scholarly journals Pathways of host cell exit by intracellular pathogens

2018 ◽  
Vol 5 (12) ◽  
pp. 525-544 ◽  
Author(s):  
Antje Flieger ◽  
Freddy Frischknecht ◽  
Georg Haecker ◽  
Mathias W. Hornef ◽  
Gabriele Pradel
Keyword(s):  
Host Cell ◽  
Intracellular Pathogens

scholarly journals The dps Gene of Symbiotic “Candidatus Legionella jeonii” in Amoeba proteus Responds to Hydrogen Peroxide and Phagocytosis

2006 ◽  
Vol 188 (21) ◽  
pp. 7572-7580 ◽  
Author(s):  
Miey Park ◽  
Seong Tae Yun ◽  
Sue-Yun Hwang ◽  
Choong-Ill Chun ◽  
Tae In Ahn
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Host Cell ◽  
Genomic Library ◽  
Amoeba Proteus ◽  
Host Cells ◽  
Intracellular Pathogens ◽  
Protective Mechanisms ◽  
Dps Protein ◽  
Cloned Gene

ABSTRACT To survive in host cells, intracellular pathogens or symbiotic bacteria require protective mechanisms to overcome the oxidative stress generated by phagocytic activities of the host. By genomic library tagging, we cloned a dps (stands for DNA-binding protein from starved cells) gene of the symbiotic “Candidatus Legionella jeonii” organism (called the X bacterium) (dps X) that grows in Amoeba proteus. The gene encodes a 17-kDa protein (pI 5.19) with 91% homology to Dps and DNA-binding ferritin-like proteins of other organisms. The cloned gene complemented the dps mutant of Escherichia coli and conferred resistance to hydrogen peroxide. DpsX proteins purified from E. coli transformed with the dps X gene were in oligomeric form, formed a complex with pBlueskript SKII DNA, and protected the DNA from DNase I digestion and H2O2-mediated damage. The expression of the dps X gene in “Candidatus Legionella jeonii” was enhanced when the host amoeba was treated with 2 mM H2O2 and by phagocytic activities of the host cell. These results suggested that the Dps protein has a function protective of the bacterial DNA and that its gene expression responds to oxidative stress generated by phagocytic activities of the host cell. With regard to the fact that invasion of Legionella sp. into respiratory phagocytic cells causes pneumonia in mammals, further characterization of dps X expression in the Legionella sp. that multiplies in a protozoan host in the natural environment may provide valuable information toward understanding the protective mechanisms of intracellular pathogens.

scholarly journals A metabolic dependency for host isoprenoids in the obligate intracellular pathogenRickettsia parkeriunderlies a sensitivity for the statin class of host-targeted therapeutics

2019 ◽  
Author(s):  
Vida Ahyong ◽  
Charles A. Berdan ◽  
Daniel K. Nomura ◽  
Matthew D. Welch
Keyword(s):  
Cell Wall ◽  
Host Cell ◽  
Bacterial Growth ◽  
Spotted Fever ◽  
Intracellular Pathogens ◽  
Biosynthetic Pathways ◽  
Targeted Therapeutics ◽  
Rickettsia Parkeri ◽  
Obligate Intracellular ◽  
Intracellular Parasites

AbstractGram-negative bacteria in the order Rickettsiales are obligate intracellular parasites that cause human diseases such typhus and spotted fever. They have evolved a dependence on essential nutrients and metabolites from the host cell as a consequence of extensive genome streamlining. However, it remains largely unknown which nutrients they require and whether their metabolic dependency can be exploited therapeutically. Here, we describe a genetic rewiring of bacterial isoprenoid biosynthetic pathways in the Rickettsiales that has resulted from reductive genome evolution. We further investigated whether the spotted fever groupRickettsiaspeciesRickettsia parkeriscavenges isoprenoid precursors directly from the host. Using targeted mass spectrometry in uninfected and infected cells, we found decreases in host isoprenoid products and concomitant increases in bacterial isoprenoid metabolites. Additionally, we report that bacterial growth is prohibited by inhibition of the host isoprenoid pathway with the statins class of drugs. We show that growth inhibition correlates with changes in bacterial size and shape that mimic those caused by antibiotics that inhibit peptidoglycan biosynthesis, suggesting statins inhibit cell wall synthesis. Altogether, our results describe an Achilles’ heel of obligate intracellular pathogens that can be exploited with host-targeted therapeutics that interfere with metabolic pathways required for bacterial growth.ImportanceObligate intracellular parasites, which include viruses as well as certain bacteria and eukaryotes, extract essential nutrients and metabolites from their host cell. As a result, these pathogens have often lost essential biosynthetic pathways and are metabolically dependent on the host. In this study, we describe a metabolic dependency of the bacterial pathogenRickettsia parkerion host isoprenoid molecules that are used in the biosynthesis of downstream products including cholesterol, steroid hormones, and heme. Bacteria make products from isoprenoids such as an essential lipid carrier for making the bacterial cell wall. We show that bacterial metabolic dependency can represent an Achilles’ heel, and that inhibiting host isoprenoid biosynthesis with the FDA-approved statin class of drugs inhibits bacterial growth by interfering with the integrity of the cell wall. This work highlights a potential to treat infections by obligate intracellular pathogens through inhibition of host biosynthetic pathways that are susceptible to parasitism.

