MECHANISMS of PATHOGENESIS
Part I
Host-Microbe Relationships
and Disease Processes
Chapter 14
Definitions
NORMAL FLORA or MICROBIOTA
• HOST – any organism that harbors another organism
• NORMAL FLORA - permanent and usually not pathogenic
microorganisms
– RESIDENT FLORA – always present on or in the human body
– TRANSIENT FLORA - come & go
– For a few hours to a few months
• In utero - germ-free
• Birth - microorganisms being to establish themselves
– Lactobacilli from mother’s vagina
– Feeding and breathing - colonization of URT and GIT
NORMAL FLORA
• HOST & NORMAL FLORA exist together
– The normal flora live in SYMBIOSIS with the human body
• SYMBIOSIS – association between two or more species
• COMMENSALISM = one organism benefits - the other is not
affected
– EX: Staphylococcus epidermidis - on our skin
– The normal flora usually benefits the host by prevents pathogens from
overgrowing
NORMAL FLORA - HOST INTERACTIONS
• MUTUALISM = both organisms benefit
– EX: E. coli in intestines produce vitamin K & some B vitamins
• ANTAGONISM = competition between the microorganisms
– Active competition ie between normal flora & pathogen
– BACTERIOCINS = proteins secreted by E. coli in the large intestine to
inhibit other bacteria
• PARASITISM = one organism (microorganism) benefits - the
other is harmed
– EX: Any successful pathogenic microorganism
NORMAL FLORA INTERACTIONS
• SYNERGISM = the effect of 2 organisms acting together is
greater than the effect of either one acting alone
– EX: Mycoplasma fermentans & HIV - if 1 cell is infected by both the
cell will die much faster than when infected by either one alone
OPPORTUNISTS
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OPPORTUNISTIC ORGANISMS = do not usually cause a
disease but can become pathogenic under certain
circumstances
OPPORTUNITY KNOCKS:
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Normal flora disrupted /destroyed
Host defense mechanisms compromised
Normal protective barriers of host are disupted
EX: S. aureus - causes toxic shock syndrome (TSS)
EX: Pneumocystis carinii - causes pneumonia in AIDS patients
Evidence of Disease
• Symptoms: changes in body functions such as pain and malaise
.Signs: changes that can be seen by an observer such as rash,
fever, swelling
.Syndrome: specific symptoms and signs associated with a
disease
TYPES of DISEASES
• INFECTIOUS
– Caused by bacteria, viruses, fungi, protozoa and helminths
• COMMUNICABLE INFECTIOUS DISEASES
– Contagious – can be spread from one host to another
• NON-COMMUNICABLE INFECTIOUS DISEASES
– Caused by: individual’s normal flora; ingestion of pre-formed toxins;
organisms found in the environment
– Not “caught” from another person
• NON-INFECTIOUS
– Caused by any other factor than infectious organisms
Occurrence of Diseases
• Sporadic: occurs occasionally in a population
• Endemic: a disease that is always found in the region
• Epidemic: a disease that many people acquire in a very short
period of time
• Pandemic: is an epidemic that occurs worldwide
CLASSIFYING INFECTIOUS DISEASES: DURATION
• ACUTE DISEASES = short duration (flu, cold)
• CHRONIC DISEASES = longer duration (AIDS, leprosy)
• SUBACUTE DISEASES = intermediate duration
• LATENT DISEASES = causative agent becomes latent
– Characterized by a period of time of no symptoms
– VZV - chicken pox then shingles
SPREAD of INFECTION
• THE INFECTIOUS AGENT:
– WHERE DOES IT COME FROM?
– HOW DOES IT GET INTO THE BODY?
– HOW DOES IT GET OUT OF THE BODY?
• HOW IS IT TRANSMITTED?
• WHERE IS IT BETWEEN & DURING DISEASE?
