Cellular and Molecular Mechanism

of Bacterial and Viral Virulence

dr. Tristia Rinanda, M.Si

Bagian Mikrobiologi
Fakultas Kedokteran UNSYIAH

Terminology
Pathogen
=
A microorganism capable of causing diseases
Opportunistic pathogen
=
An agent capable of causing disease only
when the hosts resistance is impaired
Non pathogen
=
A microorganism that does not cause disease

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

VIRAL VIRULENCE

Viral Pathogenesis
Sum of the effects on the host due to virus replication
and hosts 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)

Iceberg Concept of Viral Infection

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

Local Infection

Systemic Infection

Mechanism of spread

Hematogenous VS Neuronal

Viral virulence
Viral genetic determinant
Divided into 4 classes:
Ability to replicate
Ability to modify hosts immune system
Ability to spread in the host and among host
Produce directly toxic genes products

Viral virulence
Ability to replicate:
Exhibit reduced or no replication in cell host
or many cultured cell types
Non coding sequences HCV, poliovirus

Viral virulence
Ability to modify hosts 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
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

Toxic viral proteins

NSP4 Proteins from Rotavirus
Plays important role on budding proccess
toxic to host cellsintestinal mucosa
increasing chloride secretion

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

Injury induced by viruses

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 doesnt destroy the cell, but reduced the
growth hormones (lymphocytic choriomeningitis
virus)

Injury induced by viruses

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)

Host Determinant
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

BACTERIAL VIRULENCE

Terminology
Basic concept identifying the cause
of infectious diseases
Kochs postulate molecular Kochs
postulates
Host-pathogen interaction
Virulence factors vaccines
development

Identifying bacteria that cause

disease
Kochs Postulates molecular Kochs Postulates
molecular guidelines
Kochs postulates : classification of bacteria as
pathogens, non pathogens and opportunistic
pathogens

Important stages of Bacterial

Pathogenesis
Transmission site of entry, vectors
Infection process
Virulence factors
Regulation of virulence factors

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

The infectious process

Bacteria attach /adhere to host cells
primary site of infection colonization
multiplication spread
bloodstream (bacteremia) suitable
tissue multiplication

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

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

Adherence Factors/adhesin
2)Specific adherence (anchoring) reversible
permanent attachment
Complementary receptors and adhesin
molecules Lock and key system
irreversible attachment

Adhesin

Kenneth Todar,
2009

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

Invasins

Kenneth Todar,
2009

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

Endotoxin VS Exotoxin

Kenneth Todar,
2009

BACTERIAL TOXIN

Kenneth Todar,
2009

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

Capsules
Most pathogenic bacteria
polysaccharides capsules
Poorly immunogenic, antiphagocytic
protect the microbe from intracellular killing
Immunomudulatory effects S. aureus
and E. fecalis

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

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

Macrophage Function

Antigenic heterogeneity
Surface structure of bacteria considerable
antigenic heterogeneity
Serologic classification of bacteria
Frequent switching of antigenic forms
evading the hosts immune system

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

The requirement for Iron

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 hosts immune system,

diffusion barrier for some antimicrobials

Bacterial Biofilm

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

Antimicrobial resistance
Genetic determinant spontaneous
mutation and horizontal gene transfer
Formation of biofilm

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.

Virulence Factors

Hsing Ju Wu et al, 2008)

Hsing Ju Wu et al, 2008)

Hsing Ju Wu et al, 2008)

Hsing Ju Wu et al, 2008)

http://www.mgc.ac.cn/VFs/

THANK YOU