scholarly journals Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria

Pathogens ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 614
Author(s):  
Paige E. Allen ◽  
Juan J. Martinez
Keyword(s):  
Host Cell ◽  
Mammalian Cells ◽  
Membrane Integrity ◽  
Membrane Microdomains ◽  
Intracellular Bacteria ◽  
Intracellular Pathogens ◽  
Cell Infection ◽  
Lipid Species ◽  
Host Plasma Membrane ◽  
Plasma Membrane Microdomains

Lipids are a broad group of molecules required for cell maintenance and homeostasis. Various intracellular pathogens have developed mechanisms of modulating and sequestering host lipid processes for a large array of functions for both bacterial and host cell survival. Among the host cell lipid functions that intracellular bacteria exploit for infection are the modulation of host plasma membrane microdomains (lipid rafts) required for efficient bacterial entry; the recruitment of specific lipids for membrane integrity of intracellular vacuoles; and the utilization of host lipid droplets for the regulation of immune responses and for energy production through fatty acid β-oxidation and oxidative phosphorylation. The majority of published studies on the utilization of these host lipid pathways during infection have focused on intracellular bacterial pathogens that reside within a vacuole during infection and, thus, have vastly different requirements for host lipid metabolites when compared to those intracellular pathogens that are released into the host cytosol upon infection. Here we summarize the mechanisms by which intracellular bacteria sequester host lipid species and compare the modulation of host lipid pathways and metabolites during host cell infection by intracellular pathogens residing in either a vacuole or within the cytosol of infected mammalian cells. This review will also highlight common and unique host pathways necessary for intracellular bacterial growth that could potentially be targeted for therapeutic intervention.

scholarly journals Leishmania and other intracellular pathogens: selectivity, drug distribution and PK–PD

Parasitology ◽  
2017 ◽  
Vol 145 (2) ◽  
pp. 237-247 ◽  
Author(s):  
SIMON L. CROFT
Keyword(s):  
Host Cell ◽  
Drug Distribution ◽  
Lessons Learned ◽  
New Drugs ◽  
Intracellular Pathogens ◽  
Causative Pathogen ◽  
Pharmacodynamic Effect ◽  
The Past ◽  
Discovery Research

SUMMARYNew drugs and treatments for diseases caused by intracellular pathogens, such as leishmaniasis and the Leishmania species, have proved to be some of the most difficult to discover and develop. The focus of discovery research has been on the identification of potent and selective compounds that inhibit target enzymes (or other essential molecules) or are active against the causative pathogen in phenotypic in vitro assays. Although these discovery paradigms remain an essential part of the early stages of the drug R & D pathway, over the past two decades additional emphasis has been given to the challenges needed to ensure that the potential anti-infective drugs distribute to infected tissues, reach the target pathogen within the host cell and exert the appropriate pharmacodynamic effect at these sites. This review will focus on how these challenges are being met in relation to Leishmania and the leishmaniases with lessons learned from drug R & D for other intracellular pathogens.

scholarly journals Determinants of Phagosomal pH During Host-Pathogen Interactions

2021 ◽  
Vol 8 ◽  
Author(s):  
Johannes Westman ◽  
Sergio Grinstein
Keyword(s):  
Host Cell ◽  
Microbial Growth ◽  
Intracellular Pathogens ◽  
Ion Permeation ◽  
Host Pathogen Interactions ◽  
Counter Ion ◽  
Regulatory Machinery ◽  
Different Types ◽  
Host Pathogen ◽  
Luminal Ph

The ability of phagosomes to halt microbial growth is intimately linked to their ability to acidify their luminal pH. Establishment and maintenance of an acidic lumen requires precise co-ordination of H+ pumping and counter-ion permeation to offset the countervailing H+ leakage. Despite the best efforts of professional phagocytes, however, a number of specialized pathogens survive and even replicate inside phagosomes. In such instances, pathogens target the pH-regulatory machinery of the host cell in an effort to survive inside or escape from phagosomes. This review aims to describe how phagosomal pH is regulated during phagocytosis, why it varies in different types of professional phagocytes and the strategies developed by prototypical intracellular pathogens to manipulate phagosomal pH to survive, replicate, and eventually escape from the phagocyte.

scholarly journals Recent research milestones in the pathogenesis of human rickettsioses and opportunities ahead

