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Chapter 22
Pathogenesis of Bacterial Infections
When antibiotics came into use in the middle of the last century it was supposed to be the
end for the bacteria. How wrong we were! Except for those prevented by immunization
the bacterial pathogens occupy as prominent position as any time since the widespread
implementation of public health measures a century ago. The emergence of new
pathogens and the resistance of familiar ones to the antimicrobial agents developed in the
“arms race” against them are primarily responsible. Staphylococcus aureus, the “All
Time Champion” of pathogens is just as prominent and just as confounding a cause of
disease today as when Sir Alexander Ogston observed it in the wounds of his surgical
patients in the 1880s. This chapter will lay out the basic mechanisms bacteria utilize to
produce disease.
Definitions
I. Pathogenicity – The ability of any bacterial species to cause disease in a susceptible
human host.
II. Pathogen – A bacterial species able to cause such disease when presented with
favorable circumstances (for the organism).
III. Virulence – A term which presumes pathogenicity but allows expression of degrees
from low to extremely high, for example:
1. Low virulence – Streptococcus salivarius on its own it seems incapable of
disease but if it lands on a damaged heart valve it can cause slow destruction.
2. Moderate virulence – E. coli is universally found in the colon but if
displaced to the urinary bladder regularly causes acute infection.
3. High virulence – Bordetella pertussis, the cause of whooping cough, causes
disease in almost every non-immune person it contacts
4. Extremely high virulence – Yersinia pestis, the cause of plague, is also
highly infectious and leads to death in a few days in over 70% of cases.
Humans and Bacteria
1. Commensals coexist in the normal flora
2. Opportunistic pathogens take advantage of breaks in defense
3. Primary pathogens cause disease on their own
4. Pathogens must move on to another host
5. Aerosols spread Legionella
6. Tampons enhance toxin production by some strains of Staphylococcus aureus
7. E. coli O157:H7 is spread by food processing
Attributes of Bacterial Pathogenicity
1.
2.
3.
4.
Genetic manipulation can inactivate and restore virulence
Virulence genes can be studied from genome sequences
Pathogens must establish a niche and persist long enough to produce disease
Success involves offense and confounding host defenses
I. Entry – Beating Innate Host Defenses
1.
2.
3.
4.
5.
6.
Microbes gain access from the environment
Skin is a major protective barrier
Secretions coat mucosal epithelium
IgA protease aids survival
Acids and enzymes aid in cleansing
Infection is dose-related
II. Adherence: The Search for a Unique Niche
1.
2.
3.
4.
Adhesin and receptor are required
Pili often bind mannose, fibronectin
Receptors may be specific to host cell type
Many have multiple attachment mechanisms
III. Strategies for Survival
A. Invasion: Getting into Cells
1. A few bacteria, like viruses, are obligate intracellular pathogens
2. Facultative intracellular pathogens and can grow as free-living cells in the
environment as well as within host cells
3. Invasive organisms employ invasins that direct bacterial entry into cells
4. Some invasins link to cell actin filaments
5. Bacteria enter cells initially within a membrane-bound, host-vesicular structure
6. Some bacteria enzymatically lyse the phagosome membrane and escape to the
nutrient-rich safe haven of the host cell cytosol
7. Other invasive pathogenic species remain in the phagosome and replicate
8. Some multiply in phagosome by blocking lysosome function
9. Injection secretion systems trigger invasion or tight binding.
B. Persisting in a New Environment
1. Subepithelial environment is different
2. Iron sources are important for the pathogen
3. Apoptosis may be induced
C. Confounding the Immune System
a. Antiphagocytic Activity
1. A fundamental requirement for many pathogenic bacteria is escape from
phagocytosis by macrophages and polymorphonuclear leukocytes.
2. Antiphagocytic capsule which is possessed by almost all principal pathogens
that cause pneumonia and meningitis
3. Polysaccharide capsules of interfere with complement deposition on the
bacterial cell surface by binding regulators of C3b which are present in serum
b. Antigenic Variation
1. Surface antigens can be varied
2. Antigenically different subpopulations escape immune surveillance
c. Induction of Apoptosis
1. Apoptosis may be induced in phagocytes
D. Injury
a. Exotoxins
1. Proteins secreted into their environment
2. Usually possess some degree of host cell specificity
i. A–B Exotoxins
1. B unit binds to cell receptor
2. A acts on target protein
3. Biologic effect depends on function of target protein
4. Effect may be inhibitory or stimulatory
ii. Membrane-Active Exotoxins
1. Insertion in cytoplasmic membrane creates a leaking pore
2. Pore-forming toxins are produced by some of the most
aggressive pathogens (Staphylococcus aureus, group A
streptococcus, E. coli)
iii. Hydrolytic Enzymes
1. Bacteria produce collagenase or hyaluronidase or convert serum
plasminogen to plasmin, which has fibrinolytic activity
2. Enzymatic actions cause injury, facilitate spread
iv. Superantigen Exotoxins
1. Bind directly to MHC II
2. Cytokines are released from large proportion of T cells
b. Endotoxin
1. In infections caused by Gram-negative organisms, the
lipopolysaccharide (LPS) endotoxin of the outer membrane is a significant
component of the disease process
2. LPS in the bloodstream causes shock, DIC
3. Lipid A is toxic portion
4. Peptidoglycan fragments are not called endotoxin
c. Damage Caused by Inflammation and Immune Responses
i. Persistent Inflammation
1. PMNs cause swelling, occupy space
2. Prolonged DTH is destructive
ii. Misdirected Immune Responses
1. Antibody, soluble microbial antigens, and complement can deposit immune
complexes in tissues and cause acute inflammatory
2. Antibody produced against bacterial antigens can also cross-react with certain
host tissues and initiate an autoimmune process
Genetics of Bacterial Pathogenicity
I. Plasmids
1. Genes on plasmids are multiple and related
2. Loss of virulence plasmids negates pathogenicity
II. Regulation of Virulence Genes
1. Pathogens can sense their environment
2. Virulence factors are produced just-in-time
III. Pathogenicity Islands
1. Large genomic segments transferred from an unrelated species
2. Genes for all components of virulence are included
IV. Clonality
1. Useful genes are preserved by clonality
2. Natural populations of many pathogens are proving to have a clonal structure
3. In some cases single clones are responsible for geographically widespread
disease