• Many pathogens can not survive outside the host long enough to
serve as a source of infection
– There must be sites where the pathogen can persist and maintain
infectivity
• RESERVOIR = a continual source of the disease causing
organisms, it can be living or inanimate objects
LIVING RESERVOIRS of INFECTION
• HUMAN RESERVOIRS:
– May transmit M/O directly or indirectly
– Carriers (asymptomatic people)
• AIDS, diptheria, typhoid fever, hepatitis, gonorrhea
– Convalescing patients
• ANIMAL RESERVOIRS:
– Wild and/or domestic
– ZOONOSES = a disease that occurs PRIMARILY in animals but that
CAN BE TRANSMITTED to HUMANS
– ~150 are known: anthrax, bubonic plaque, Lyme disease
– Transmitted: bites, contaminated hides/feathers, food, insect vectors
NONLIVING RESERVOIRS of INFECTION
• SOIL
– Many fungal diseases
– Clostridium tetani, Bacillus anthracis
• WATER
– HAV, pathogenic E. coli, polio and various gastrointestinal diseases,
typhoid fever
MODES of DISEASE TRANSMISSION
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New cases of infectious diseases
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Pathogen must leave reservoir or portal of exit  portal of entry in
the new host
Three categories:
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Contact transmission
Vehicle transmission
Vector transmission
CONTACT TRANSMISSION
• DIRECT: person-to-person
– HORIZONTAL transmission = from one person to another OR from one
part of the host to another part of the host
• Kissing, sexual contact, touching sores, shaking hands; direct fecaloral transmission
– VERTICAL transmission = from parent to offspring
• In egg or sperm; placenta; breast milk; birth canal
• INDIRECT TRANSMISSION:
– FOMITES ie nonliving object
• Syringe, drinking glass, contaminated linens, toys
• DROPLET TRANSMISSION:
– Coughing, sneezing, talking
VEHICLE TRANSMISSION
• Is transmission through a medium
A non-living carrier of an infectious agent from its reservoir
to a susceptible host
WATER
– Often due to fecal contamination
• Ex: Cholera, shigellosis, leptospirosis
FOOD
– Often due to incompletely cooked food or improperly
refrigerated foods  food poisoning
• Ex: Botulism, typhoid fever
AIR
– Mucus droplets – can travel a long distance
• Ex: Histoplasmosis, the flu, measles, tuberculosis
BODY FLUIDS
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VECTOR TRANSMISSION
• Usually an arthropod (insect)
• Transfer of M/O from feet or other body parts of insects to
food or skin of person
– Or person can be bitten by insects that are harboring these M/O and
thus introduce them to the body
• BIOLOGICAL transmission
– M/O replicates in vector (or at least part of the M/Os replicative cycle
occurs in the vector)
• Ex: Lyme disease, malaria
• MECHANICAL transmission
– Passive – no replication of M/O within vector
– Ex: shigellosis, typhoid fever
Emerging Infectious Diseases
• Diseases that are either new or changing
• Many different factors
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A new strain of pathogen that is more virulent
Overuse of antibiotics promotes resistant strains
Global warming increases survival of reservoirs and vectors
Modern transportation
Natural disasters
Animal control measures increase # of animals that carry microbes
Failure to comply with public health measures
AGE OF ANTIBIOTICS = NO DISEASE?
• EMERGING INFECTIOUS DISEASES
• New or changing diseases
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E. coli O157:H7
HIV
Ebola virus
Hepatitis C Virus
Drug resistant T.B.
• http://www.cdc.gov/ncidod/eid/eid.htm
NOSOCOMIAL INFECTIONS
• Hospital or other medical facility acquired
– 5-15% of patients affected
• ~2 million (10%) in American Hospitals
• 20,000 or more patients die/year
• THREE FACTORS:
– M/O in hospital
– Patient’s general health
– Chain of transmission
NOSOCOMIAL MICROORGANISMS
• Often the most pathogenic will be in the hospital
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S. aureus - urinary & respiratory infections
Pseudomonas aeruginosa - burns & surgical wounds
E. coli - urinary tract, neonatal meningitis
Enterococcus - urinary tract & wound
• Many M/O contain R plasmids = antibiotic resistance
• Endogenous infections
– Caused by opportunistic M/O among patient’s own normal flora
• Exogenous infections
– Caused by M/O that enter the patient through the environment
HOSPITAL PATIENTS
• Host is usually immunocompromised
• Resistance to infection is reduced
– Broken skin or mucous membranes
– Surgery, burns, catheters
• Suppressed immune system
– Drugs, diabetes, stress, HIV etc
CHAIN of TRANSMISSION
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Hospital staff ---> patient
Patient ---> patient
Fomites ---> patient
Ventilation system ---> patient
CONTROL:
– Educate personnel
– Practice good techniques
– Monitor for drug resistance
HOW VIRUSES CAUSE DISEASE
• Evade host immune system
– Sometimes can destroy cells of the immune system (cytocidal)
• CPE: Cytopathic Effects
– Abnormalities in the host cell induced by virus
• Inhibition of DNA, RNA and protein synthesis
– Inclusion bodies
• Small granules containing viral nucleic acids & proteins; found in
nucleus and cytoplasm
– Syncytia formation (giant cells)
• Cause several host cells to fuse together
EXTENT of HOST INVOLVEMENT
• SEPTICEMIA – “blood poisoning”
– Pathogens are present and multiplying in the blood
• BACTEREMIA - presence of bacteria in the blood
– Bacteria are being transported but are NOT multiplying in the blood
• VIREMIA - presence of viruses in the blood
– Viruses are being transported but are NOT multiplying in the blood
• TOXEMIA - presence of toxins in the blood causing symptoms
Definitions
• PATHOGENICITY: Is the ability of an organism to cause
disease
• VIRULENCE: Is the degree of pathogenicity
PORTALS of ENTRY
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Organisms need to ENTER to establish disease
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These portals of entry differ for different M/O
Some M/O have only 1 portal and some have several portals
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Respiratory, GI, & genitourinary tracts, conjunctiva (eyes)
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Largest organ & outermost protective layer
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Deposition directly under the skin into the tissues beneath skin or
mucous membranes
• Bites, burns, injections etc.
