Transcript Lecture 17

Chapter 15
Microbial Mechanisms of Pathogenicity
Microbial Mechanisms of Pathogenicity
• Pathogen – any microorganism that has the capacity to cause
disease
– Pathogenic microorganisms have special properties that allow them to
invade the human body or produce toxins.
• Pathogenicity is the ability of a pathogen (microorganism) to
produce a disease by overcoming the defenses of the host.
–
–
–
–
Portals of entry
Penetrate host defenses
Damage host cells
Portal of exit
• Virulence is the degree of pathogenicity.
– Provides a quantitative measure of the pathogenicity or the likelihood
of causing disease.
Microbial mechanism of pathogenicity
Number of
invading
microbes
Penetration or
evasion of
host defenses
Portals of entry
Adherence
Virulence factors
Damage
to host
cells
Portal of exit
Portal of entry
• Portal of entry - The specific route by which a particular pathogen
gains access to the body
1. Skin
• Most microorganisms cannot penetrate intact skin.
• Enter hair follicles and sweat ducts.
• Certain fungi (dermatophytes) grow on skin and produce enzymes that break down
keratin.
2. Mucous membranes
• Respiratory tract (most common portal of entry)
– Microorganisms that are inhaled with droplets of moisture and dust particles gain access to the
respiratory tract .
• Gastrointestinal tract
– Microorganisms enter the gastrointestinal tract via food, water, and contaminated fingers.
• Genitourinary tract
• The conjunctiva
3. Parenteral route
• Microbes are deposited directly into the tissues beneath the skin or mucous membranes.
(bites, injections, and other wounds).
• The Preferred Portal of Entry - many microorganisms can cause infections only
when they gain access through their specific portal of entry.
Numbers of Invading Microbes
Virulence can be expressed as:
ID50 - Number of microbes that will cause a demonstrable infection in 50%
of inoculated test animals - Infectious Dose
LD50 - Number of microbes that will kill 50% of inoculated test animals Lethal Dose
Bacillus anthracis
Portal of entry
ID50
Skin
10-50 endospores
Inhalation
10,000-20,000 endospores
Ingestion
250,000-1,000,000 endospores
Toxins
ID50
Botulinum toxin
0.03 ng/kg
Shiga toxin
250 ng/kg
Staphylococcal enterotoxin
1350 ng/kg
Pathogenicity – Adherence
• Colonization - the first stage of microbial infection - the
establishment of the pathogen at the appropriate portal of entry
• Adherence (attachment) is often an essential step in bacterial
pathogenesis or infection, required for colonizing a new host
– Adhesion - Process by which microorganisms attach themselves to cells.
• Requires the participation of two factors: a receptor and an ligand
– Microbial adherence to a eukaryotic cell or tissue surface involves
complementary chemical interactions between the host cell or tissue surface
and the bacterial surface.
Pathogenicity - Adherence
• Ligands or Adhesins : Surface molecules on
pathogen that bind specifically to host cell surface
molecules.
– The adhesins of bacterial cells are chemical components of capsules, cell walls
(lipopolysaccharide), glycocalyx, pili or fimbriae.
– Viral capsid, or components of the envelope.
• Receptors : Surface molecules on host tissues to which pathogen
adhesins bind.
– The host receptors are usually glycoproteins located on the cell membrane or
tissue surface (mucous - the mucopolysaccharide layer of glycosaminoglycan
covering animal cell mucosal surfaces)
• Interaction of ligand with host receptor can determine specificity for
host cells
– Inability to make attachment proteins or adhesins renders the microorganisms
avirulent
– Ability to change or block the ligand or its receptor can prevent infection
Pathogenicity - Adherence
• Biofilms - masses of microbes and their extracellular products
– attachment of free-floating microorganisms to
a surface using cell adhesion structures
– the first colonists facilitate the arrival of other cells
– during this colonization that the cells are able to
communicate via quorum sensing
– the biofilm grows through a combination of
cell division and recruitment
• Microbes form a biofilm in response to many factors
– cellular recognition of specific or non-specific attachment sites on a surface
– nutritional cues
– in some cases, by exposure of planktonic cells to sub-inhibitory concentrations of
antibiotics
• Biofilms have been found to be involved in a wide variety of
microbial infections in the body, by one estimate 80% of all infections
– The development of a biofilm may allow for an aggregate cell colony (or colonies) to be
increasingly antibiotic resistant.
