coordinated pattern of gene expression, but the molecular mechanisms of this cross talk are poorly understood. This review is therefore an attempt to present the current knowledge of MAPK pathways in yeast and some directions for future research in this area.

scholarly journals The Legionella pneumophila Metaeffector Lpg2505 (MesI) Regulates SidI-Mediated Translation Inhibition and Novel Glycosyl Hydrolase Activity

2020 ◽  
Vol 88 (5) ◽  
Author(s):  
Ashley M. Joseph ◽  
Adrienne E. Pohl ◽  
Theodore J. Ball ◽  
Troy G. Abram ◽  
David K. Johnson ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Glycosyl Hydrolase ◽  
Protein Translation ◽  
Effector Proteins ◽  
Hydrolase Activity ◽  
Intracellular Replication ◽  
Content Type ◽  
Translation Inhibition ◽  
Legionnaires Disease ◽  
The Impact

ABSTRACT Legionella pneumophila, the etiological agent of Legionnaires’ disease, employs an arsenal of hundreds of Dot/Icm-translocated effector proteins to facilitate replication within eukaryotic phagocytes. Several effectors, called metaeffectors, function to regulate the activity of other Dot/Icm-translocated effectors during infection. The metaeffector Lpg2505 is essential for L. pneumophila intracellular replication only when its cognate effector, SidI, is present. SidI is a cytotoxic effector that interacts with the host translation factor eEF1A and potently inhibits eukaryotic protein translation by an unknown mechanism. Here, we evaluated the impact of Lpg2505 on SidI-mediated phenotypes and investigated the mechanism of SidI function. We determined that Lpg2505 binds with nanomolar affinity to SidI and suppresses SidI-mediated inhibition of protein translation. SidI binding to eEF1A and Lpg2505 is not mutually exclusive, and the proteins bind distinct regions of SidI. We also discovered that SidI possesses GDP-dependent glycosyl hydrolase activity and that this activity is regulated by Lpg2505. We have therefore renamed Lpg2505 MesI (metaeffector of SidI). This work reveals novel enzymatic activity for SidI and provides insight into how intracellular replication of L. pneumophila is regulated by a metaeffector.

scholarly journals Endocrinology of thermoregulation in birds in a changing climate

2019 ◽  
Author(s):  
Suvi Ruuskanen ◽  
Bin-Yan Hsu ◽  
Andreas Nord
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Extreme Weather ◽  
Extreme Weather Events ◽  
Future Research ◽  
Endocrine Regulation ◽  
Thermal Environments ◽  
Changing Climate ◽  
Weather Events ◽  
Wide Range

The ability to maintain a (relatively) stable body temperature in a wide range of thermal environments is a unique feature of endotherms such as birds. Endothermy is acquired and regulated via various endocrine and molecular pathways, and ultimately allows wide aerial, aquatic, and terrestrial distribution in variable environments. However, due to our changing climate, birds are faced with potential new challenges for thermoregulation, such as more frequent extreme weather events, lower predictability of climate, and increasing mean temperature. We provide a compact overview on thermoregulation in birds and its endocrine and molecular mechanisms, pinpointing gaps in current knowledge and recent developments, focusing especially on non-model species to understand the generality of, and variation in, mechanisms. We highlight plasticity in thermoregulation and underlying endocrine regulation, because thorough understanding of plasticity is key to predicting responses to changing environmental conditions. To this end, we discuss how changing climate is likely to affect avian thermoregulation and associated endocrine traits, and how the interplay between these physiological processes may play a role in facilitating or constraining adaptation to a changing climate. We conclude that while the general patterns of endocrine regulation of thermogenesis are quite well understood, at least in poultry, the molecular and endocrine mechanisms that regulate e.g. mitochondria function and plasticity of thermoregulation over different time scales (from transgenerational to daily variation) need to be unveiled. Plasticity may ameliorate climate change effects on thermoregulation to some extent, but the increased frequency of extreme weather events, and associated in resource availability, may be beyond the scope and/or speed for plastic responses. This could lead to selection for more tolerant phenotypes, if the underlying physiological traits harbour genetic and individual variation for selection to act on – a key question for future research.

scholarly journals Chemical and molecular factors in irritable bowel syndrome: current knowledge, challenges, and unanswered questions

2016 ◽  
Vol 311 (5) ◽  
pp. G777-G784 ◽  
Author(s):  
Michael Camilleri ◽  
Ibironke Oduyebo ◽  
Houssam Halawi
Keyword(s):  
Fatty Acids ◽  
Irritable Bowel Syndrome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Short Chain Fatty Acids ◽  
Mucosal Barrier ◽  
Future Research ◽  
Enteroendocrine Cell ◽  
The Central Nervous System ◽  
Irritable Bowel

Several chemical and molecular factors in the intestine are reported to be altered and to have a potentially significant role in irritable bowel syndrome (IBS), particularly in IBS with diarrhea. These include bile acids; short-chain fatty acids; mucosal barrier proteins; mast cell products such as histamine, proteases, and tryptase; enteroendocrine cell products; and mucosal mRNAs, proteins, and microRNAs. This article reviews the current knowledge and unanswered questions in the pathobiology of the chemical and molecular factors in IBS. Evidence continues to point to significant roles in pathogenesis of these chemical and molecular mechanisms, which may therefore constitute potential targets for future research and therapy. However, it is still necessary to address the interaction between these factors in the gut and to appraise how they may influence hypervigilance in the central nervous system in patients with IBS.

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