intracellular parasitism

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Information about intracellular parasitism

Published on April 26, 2014

Author: ira.praharaj


Intracellular Parasitism: Intracellular Parasitism Ira Praharaj INTRODUCTION:  INTRODUCTION Parasite(Greek: Parasitos,i.e. “eat together”) Many organisms in the course of evolution have developed the capability to survive in intracellular environment Intracellular adaptation –a double edged sword Intracellular parasites,particularly obligate intracellular parasites present unique challenge to biologists because they cannot be studied free of their host Intracellular parasitism can be shown by viruses,prokaryotes(bacteria),eukaryotes (fungi,protozoa) PowerPoint Presentation: Furthest extremes of intracellular parasitism(adaptation) -Mitochondria(from aerobic heterotrophic prokaryote) -Chloroplast(from Cyanobacteria) Endosymbiosis PowerPoint Presentation: Inside of a potential host cell is a hostile uninviting environment But host cells also largely unexploited food sources If a parasite adapts successfully to an intracellular niche,it may thrive unimpeded by interspecies competition THE PROBLEMS: THE PROBLEMS How to get in? How to survive? How to multiply? How to get my babies out? From old cells to new ones? Problems in intracellular parasitism: Problems in intracellular parasitism How to get inside of host cells? How ,once inside ,to prevent being killed? How to multiply intracellularly? How to maintain host functions essential for parasite multiplication? How to get new generations of parasites out of the host cells in which they were made? How to get from old host cells to new ones? How to get inside host cells?: How to get inside host cells? Translocation from outside to inside a host cell can be described with relative ease compared to the other steps of intracellular adaptation The step in intracellular parasitism about which we know the most :  ENTRY Diacytosis Endocytosis Hole in outer layer of host cell Parasite enters surrounded by Parasite never enveloped in host derived membrane host derived membrane E.g Bdellovibrios,Microsporidia Parasite specified Host specified Endocytosis Endocytosis Entry facilitating adaptation by parasite adaptation by host Specialised organelles of parasite No specialised No specialised Specialised for attachment and entry entry organelles ligands ligands to bind parasite to host cell E.g.Malarial parasites Parasite expends energy Parasite doesn’t expend energy E.g Shigella,T cruzi trypomastigotes, E.g. Chlamydiae rickettsiae Modes of Entry : Modes of Entry “Diacytosis”-Parasite “punches a hole” in the host cell membrane E.g. Bdellovibrio -Soil inhabiting bacteria attacking mostly Gm –ve bacteria Bdellovibrio attacks susceptible bacterial cell Makes hole in cell wall and lodges in periplasmic space Kills the host using host macromolecules to produce brood of parasites Microsporidia –Good example of Diacytosis PowerPoint Presentation: “Endocytosis”-Parasite enters in a host derived membrane without disrupting the integrity of the host cell Host cells don’t appear to internalize intracellular parasites unless either host or parasite makes some evolutionary adaptation that facilitates uptake Parasite specified Endocytosis Host specified Endocytosis “Non-Professional” phagocytes taking up parasite-Parasite has made an adaptation that promotes entry Professional Phagocytes –adaptations which make them capable of taking up a large variety of particles Phagocytosis-The Trojan Horse of Intracellular Parasitism : Phagocytosis-The Trojan Horse of Intracellular Parasitism Important part of host defenses which can act once the epithelial surface breached Phagocytosis can be of 2 main types Type 1-Fc γ R mediated-accompanied by respiratory burst. Not the type useful for intracellular parasitism Type 2-CR3(Complement receptor 3 mediated)-doesn’t activate respiratory burst. Used by intracellular pathogens PowerPoint Presentation: Parasite directed Endocytosis -Malaria parasites - the best understood example -Host cells are erythrocytes(least phagocytically competent) -Parasites have evolved complex organelles of entry - Plasmodium -Merozoite entry has been extensively studied PowerPoint Presentation: Merozoites adhere to host cell by thick cell coat (acidic glycoprotein surrounding the merozoite