MUCOUS MEMBRANES
SKIN
PARENTERAL ROUTE
ENTRY of M/O into HOST
• PREFERRED PORTALS of ENTRY
– Route of entry that is required for establishment of disesase
• NUMBERS of INVADING M/O
– Number required for disease may vary from person to person
• ADHERENCE
– To tissue surfaces to establish infection
– ADHESINS = surface molecules on the pathogen that bind to
RECEPTORS on the surface of the host cell/tissues
– Can be found on capsules, fimbriae, capsid, or envelope of a virus
PORTALS of EXIT
• Usually pathogens leave host with body fluids or feces
• Gastrointestinal tract
– Diarrhea, vomitting
• Urogenital tract
– Sexual contact, urine
• Blood
– Insects, needles
– Wounds
• Respiratory tract
– Coughing, sneezing, speaking
ESTABLISHMENT of DISEASE
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To cause an infection or disease, microorganisms need to:
ENTER the organism (Portal of Entry – Chpt 15)
ADHERE to tissues
PENETRATE the tissues
DAMAGE CELLS to establish disease
HOW BACTERIA CAUSE DISEASE
• VIRULENCE FACTORS – characteristics that help M/O cause
infection and disease
– Structural: pili for adhesion
– Physiological: enzymes help to evade host defenses; toxins
• DIRECT ACTIONS by BACTERIA
– Adhesins – proteins/glycoproteins allow M/O to adhere to host cells
– Colonization – growth of M/O on epithelial cell surfaces (skin, mucous
membranes)
– Invasiveness – degree to which a M/O can invade and grow in host
tissues – related to virulence factors
– Toxins – any substance poisonous to other organisms
HOW BACTERIA CAUSE DISEASE
• VIRULENCE FACTORS – characteristics that help M/O cause
infection and disease
– Structural: pili for adhesion
– Physiological: enzymes help to evade host defenses; toxins
• DIRECT ACTIONS by BACTERIA
– Adhesins – proteins/glycoproteins allow M/O to adhere to host cells
– Colonization – growth of M/O on epithelial cell surfaces (skin, mucous
membranes)
– Invasiveness – degree to which a M/O can invade and grow in host
tissues – related to virulence factors
– Toxins – any substance poisonous to other organisms
BACTERIAL VIRULENCE FACTORS
• CAPSULES – resist host defenses
– Phagocytosis and complement
• CELL WALL COMPONENTS – some may help
– Streptococcus pyogenes - protein M
– Mycobacteria – waxes (mycolic acid)
• ENZYMES – extracellular enzymes
– Help to breakdown and dissolve material found between/around cells
• Hyaluronidase – “spreading factor”
– Streptococci produce - digests hyaluronic acid
• Coagulase – increases clotting (coagulation)
– Staphylococcus aureus produces – keeps organism from spreading BUT
also walls off M/O from immune system
BACTERIAL VIRULENCE FACTORS cont’d
• Streptokinase – dissolves clots (digests fibrin)
Streptococcus pyogenes- pathogens trapped in clots free
themselves to spread to other tissues
• Collagenases – breaks down collagen
– Produced by some Clostridia
• Hemolysins – hemolyze RBCs
– Alpha – partially digests hemoglobin  greenish color
– Beta – completely digests hemoglobin  clear area
– Staphylococci, Streptococci, Clostridium perfringes
• Streptolysin O (SLO) is sensitive to oxygen
• Streptolysin S (SLS) is not sensitive to oxygen
• Leukocidins – destroys neutrophils
– A type of WBC important for phagocytosis
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Produced by Staphylococci and Streptococci
BACTERIAL TOXINS
• TOXINS: poisonous substances produced by some M/O
– Some produce fever, cardiovascular disturbances; neurological
disturbances; diarrhea, shock
• INTOXICATION
– Diseases due to ingestion of the toxin (vs the M/O)
• EXOTOXINS
– Produced by bacterial and released into the surrounding medium
• ENDOTOXIN
– Lipid A portion of LPS released from cell wall of Gram –ve bacteria
BACTERIAL ENDOTOXIN
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ENDOTOXIN –
Causes chills, fever, weakness, aches & sometimes shock and death
