Cellular and Molecular Mechanism of Bacterial and Viral Virulence
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Transcript of Cellular and Molecular Mechanism of Bacterial and Viral Virulence
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Cellular and Molecular Mechanism of Bacterial and Viral Virulence
dr. Tristia Rinanda, M.Si Bagian Mikrobiologi Fakultas Kedokteran UNSYIAH
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Terminology Pathogen
= A microorganism capable of causing diseases
Opportunistic pathogen =
An agent capable of causing disease only when the host’s resistance is impaired
Non pathogen =
A microorganism that does not cause disease
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Terminology Infection
= Multiplication of an infectious agent within the
body
Pathogenicity =
The ability of an infectious agent to cause disease Virulence
= The quantitative ability of an agent to cause
disease/degree of pathogenicity
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VIRAL VIRULENCE
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Viral Pathogenesis
Sum of the effects on the host due to virus replication and host’s immune system Involving several steps/factors: Viral dissemination in host (entry and primary
replication, spread, tropism, shedding and transmission) Viral virulence Injury induced by viruses Host determinant (host susceptibility)
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Iceberg Concept of Viral Infection
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Viral Dissemination Viral attachment and entry Replicate at the primary site of
entry (local spread) Systemic spread Presence of virus in a blood
viremia Viral attachment and spread
the role of tissue tropism Shedding: To maintain a viral infections in
population of host Usually occurs from the body
surface = viral entry Ability to survive in environment
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Local Infection
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Systemic Infection
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Mechanism of spread
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Hematogenous VS Neuronal
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Viral genetic determinant Divided into 4 classes: Ability to replicate Ability to modify host’s immune system Ability to spread in the host and among host Produce directly toxic genes products
Viral virulence
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Ability to replicate: Exhibit reduced or no replication in cell host or many cultured cell types Non coding sequences HCV, poliovirus
Viral virulence
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Ability to modify host’s immune system Virokin secreted proteins that mimic cytokines, growth factors or extracellular immune regulator Viroreceptor homolog of host receptors or cell surface immune molecules
Apoptosis Virus akan menghambat apoptosis Direct Indirect
Viral virulence
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Ability to spread in the host Specific genes encoding specific proteins specific recognition to host cells specific pathogenesis/virulence Example: reovirus type 1 dan 3, bunyavirus (La Cross virus) plaques
Viral virulence
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Toxic viral proteins NSP4 Proteins from Rotavirus Plays important role on budding proccess toxic to host cellsintestinal mucosa increasing chloride secretion
Viral virulence
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Injury induced by viruses
Caused temporary and permanent damage due to several process: Direct effects to virus replication Consequences of host adaptive and innate
immune system or both
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Direct Effects by cytolytic virus Increased permeability of cell membranea
leakage Fused cell syncytia (paramyxovirus) Vacuolization, polyokaryocytosis, inclusion bodies herpesvirus
Pathogenic effects of non cytolytic virus Virus doesn’t destroy the cell, but reduced the
growth hormones (lymphocytic choriomeningitis virus)
Injury induced by viruses
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Indirect Effect of viral infection Cellular response damaged due to proteolytic
enzymes, reactive radicals and cytokines Immunopathological lesion associated with T
cells (CD8+ and CD4+) and B cells Autoimmune disease molecular mimicry Ex. Herpes simplex infection caused stromal keratitis
(UL6 similar to IgG2)
Injury induced by viruses
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Host genetic determinant Responsible genes for immune system Determining host susceptibility to viral disease Genetic determinant polymorphism in MHC1 dan
MHC II Host proteins involve in replication, transcription and
translation Host cell receptor
Non genetic determinant age, sex, pregnancy, malnutrition, cigarette, temperature, mental status
Host Determinant
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BACTERIAL VIRULENCE
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Basic concept identifying the cause of infectious diseases
Koch’s postulate molecular Koch’s postulates
Host-pathogen interaction Virulence factors vaccines
development
Terminology
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Identifying bacteria that cause disease
Koch’s Postulates molecular Koch’s Postulates molecular guidelines Koch’s postulates : classification of bacteria as
pathogens, non pathogens and opportunistic pathogens
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Important stages of Bacterial Pathogenesis
Transmission site of entry, vectors Infection process Virulence factors Regulation of virulence factors
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Transmission
Asymptomatic infection enhancing the possibility of transmission Some bacteria cause disease in human, exist primarily in animal, incidentally infect human Clinical manifestation transmission routes Most frequent portals of entry mucous membranes meet the skin
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The infectious process
Bacteria attach /adhere to host cells primary site of infection colonization multiplication spread bloodstream (bacteremia) suitable tissue multiplication