How Bacterial Pathogens Penetrate Host Defenses
1. Capsules - Some pathogens have capsules that prevent them
from engulfment by phagocytes
 Streptococcus pneumoniae
 Haemophilus influenzae
 Bacillus anthracis
2. Cell Wall Components - Proteins in the cell wall can facilitate
adherence or prevent a pathogen from being phagocytized.
– M protein resists phagocytosis
 Streptococcus pyogenes
– Opa protein inhibits T helper cells
 Neisseria gonorrhoeae
– Mycolic acid (waxy lipid) resists digestion
 Mycobacterium tuberculosis
How Bacterial Pathogens Penetrate Host Defenses
3. Enzymes
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Leukocidins destroy neutrophils and macrophages.
Coagulase - cause fibrin clot
Kinases - destroy blood clots
Hyaluronidase - which destroys a mucopolysaccharide that holds cells
together
– Collagenase - hydrolyzes connective tissue collagen
– IgA proteases destroy IgA antibodies.
4. Penetration into Host Cells
– Invasins : proteins expressed on the cell surface of various pathogens that
alter actin filaments of host cell cytoskeleton, allowing microbes to enter cells.
• Salmonella typhinurium - . cause the actin of the host cell’s cytoskeleton to form a
basket that carries the bacteria into the cell (Membrane Ruffling)
How Bacterial Pathogens Damage Host Cells
1. Using the Host’s Nutrients:
–
Siderophores - (Greek: "iron carrier") are small, high-affinity iron chelating
compounds secreted by microorganisms such as bacteria and fungi.
2. Direct Damage –
–
–
Host cells can be destroyed when pathogens metabolize and multiply inside
the host cells.
Disrupt host cell function
Produce waste products
3. Most bacterial damage is carried out by toxins.
Toxin production
• Toxins - Poisonous substances produced by microorganisms
– Toxigenicity - The ability to produce toxins.
– Toxemia refers to the presence of toxins in the blood.
Toxin production - Exotoxins
• Exotoxins are produced by bacteria and released into the surrounding
medium.
• Proteins : Enzymes that carry out specific reactions.
• A-B toxins are are two-component protein
complexes
– B- Binding to host membrane
– A - Active
• Soluble in body fluids, rapidly transported throughout body in blood
or lymph.
• Exotoxins, not the bacteria, produce the disease symptoms.
• Produced mainly by gram-positive bacteria.
Exotoxins
• Cytotoxins : Kill or damage host cells.
– Membrane –disrupting toxins lyse host’s cells by:
 Making protein channels in the plasma membrane
– Leukocidins, Hemolysins, Streptolysins
 Disrupting phospholipid bilayer
• Neurotoxins : Interfere with nerve impulses.
• Enterotoxins : Affect lining of gastrointestinal tract.
• Antibodies called antitoxins provide immunity.
– Superantigen
• Overstimulating the body's immune response due to release of cytokines from host
cells
• Symptoms: fever, nausea, vomiting, diarrhea, shock, and death
• Toxoids : Toxins that have been altered by heat or chemicals.
– Usedas vaccines for diphtheria and tetanus
• Most genes for toxins are carried on plasmids or phages.
Exotoxin
Source
Relation to microbe
Chemistry
Fever?
Neutralized by
antitoxin?
LD50
Mostly Gram +
By-products of growing
cell
Protein
No
Yes
Small
Figure 15.4a
Toxin production - Endotoxin
• Endotoxin is lipid portion of lipopolysaccharides (LPS), called
lipid A.
– Part of outer membrane surrounding gram-negative bacteria.
– Release of endotoxins - bacterial cell death
•
•
•
•
Autolysis
External lysis mediated by complement and lysozyme
Phagocytic digestion of bacterial cells.
