Transcript Bacterial Pathogenesis

Bacterial Pathogenesis
Nov 4, 2013
I-Hsiu Huang
Ref: http://www.ifood.tv/blog/10-dirtiest-and-worst-foods-in-america
Normal Flora
(Commensal Microbes)
• Introduction
• Significance of the
Normal Flora
• Distribution of the
Normal Flora
Bacterial Pathogenesis
• Introduction
• Host Susceptibility
• Pathogenesis
Mechanisms
• Virulence Factors
Normal flora and pathogenesis
• Outcomes of exposure to organisms
1. Transient colonization
2. Permanent colonization
3. Disease
• Colonization vs Infection
– Establishment of a site of reproduction of microbes on
a person without necessarily resulting in tissue
invasion or damage.
– Growth and multiplication of a microbe in or on the
body of the host with or without causing disease.
Normal flora:
The closest neighbor of a human
• Where: Mucosal surfaces and skin of the
entire body
• When: Right after birth  death
• How many: 1014 bacteris vs 1013 human cells
“characterization of the
human microbiota and
analysis of their role in
human health and disease.”
The Human Microbiome Project (HMP)
• 500 to 1000 species of bacteria live in the human gut
• The weight of all the bacteria in your body is about 1-3%
of your body weight
• Diverse species of bacteria has learned to live in many
difference area of our body by using carbohydrates
differently
• Questions: Can we tailor our medicine, diet, and life
style according to the bacteria in our body?
Normal flora
• What can it do for/to us?
– Aid the host (i.e. digestion, combat pathogens)
– Harm the host (opportunistic bacteria)
– Exist as commensals (no effect, or no known effect)
• What about other microorganisms?
– Viruses and parasites are NOT normal microbial
flora
– At least so far that’s what scientists believe in
Significance of Normal flora
• Influences our anatomy, physiology,
susceptibility to pathogens, and morbidity
• Germ-free animal studies
– Cesarean section  germ-free animals
– Free of bacteria, viruses, fungi, others
– Germ-free animal lived much longer
– 2x longer
Significance of Normal flora
Germ-free Animals
Regular
Counterparts
Lifespan
Twice
One
Cause of
death
Intestinal Atonia
Infection
Anatomic &
Physiological
Changes
1. Alimentary lamina
propria underdeveloped
2. No Ab
3. Intestinal epithelial cell
renewal rate down half
Significance of Normal flora
• How do normal flora help us?
Vitamin K, B12
Vitamin B groups
– Digestion, Vitamin production
– Help developing mucosal immunity
– Protect host from colonization by pathogens
106 pathogenic
microbes
GI infection
w/ normal flora
10 pathogenic
microbes
w/ reduced flora after
Streptomycin treatment
GI infection
Normal Flora Competing with Invading
Pathogens
Normal flora: Frenemies
(Friends or Enemies?)
• Opportunistic pathogens
• Immuno-suppression
– AIDS
• Radiation therapy
• Chemotherapy
– Cancer treatment
• Damage in mucosa
– injuries
Sites of human body that the normal
flora microbes colonize
• Respiratory tract and head
– Ear, eye, mouth, oropharynx, nasopharynx
– Sterile when healthy: sinuses, middle ear, brain, lower
respiratory tract (trachea, brochiole, lung)
• Gastrointestinal tract
– Esophagus, stomach, small and large intestine
• Genitourinary tract
– Urethra, vagina
– Sterile when healthy: bladder, cervix, uterus
• Skin
Distribution of Normal Flora in Human
Body
Adopted from Samuel Baron “Medical Microbiology”
Factors influencing normal flora
• Surrounding environment
– pH, temperature, redox potential, oxygen, water,
nutrient level and availability
• Diet
– Meat vs vegetarian diet
– High sugar diet
• Age
• Health condition
• Antibiotic/drug use
Normal Flora
(Commensal Microbes)
• Introduction
• Significance of the
Normal Flora
• Distribution of the
Normal Flora
Bacterial Pathogenesis
• Introduction
• Host Susceptibility
• Pathogenesis
Mechanisms
• Virulence Factors
Bacterial Pathogenesis
• Infection: growth and multiplication of a microbe
in or on our body with or without the production
of disease
• The capacity of a bacterium to cause disease
reflects its relative “Pathogenicity.”
• Virulence is the measure of the pathogenicity of a
microorganism.
• Pathogenesis refers both to (1) the mechanism of
infection and to (2) the mechanism by which
disease develops.
Host susceptibility
• Susceptibility to bacterial infections
– Host Defenses vs Bacterial Virulence
• Host defenses
– Barriers (skin & mucus) – the first line
– Innate Immunity (complement, macrophages & cytokines)
the early stage
– Adaptive Immunity (Ag-specific B & Tcells)  the later
stage
• Host defenses can be damaged by destructing barriers
or defective immune response
– e.g. Cystic Fibrosis (囊腫纖維症)
•  Pseudomonas aerugionsa (綠膿桿菌)infection
Strict pathogens
are more virulent and can
cause diseases in a normal
person.
Opportunistic pathogens are
typically members of
normal flora and cause
diseases when they are
introduced into
unprotected sites; usually
occur in people with
underlying conditions.
Transmission of infection
• Asymptomatic infection
– By producing none to mild disease, it help spreading
from person to person without detection
• Carrier
– Person or animal without symptoms but can spread
the disease
• Zoonosis
– Diseases transmitted between animals and men
• Hospital & Community-acquired infection
Entry into the human body
• Nature barrier
breakdown
• Skin, mucus, ciliated
epithelium
• Routes
– Ingestion, Inhalation
– Trauma, Needlestick
– Catheters, Bug bite
– Sexual transmission
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How do we measure pathogenicity?