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Virulence Factors Adherence
factors/adhesins Invasion of host cells
(Invasins) Capsule Motility Toxins Enzymes Antiphagocytic factors
Antigenic heterogeneity The requirement for iron Intracellular
pathogenicity Biofilm formation Resistance to antibiotics
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Adherence Factors/adhesin
Specificity of adherence tissue tropism, species specificity, genetic specificity within the species Mechanism of adherence may involve two steps:
1)Non specific adherence (docking) reversible attachment of bacteria to eukaryotic cells, due to several conditions: Hydrophobic interaction Electrostatic attraction Brownian movement Atomic and molecular vibration Trapping by biofilm polymer
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Adherence Factors/adhesin
2)Specific adherence (anchoring) reversible permanent attachment Complementary receptors and adhesin molecules Lock and key system irreversible attachment
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Adhesin
Kenneth Todar, 2009
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Invasion to host cells
Production of extracellular substances breaking down primary or secondary defenses of the body INVASINS Consist of spreading factors, hemolytic enzymes, extracellular digestive enzymes, toxins with short range effects related to invasion
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Invasins
Kenneth Todar, 2009
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Bacterial Toxins
Endotoxins (Lipopolysaccharide and peptidoglycan) and exotoxins (proteins) LPS Lipid A (toxicity), polysaccharide (antigenicity), O antigen (antigenicity) Peptidoglycan much less potent than LPS Fever, leukopenia, hypoglycemia, hypotension, DIC
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Endotoxin VS Exotoxin
Kenneth Todar, 2009
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BACTERIAL TOXIN Kenneth Todar, 2009
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Motility
Flagella, actin-based motility Flagella function in attachment, biofilm formation, colonization of host tissues, export of substances associated with virulence Induce strong immune system and manifest antigenic variation
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Capsules
Most pathogenic bacteria polysaccharides capsules Poorly immunogenic, antiphagocytic protect the microbe from intracellular killing Immunomudulatory effects S. aureus and E. fecalis
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Antiphagocytic factors
Evade phagocytosis or leucocyte microbicidal mechanism absorbing normal host components to their
surfaces Polysaccharide capsules Pili
Show antigenic heterogeneity protection to the same type, no cross immunity Toxin that inhibits chemotaxis by leucocytes
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Intracellular pathogenicity
Live and grow in hostile environment in PMNs cell, macrophages and monocytes, due to abilities: Avoid entry to phagolysosome, live in cytosol of the
phagocyte Prevent phagosome-lysosome fusion, live within
the phagosome Resistant to lysosomal enzymes, survive within the
phagolysosome Escaping oxidative burst
Live within non-phagocytic cells
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Macrophage Function
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Antigenic heterogeneity
Surface structure of bacteria considerable antigenic heterogeneity Serologic classification of bacteria Frequent switching of antigenic forms evading the host’s immune system
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The requirement for Iron Iron is the most studied nutrient essential to infectious process Wide oxidation-reduction potential metabolic function Human and animal Abundant amount of iron >>> intracellular Free iron ( ferric compound)
Most bacteria Low affinity iron assimilation system (using polymeric form of iron) Some bacteria high affinity iron assimilation system (using
siderophore) Availability of Iron affects the virulence of pathogens
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The requirement for Iron
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Bacterial Biofilm Biofilm aggregate of interactive bacteria attached to a solid
surface or to each other and encased in exopolysaccharide matrix Single or multiple species Related to persistent and difficult to treat human infection Biofilm formation: Colonization of the surface (using flagella, pili)secrete low level of
molecules (quorum sensing signal) concentration of signals increase treshold is reached bacteria respond and change their behavior (changing activation of genes) Activated genes : influence metabolic pathways and production of
virulence factors Biofilm matrix : protect bacteria from host’s immune system,
diffusion barrier for some antimicrobials
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Bacterial Biofilm
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Pathogenicity Island
Located in bacterial chromosomes or plasmid Contain of large genome, encode genes which contribute to virulence, survival under stressful condition Pathogen that undergo gene transfer; plasmid, phaga, transposon acquired by horizontal gene transfer
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Antimicrobial resistance
Genetic determinant spontaneous mutation and horizontal gene transfer Formation of biofilm
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Regulation of bacterial virulence factors
Pathogenic bacteria adapted to saprophytic or free living states Evolving complex signal transduction systems to
regulate the genes important for virulence Environmental signals control the expression;
temperature, iron availability, osmolality, growth phase, pH, specific ions, nutrient factors.
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Virulence Factors
Hsing Ju Wu et al, 2008)
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Hsing Ju Wu et al, 2008)
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Hsing Ju Wu et al, 2008)
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Hsing Ju Wu et al, 2008)
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