Two outcomes possible:
Fever or pyrogenic response
Septic shock
ENDOTOXIN & the PYROGENIC RESPONSE
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Pyrogenic or Fever Response
Macrophage phagocytosis Gram -ve cell
Cell degraded releasing endotoxin
Endotoxin stimulates macrophage to secrete IL-1
– IL-1 = INTERLEUKIN 1 (Endogenous pyrogen)
• IL-1 causes the hypothalamus of brain to produce
prostaglandins
• PGs causes the body temperature to rise
ENDOTOXIC (SEPTIC) SHOCK #1
• Reaction is due to a cascade of events
• Fairly high fatality rate
– 100,000 die / year (USA)
– 13th leading cause of death in the USA
• Macrophage may also secrete tumor necrosis factor (TNF) or
cachetin in response to endotoxin
• TNF + IL-1 activate other cells in the immune system which
release MEDIATORS
– Constriction of small blood vessels & increased permeability of
capillaries
– Rapid decrease in blood pressure (HYPOTENSION)
– Impaired blood flow to the kidneys
ENDOTOXIC (SEPTIC) SHOCK #2
• RESULTS: Chills, fever, vomitting, diarrhea, rapid decrease in
b.p., convulsions, shock  death
• NORMAL? - a low level response allows for cells of the immune
system to leave the blood and enter the site of infection
• MAJOR PRODUCERS
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P. aeruginosa
E. coli
Klebsiella
Proteus
Enterobacter
Salmonella typhi
BACTERIAL EXOTOXINS #1
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EXOTOXINS –
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Usually proteins and enzymes, mainly produced by Gram +ve bacteria
Genes often carried on plasmids or bacteriophages
Easily diffuse to blood & lymph
Exotoxins can be destroyed by heat or chemicals to become
TOXOIDS.used as vaccines
Three categories of exotoxins based on effect:
CYTOTOXINS - Kill cells & affect their function
NEUROTOXINS - Interfere with normal nerve impulses
ENTEROTOXINS - Affect the GI tract
BACTERIAL EXOTOXINS #2
• DIPTHERIA Toxin - Corynebacterium diptheria
– Infected with a lysogenic phage
– Cytotoxin that inhibits protein synthesis, AB toxin
• Polypeptide B binds to cells; Polypeptide A inhibits protein synthesis
• ERYTHROGENIC Toxin – Streptococcus pyogenes
– 3 types: A, B and C
– Damages blood capillaries under the skin  rash of Scarlet Fever
• BOTULINUM Toxin – Clostridium botulinum
– Neurotoxin acts at neuromuscular junction
• Prevents impulses from nerve  muscle and inhibits release of
acetylcholine  flaccid paralysis
BACTERIAL EXOTOXINS #3
• TETANUS Toxin – Clostridium tetani
– Neurotoxin (tetanospasmin) – inhibits nerve cell impulses for muscle
relaxtion  uncontrollable muscle contractions
• VIBRIO Enterotoxin (Cholera Toxin)
– Vibrio cholerae – AB toxin
• Polypeptide B binds to cells; Polypeptide A induces formation of
cAMP  release of large amounts of fluid & electrolytes  “rice
water stools”
• STAPHYLOCOCCAL Enterotoxin
– Affects intestinal tract similar manner to cholera toxin
• STAPHYLOCOCCAL TSS Toxin
– Toxic Shock Syndrome Toxin
EXOTOXINS vs. ENDOTOXINS
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Gram positive and gram negative bacteria
Protein
Neurotoxin, cytotoxin, enterotoxin
Destroyed by heat
Can be made into TOXOID, neutralized by antitoxin
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Only gram negative bacteria
Lipid
Found in LPS of gram negative cells, LIPID A
Fever, toxic shock
Cannot be destroyed by heat
Cannot be made into toxoid, no neutralizing Ab.
PLASMIDS, LYSOGENY & PATHOGENICITY
• R factors - antibiotic resistance increases pathogenicity
• Plasmids that code for virulence factors
– Staph enterotoxin
– Certain fimbriae of E. coli
– Tetanus toxin
• LYSOGENY = incorporation of a phage into a bacterial
chromosome often containing gene for toxins
– C. diptheriae - prophage beta codes for diptheria toxin
– Streptococcus pneumoniae - phage codes for capsule