with erect filaments) For invasion, attachment by Apical complex (structure made of polar rings and interconnected secretory vesicles) essential Plasma membrane of host never breached(although erythrocyte membrane is altered) during entry PowerPoint Presentation: Mycobacteria - M. tuberculosis can activate alternate pathway of complement activation(opsonisation with C3b and C3bi) Coated bacteria can bind to CR1,CR3 and CR4 Phagocytosed in membrane bound phagosomes - M.tuberculosis can bind to CR3 at 2 distinct sites of the receptor PowerPoint Presentation: Rickettsiae-Obligate intracellular parasites - In natural hosts preferentially enter endothelial cells lining the small blood vessels -Host damage due to parasitisation of these cells - R .tsutsugamushi and R.prowazekii readily enter both professional and non-professional phagocytes in vivo and in vitro by mechanism resembling phagocytosis PowerPoint Presentation: Chlamydiae -Obligate parasitism in a wide range of hosts -2 Chlamydial cell types- -Elementary body -Reliculate body -Elementary bodies never divide -Role is to carry infection from one host cell to another -Reticulate bodies divide by binary fission. Are noninfectious PowerPoint Presentation: Single elementary bodies attach to host cell plasma membrane Enveloped by microvilli Enter cells within membrane bound vacuole Host Directed endocytosis: Host Directed endocytosis Macrophages ingest intracellular organisms in the same way they phagocytose other organisms E.g- Leishmania donovani - M.tuberculosis - Trypanosoma cruzi Survival Inside Host cell: Survival Inside Host cell How Host Cells kill parasites intracellularly?: How Host Cells kill parasites intracellularly? Ingestion of pathogen with no provision for intracellular survival series of events leading to the death of the pathogen Increased O2 consumption Production of H 2 O 2 and superoxide radicals Activation of myeloperoxidase Lysosomes fuse with pathogen containing phagosome and release acid hydrolases PMNs exhibit all these potential microbicidal activities,macrophages most of them,nonprofessional phagocytes only the lysosomal enzymes PowerPoint Presentation: Polymorphonuclear leukocytes rarely serve as hosts for intracellular parasites(exception- Ehrlichia spp) Many different kinds of intracellular parasites thrive within macrophages where they must successfully resist many microbicidal mechanisms the macrophages possess :  Microorganism trafficking through endocytic vesicles is a complex phenomenon leading to successive formation of Early endosomes Late endosomes True Phagolysosomes(organisms digested because of low pH <5 and enzymes like acid hydrolases Organisms surviving within phagocytic cells may be Intracytoplasmic after exit from endosomal compartment with/without fusion of the phagosomal vacuole with lysosomes Residing in nonfused phagosomes Residing in selectively fused phagosomes(early phagosome modified by selective fusion event) Residing in lysosomes when endocytic cascade complete Intracellular parasite: 25 Intracellular parasite No fusion Lysozome Phagosome Fusion Enter cytoplasm Bacteria Macrophage or neutrophil Evasion of lethal consequences of Lysosome-Phagosome fusion: Evasion of lethal consequences of Lysosome-Phagosome fusion Adaptation to a host cell without lysosomes Erythrocytes(lysosome free,nonnucleated)- - Plasmodium species and other hemosporidia - Bartonellaceae Escape from the phagosome Soon after it enters the host cell. - Trypanosoma cruzi -Trypomastigotes in unstimulated mouse macrophages remain in phagosomes for an hr;free of phagosomal membranes and multiplying in cytoplasm by 24-48 hrs - Rickettsiae -Enter host cells in membrane bound vacuoles but are free in the cytoplasm a short time later PowerPoint Presentation: Resistance to lysosomal enzymes Coxiella burnetti Salmonella Typhimurium Yersinia pestis Leishmania spp PowerPoint Presentation: Shown in in-vitro models with mouse macrophages that Leishmania amastigotes survive and multiply in phagolysosomes How Leishmania survive and multiply in phagolysosomes? Evolving an enzyme resistant cell surface(Surface glycoproteins) Secreting enzyme inhibitors and inactivators Ammonia produced by highly active leishmanial proteases- Raised pH and inactivation of lysosomal enzymes PowerPoint Presentation: Coxiella burnetti - Well adapted