Antibiotics
• Endotoxins cause:
–
–
–
–
–
fever (by inducing the release of interleukin-1)
shock (because of a TNF-induced decrease in blood pressure)
blood clotting
tissue death
death
• Endotoxins can cause a weakening of the blood–brain barrier
and allow more bacteria from the bloodstream to cross it.
• Endotoxins do not promote the formation of effective antibodies.
Endotoxins and the Pyrogenic Response
• Fever: Pyrogenic response is caused by endotoxins
Medical equipment that has been sterilized may still contain
Figure 15.6
endotoxins
Endotoxins
Source
Relation to Microbe
Chemistry
Fever?
Neutralized by
Antitoxin?
LD50
Gram
Outer membrane
Lipid A
Yes
No
Relatively large
Figure 15.4b
Plasmids, Lysogeny, and Pathogenicity
•
Plasmids may carry and spread through conjugation genes for:
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–
–
–
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antibiotic resistance
toxins production
capsules
fimbriae
Lysogenic conversion can result in bacteria after bacteriophage
infection
– toxins production
– capsules.
Exotoxins & Lysogenic Conversion
Exotoxin
Lysogeny
A-B toxin
+
Streptococcus pyogenes
Membrane-disrupting
erythrogenic toxin
+
Clostridium botulinum
A-B toxin; neurotoxin
+
C. tetani
A-B toxin; neurotoxin
Vibrio cholerae
A-B toxin; enterotoxin
+
Superantigen
+
Corynebacterium diphtheriae
Staphylococcus aureus
Pathogenic Properties of Viruses
• Viruses gain access to host cells because they have attachment sites for
receptors on the host cell.
• Viruses avoid the host’s immune response by growing inside cells.
•
Viruses cause:
– Cytocidal effects (cell death)
– Noncytocidal effects (damage but not death).
• Visible signs of viral infections are called cytopathic effects (CPE).
– Cytopathic effects include:
• stopping of mitosis
• lysis - release of lysosomal enzymes
• transformation - abnormal cells that have lost contact inhibition.
• the formation of inclusion bodies
• cell fusion
• antigenic changes-on cell surface, causing destruction of infected cells
by immune system.
• chromosomal changes
Pathogenic Properties of Fungi, Protozoa, and
Algae
• Fungal infections don’t have well defined virulent factors.
• Secrete enzymes
• Toxins
• Allergic responses.
• Protozoa :
• Can cause damage to host tissue
• By the metabolic waste products of the parasite can produce disease symptoms.
– Some protozoa can change their surface antigens while growing in a host thus avoiding
destruction by the host’s antibodies.
• Some algae produce neurotoxins that cause paralysis when ingested
by humans.
Portals of Exit
• Just as pathogens have preferred portals of entry, they also have
definite portals of exit.
• Where microbes leave the body
• How they spread through the population
• Three common portals of exit are:
– the respiratory tract via coughing or sneezing
– the gastrointestinal tract via saliva or feces
– the genitourinary tract via secretions from the vagina or penis
• Arthropods and syringes provide a portal of exit for microbes in
blood.
Microbial mechanism of pathogenicity
Learning objectives
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Identify the principal portals of entry.
Define LD50 and ID50.
Using examples, explain how microbes adhere to host cells.
Explain how capsules and cell wall components contribute to pathogenicity.
Compare the effects of coagulases, kinases, hyaluronidase, and collagenase.
Define and give an example of antigenic variation.
Describe how bacteria use the host cell’s cytoplasm to enter the cell.
Describe the function of siderophores.
Provide an example of direct damage, and compare this to toxin production.
Contrast the nature and effects of exotoxins and endotoxins.
Outline the mechanisms of action of A-B toxins, membrane-disrupting toxins,
and superantigens. Classify diphtheria toxin, erythrogenic toxin, botulinum
toxin, tetanus toxin, Vibrio enterotoxin, and staphylococcal enterotoxin.
• Using examples, describe the role of plasmids and lysogeny in pathogenicity.
• List cytopathic effects of viral infections.