2020 ◽  
Vol 15 (9) ◽  
pp. 753-765 ◽  
Author(s):  
Hema P Narra ◽  
Abha Sahni ◽  
David H Walker ◽  
Sanjeev K Sahni
Keyword(s):  
Host Cell ◽  
Salient Feature ◽  
Intracellular Pathogens ◽  
Rickettsia Species ◽  
Point Of Entry ◽  
Rickettsial Infections ◽  
Host Cell Interactions ◽  
Pathogen Vector ◽  
Potential Exploitation ◽  
Host Tissues

Infections caused by pathogenic Rickettsia species continue to scourge human health across the globe. From the point of entry at the site of transmission by arthropod vectors, hematogenous dissemination of rickettsiae occurs to diverse host tissues leading to ‘rickettsial vasculitis’ as the salient feature of pathogenesis. This perspective article accentuates recent breakthrough developments in the context of host–pathogen–vector interactions during rickettsial infections. The subtopics include potential exploitation of circulating macrophages for spread, identification of new entry mechanisms and regulators of actin-based motility, appreciation of metabolites acquired from and effectors delivered into the host, importance of the toxin–antitoxin module in host–cell interactions, effects of the vector microbiome on rickettsial transmission, and niche-specific riboregulation and adaptation. Further research on these aspects will advance our understanding of the biology of rickettsiae as intracellular pathogens and should enable design and development of new approaches to counter rickettsioses in humans and other hosts.

scholarly journals Prison Break: Pathogens' Strategies To Egress from Host Cells

2012 ◽  
Vol 76 (4) ◽  
pp. 707-720 ◽  
Author(s):  
Nikolas Friedrich ◽  
Monica Hagedorn ◽  
Dominique Soldati-Favre ◽  
Thierry Soldati
Keyword(s):  
Host Cell ◽  
Pathogenic Bacteria ◽  
Wide Spectrum ◽  
Host Cells ◽  
Host Immune System ◽  
Intracellular Pathogens ◽  
Pathogenic Yeast ◽  
Apicomplexan Parasites ◽  
Strategic Process ◽  
Intimate Association

SUMMARYA wide spectrum of pathogenic bacteria and protozoa has adapted to an intracellular life-style, which presents several advantages, including accessibility to host cell metabolites and protection from the host immune system. Intracellular pathogens have developed strategies to enter and exit their host cells while optimizing survival and replication, progression through the life cycle, and transmission. Over the last decades, research has focused primarily on entry, while the exit process has suffered from neglect. However, pathogen exit is of fundamental importance because of its intimate association with dissemination, transmission, and inflammation. Hence, to fully understand virulence mechanisms of intracellular pathogens at cellular and systemic levels, it is essential to consider exit mechanisms to be a key step in infection. Exit from the host cell was initially viewed as a passive process, driven mainly by physical stress as a consequence of the explosive replication of the pathogen. It is now recognized as a complex, strategic process termed “egress,” which is just as well orchestrated and temporally defined as entry into the host and relies on a dynamic interplay between host and pathogen factors. This review compares egress strategies of bacteria, pathogenic yeast, and kinetoplastid and apicomplexan parasites. Emphasis is given to recent advances in the biology of egress in mycobacteria and apicomplexans.

scholarly journals Vacuolar escape of foodborne bacterial pathogens

2020 ◽  
Vol 134 (5) ◽  
pp. jcs247221
Author(s):  
Frans Bianchi ◽  
Geert van den Bogaart
Keyword(s):  
Host Cell ◽  
Foodborne Pathogens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Vacuolar Membrane ◽  
Intracellular Pathogens ◽  
New Therapeutic Approaches ◽  
Contaminated Food ◽  
Membrane Bound ◽  
Gain Access

ABSTRACTThe intracellular pathogens Listeria monocytogenes, Salmonella enterica, Shigella spp. and Staphylococcus aureus are major causes of foodborne illnesses. Following the ingestion of contaminated food or beverages, pathogens can invade epithelial cells, immune cells and other cell types. Pathogens survive and proliferate intracellularly via two main strategies. First, the pathogens can remain in membrane-bound vacuoles and tailor organellar trafficking to evade host-cell defenses and gain access to nutrients. Second, pathogens can rupture the vacuolar membrane and proliferate within the nutrient-rich cytosol of the host cell. Although this virulence strategy of vacuolar escape is well known for L. monocytogenes and Shigella spp., it has recently become clear that S. aureus and Salmonella spp. also gain access to the cytosol, and that this is important for their survival and growth. In this Review, we discuss the molecular mechanisms of how these intracellular pathogens rupture the vacuolar membrane by secreting a combination of proteins that lyse the membranes or that remodel the lipids of the vacuolar membrane, such as phospholipases. In addition, we also propose that oxidation of the vacuolar membrane also contributes to cytosolic pathogen escape. Understanding these escape mechanisms could aid in the identification of new therapeutic approaches to combat foodborne pathogens.

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