to acidic environment of the phagolysosome -Intact cells of Coxiella utilise glucose and glutamate very vigorously at pH 5 and below :  Prevention of Phagosome lysosome fusion Adopted by a phylogenetically dissimilar group of intracellular micro-organisms - M.tuberculosis -Chlamydia psittaci -Legionella pneumophila -Toxoplasma gondii -Bordetella pertussis - Aspergillus flavus PowerPoint Presentation: Mycobacterium M .lepraemurium lives in phagosomes that have fused with lysosomes M.leprae -Part of its intracellular residence in phagosomes and part free in the cytoplasm M .microti and M .tuberculosis -live in phagosomes that seldom provoke lysosomal fusion PowerPoint Presentation: M tuberculosis /M bovis supports its own phagocytosis by MP via 2 mechanisms - Secrete abundant quantities of fibronectin binding molecules of 30-32KDa and 50-60kDa which promote phagocytosis by fibronectin receptors present on the macrophages -Induces C3 activation and deposition of C3b.This entry bypasses Reactive Oxygen Intermediates(ROI) induction Mycobacterium generates large amounts of NH 4 + in cultures Ammonia is involved in- -Neutralization of acidic endosomal pI -Blocking of ROI production -Inhibition of lysosomal movements and fusion with phagosomes PowerPoint Presentation: M tuberculosis has evolved 2 ways of evading consequences of lysosomal fusion Prevention of lysosomal fusion-Mycobacterial products(Mycobacterial sulfatides,Polyanionic trehalose glycolipids) render lysosomal membranes nonfusible Macrophage lysosomal enzymes don’t inhibit growth of M tuberculosis Legionella-an intravacuolar pathogen: Legionella -an intravacuolar pathogen Growth within lung macrophages after aerosols inhaled from contaminated water sources Ability to manipulate host cell vesicular trafficking pathways and establish a membrane bound replication vacuole Vesicles derived from endoplasmic reticulum and mitochondria appear in close proximity to LCV(Legionella Containing Vacuole) surface Vesicles surrounding the LCV docked and extend out onto the surface Membrane surrounding the bacterium become similar to RER(studded with ribosomes) PowerPoint Presentation: Effectors secreted by Type 4 secretion system inhibit phagosome maturation Effectors encoded by Dot/Icm gene(Intracellular multiplication /Defect in organelle trafficking genes) Phagosomes covered by ER vesicles Inside the ER vesicle,bacterium hidden from lysosomes Listeria monocytogenes: Listeria monocytogenes Experimental listeriosis of mice –a widely studied model for intracellular bacterial infections “Zipper-type” mechanism of invasion of nonphagocytic cells(like intestinal and hepatic cells)-bacterium gradually sinks into diplike structures of the host cell surface until engulfed Listeria containing vacuolar compartments acidified soon after uptake Phagosomal maturation to Phagolysosomal stage inhibited Membrane of the phagosome disrupted by phospholipases and pore forming toxin “listeriolysin O” (escape from phagosome before lysosomal fusion) PowerPoint Presentation: Actin polymerization occurs once the bacterium is in the cytosol(due to surface protein ActA) Actin polymerisation allows bacteria to pass into neighbouring cells by formation of “listeriopods”(pseudopodlike projections) Entry into neighbouring cell –bacteria presented in double-membraned vacuole from which escape by phospholipase and LLO MULTIPLICATION:  MULTIPLICATION General aspects of multiplication: General aspects of multiplication 3 broad areas of host cell activity which may be diverted by an intracellular parasite to its own ends Synthesis of intermediates Generation of energy Synthesis of macromolecules Only viruses supposed to exploit host cell macromolecules Chlamydiae –totally dependent on host cells for ATP and energy rich molecules Partial dependency-Rickettsiae Malarial parasites Microsporidia Chlamydiae and Rickettsiae - “Energy Parasitism”: Chlamydiae and Rickettsiae - “Energy Parasitism” Utilisation of exogenous ATP (from the host)- requires presence in intracellular parasite of membrane located ATP-ADP transport system Present in Rickettsiae and Chlamydiae This enzyme system otherwise present only in mitochondria(intracellular parasites of only the most distant phylogenetic kinship) PowerPoint Presentation: Chlamydiae- multiplying reticulate bodies more active metabolically than