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Transmissibility
Adherence to host cells
Invasion of host cells and tissues
Evasion of immune system
Toxigenicity
Bacterium may cause disease by
– Destroying tissues
– Producing toxins
– Over-stimulate immune response
Pathological mechanism of bacteria
infections
• Bacteria-mediated
• Host-mediated
• Virulence factors
– Bacterial factors that
cause disease
– e.g. toxins
How do bacteria become virulent?
Bacterial virulence mechanism
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Adherence
Invasion
Byproducts of growth (gas, acid)
Toxins
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Degradative enzymes
Cytotoxic proteins
Endotoxin
Superantigen
Induction of excess inflammation
Evasion of phagocytic and immune clearance
Capsule
Resistance to antibiotics
Intracellular growth
Ref: Chapter 14. Box 14-1. “Medical Microbiology”
Bacterial virulence factors
Adhesins
Pili (fimbriae)
Nonfimbrial adhesins
Invasion of host cells
Tissue damage
Growth byproducts
Tissue-degrading enzymes
Toxins
Exotoxins (cytolytic enzymes
and A-B toxins); enterotoxins;
superantigens;
Endotoxin and other cell wall
components
Antiphagocytic factors
Intracellular survival
Antigenic heterogeneity
Antigenic variation
Phase variation
Iron acquisition
Siderophores
Receptors for
iron-containing molecules
Resistance to antibiotics
Adhesion
• Adherence to epithelial or endothelial cells
• Without adhesion, there’s no colonization
• Adhesins
– Structures allowing bacteria to adhere
– Pili (fimbriae). e.g. E. coli P fimbriae 
erythrocytes and uroepithelial cells
– Lipotechoic acid (Gram-positive)
– Other surface proteins (Collagen-binding protein)
Adhesion
• Biofilm
– Ability of large number of bacteria to form a
“community” structure
– Bound by sticky polysaccharide
– Allow bacteria-bacteria and bacteria-host
attachment
– Dengue plaque, catheters,
– Immune evasion, stress resistant
Examples of biofilm formation
Invasion without prior damage
Shigella,
Salmonella,
Yersinia
Adherence
Injection of proteins
Endocytosis
Bacteria replication
Dormancy
Cell death
Tissue destruction
• Bacterial growth byproduct
– Through fermentation  acid, gas, etc
• Degradative enzymes
• Ex: anaerobic pathogens Clostridium
perfringens
– Collagenase, protease, hyaluronidase, toxins, acid,
gas
Endotoxin (LPS) mediated activity
Pathogenesis of
sepsis (septicemia)
Lipid A of LPS is
responsible for
endotoxin activity
Endotoxin-mediated toxicity
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Fever, leukopenia followed by leukocytosis,
Activation of complement, thrombocytopenia,
Disseminated intravascular coagulation,
Decreased peripheral circulation and perfusion to
major organs (multiple organ system failure),
• Shock and death.
• Peptidoglycan, teichoic and lipoteichoic acids of
gram-positive bacteria stimulate pyrogenic acute
phase responses and produce endotoxin-like
toxicity.
Exotoxins
• Made by both gram-positive and gram-negative
bacteria
• Often encoded on plasmid  gene transfer
• Cytolytic toxins
– α-toxin of C. perfringens  membrane-disruption
(sphingomyelins, membrane phospholipids)
• AB-toxins
– Binding domain, Action domain. Tissue-specific.
– Ribosomes, transporters, intracellular signaling
• Superantigens
Superantigen-mediated toxicity
• Bind to TCR and activate Tcells w/o Ag
• Autoimmune-like response
• Excess amount of
interleukins (cytokine)
• Staphylococcus aureus
– Toxic shock syndrome
toxin-1
• Streptococcus pyogenes
– Streptococcal pyrogenic
toxin (SpeA/C)
A-B toxins
• A chain has the inhibitory activity against
some vital function
• B chain binds to a receptor and promotes
entry of the A chain
• Modes of action
– Inhibit protein synthesis
– Inhibit neurotransmitter release
– Hyperactivation
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Immunopathogenesis
• Symptoms produced not by the bacteria
themselves
• But, through excessive immune responses
– Innate, immune, inflammatory
• Host protective mechanism overload
– When limited, it help to clear the pathogen
– When out of control, can be life threatening
• Cytokine storm – superantigen, toxins
• TB granuloma formation  tissue destruction
Bacteria fights back
• Encapsulation (Inhibition of phagocytosis and serum bactericidal
effect)
• Antigenic mimicry, masking, phase variation
• Intracellular multiplication
• Escape phagosome
• Inhibition of phagolysosome fusion
• Resistance to lysosomal enzymes
• Inhibition of chemotaxis
• Destruction of phagocytes
• Production of anti-immunoglobulin proteases
Mechanisms for escaping
phagocytic clearance and
intracellular survival
Mechanisms for escaping
phagocytic clearance and
intracellular survival
Mechanisms for escaping
phagocytic clearance and
intracellular survival
Summary
• Normal flora
– Skin and mucosal surfaces
– Helps host in many ways
• Digestion, vitamin production, mucosal immunity
development, combat pathogen colonization
– Could become pathogen
• Opportunistic infection
• Immune-suppressed individuals, barrier-broken
Summary
• Host defenses
– Barriers – Front line defense
– Innate immune response (macrophages,
cytokines)
– Adaptive immune responses (Ag-specific B & T
cells)
• Balance between host defense vs bacterial
virulence (the see-saw model)
Summary
• Disease symptoms can be caused by:
1. Bacterial mediated
- toxins, metabolic byproducts
2. Host mediated
- Hyper-stimulation of immune-responses leading to
further damages or even death
You be the pathogen!
A fun game to play
• 瘟疫公司Plague Inc