the infectious elementary bodies Host free Reticulate bodies-move ATP in and ADP out of their intracellular space with a translocase Hydrolyse ATP to ADP Use energy liberated for macromolecule synthesis Developmental Cycle of Chlamydia: Developmental Cycle of Chlamydia EB bind to host cells Epithelial Macrophage Internalization Endocytosis Phagocytosis Inhibition of phagosome-lysosome fusion Reorganization into RB Breakdown of disulfide bonds Growth of RB Developmental Cycle of Chlamydia: Developmental Cycle of Chlamydia Reorganization into EB Inclusion bodies Release of EB Lysis - C. psittaci Extrusion - C. trachoma tis and C. pneumoniae Replication of Rickettsia : Replication of Rickettsia Infect endothelial cells in small blood vessels - Induced phagocytosis Lysis of phagosome and entry into cytoplasm - Phospholipase Replication Release Rickettsiae-obtain most of their metabolic energy by coupling ADP phosphorylation with oxidation of Glutamate via the TCA cycle PowerPoint Presentation: Malarial Parasite -Multiplication almost entirely restricted to blood stages -Erythrocytic stages of malarial parasites live in nondividing host cells -Change and consume their hosts(erythrocytes) to a great extent -Glucose-preferred energy source(increase in rate at which glucose enters the parasitised RBC) -Catabolise Glucose to Lactic acid -ATP synthesised by substrate level phosphorylation -Synthesis of Histidine Rich Protein may have appeared as positive adaptation to intracellular life Preservation of Host Cell function:  Preservation of Host Cell function PowerPoint Presentation: For most intracellular parasites hosts either not killed at all or only after reproduction of the parasites and the dissemination of their progeny is assurred E.g. Malarial parasites partially consume their host cells but depend on erythrocyte function to bring them nutrients from outside Rickettsiae and Chlamydiae injure host cells to varying levels but need not always injure host cell function to multiply Rate at which an intracellular parasite multiplies probably most important determinant of host cell injury and preservation Release: Release MECHANISMS OF EXIT PowerPoint Presentation: Cytolysis Host cell lysis by proteolysis- Chlamydia spp(Cysteine proteases) Plasmodium falciparum Pore forming protein – Leishmania spp Killing of the host cell,possibly by necrotic pathways Actin based protrusion -Single bacterium uses motile force generated from tails of actin polymerization to extend outwards into membrane bound projections -Projections internalised by adjacent cells - Listeria monocytogenes -Rickettsia rickettsii -B.pseudomallei -S.flexneri PowerPoint Presentation: Extrusion of organisms Organisms exit into extracellular environment and leave host cells intact -Budding of O.tsutsugamushi -Chlamydia spp extrusion - Cryptococcus neoformans expulsion -Host cell remains intact after microbial escape PowerPoint Presentation: Pyroptosis and Apoptosis Intracellular pathogens have evolved numerous mechanisms to modulate apoptosis in macrophages and non-phagocytic cells and promote infection In many cases programmed cell death coincident with a proinflammatory response New pathway described for proinflammatory cell death- “Pyroptosis” Pyroptosis characterised by Cysteine Protease Caspase 1 activation Membrane breakdown Activation and release of proinflammatory cytokines(IL-1, IL-18) Apoptosis-Programmed cell death without any inflammation PowerPoint Presentation: Pyroptosis found in Shigella flexneri Salmonella spp Legionella pneumophila Francisella tularensis Conclusion: Conclusion Many organisms with diverse phylogenetic beginnings have adapted to the intracellular way of life Adaptation to intracellular life,though not rare,is not easy New mechanisms of intracellular parasitism are being elucidated This could help develop strategies and drugs to combat these intracellular pathogens more effectively References: References Comparative Biology of Intracellular Parasitism JAMES W. MOULDER Department of Molecula'r Genetics and Cell Biology, The University of Chicago, Chicago, Illinois MICROBIOLOGICAL REVIEWS, Sept. 1985, p. 298-337 Mims' Pathogenesis of Infectious Disease - 5th Ed IMMUNITY TO INTRACELLULAR BACTERIA Stefan H. E. Kaufmann Annu. Rev. lmmunol. 1993. 11:12943

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