Microbial Mechanisms of Pathogenicity Prof. Khaled H. Abu-Elteen.
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Transcript of Microbial Mechanisms of Pathogenicity Prof. Khaled H. Abu-Elteen.
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Microbial Mechanisms of Pathogenicity
Prof. Khaled H. Abu-Elteen
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Infection and Disease
A. Definitions
B. Generalized Stages of Infection
C. Virulence Factors and Toxins
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A. Definitions
Disease and Infectious Disease• Disease
• Any deviation from a condition of good health and well-being
• Infectious Disease
A disease condition caused by the presence or growth of infectious microorganisms or parasites
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A. Definitions Pathogenicity and Virulence
• Pathogenicity
• The ability of a microbe to cause disease
• This term is often used to describe or compare species
• Virulence
• The degree of pathogenicity in a microorganism
• This term is often used to describe or compare strains within a species
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Definitions
Acute infection vs. chronic infection • Acute Infection
• An infection characterized by sudden onset, rapid progression, and often with severe symptoms
• Chronic Infection
• An infection characterized by delayed onset and slow progression
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Definitions
Primary infection vs. secondary infection • Primary Infection
• An infection that develops in an otherwise healthy individual
• Secondary Infection
• An infection that develops in an individual who is already infected with a different pathogen
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Definitions
Localized infection vs. systemic infection • Localized Infection
• An infection that is restricted to a specific location or region within the body of the host
• Systemic Infection
• An infection that has spread to several regions or areas in the body of the host
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Definitions
Clinical infection vs. subclinical infection • Clinical Infection
• An infection with obvious observable or detectable symptoms
• Subclinical Infection
• An infection with few or no obvious symptoms
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Definitions
Opportunistic infection• An infection caused by microorganisms that are
commonly found in the host’s environment. This term is often used to refer to infections caused by organisms in the normal flora.
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Definitions
The suffix “-emia”• A suffix meaning “presence of an infectious agent”
• Bacteremia = Presence of infectious bacteria
• Viremia = Presence of infectious virus
• Fungemia = Presence of infectious fungus
• Septicemia = Presence of an infectious agent in the bloodstream
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Definitions
The suffix “-itis” • A suffix meaning “inflammation of”
• Examples:
– Pharyngitis = Inflammation of the pharynx
– Endocarditis = Inflammation of the heart chambers
– Gastroenteritis = Inflammation of the gastointestinal tract
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Definitions Epidemiology
• The study of the transmission of disease
Communicable Disease • A disease that can be transmitted from one
individual to another
Noncommunicable Disease • A disease that is not transmitted from one
individual to another
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Definitions
Endemic Disease• A disease condition that is normally found in a
certain percentage of a population
Epidemic Disease• A disease condition present in a greater than
usual percentage of a specific population
Pandemic Disease• An epidemic affecting a large geographical
area; often on a global scale
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Definitions
Reservoir of Infection • The source of an infectious agent
Carrier• An individual who carries an infectious agent
without manifesting symptoms, yet who can transmit the agent to another individual
Fomites• Any inanimate object capable of being an
intermediate in the indirect transmission of an infectious agent
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Definitions• Animal Vectors
• An animal (nonhuman) that can transmit an infectious agent to humans
• Two types: mechanical and biological • Mechanical animal vectors: The infectious agent is
physically transmitted by the animal vector, but the agent does not incubate or grow in the animal; e.g, the transmission of bacteria sticking to the feet of flies
• Biological animal vectors: The infectious agent must incubate in the animal host as part of the agent’s developmental cycle; e.g, the transmission of malaria by infected mosquitoes
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Definitions
Direct Mechanisms of Disease Transmission• Directly From Person to Person
• Examples: Direct Skin ContactAirborne (Aerosols)
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Definitions
Indirect Mechanisms of Disease Transmission• Examples:
Food & Waterborne Transmission Fomites Animal Vectors
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Pathogenicity - ability to cause disease
Virulence - degree of pathogenicity
Many properties that determine a microbe’s pathogenicity or virulence are unclear or unknown
But, when a microbe overpowers the hosts defenses, infectious disease results!
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Molecular Determinants of Pathogenicity
Production and delivery of various
factors
Attachment to host tissues
Replication and evasion of immunity
Damage to host tissues
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Microbial Mechanisms of Pathogenicity: How Microorganisms Cause Disease
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Portals of Entry
1. Mucus Membranes
2. Skin
3. Parentarel
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1. Mucus Membranes
A. Respiratory Tract• microbes inhaled into
mouth or nose in droplets of moisture or dust particles
• Easiest and most frequently traveled portal of entry
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Common Diseases contracted via the Respiratory Tract
Common cold Flu Tuberculosis Whooping cough Pneumonia Measles Diphtheria
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Mucus Membranes
B. Gastrointestinal Tract• microbes gain entrance thru
contaminated food & water or fingers & hands
• most microbes that enter the G.I. Tract are destroyed by HCL & enzymes of stomach or bile & enzymes of small intestine
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Common diseases contracted via the G.I. Tract Salmonellosis
• Salmonella sp.
Shigellosis• Shigella sp.
Cholera• Vibrio cholorea
Ulcers• Helicobacter pylori
Botulism• Clostridium botulinum
Clostridium botulinum
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Fecal - Oral Diseases
These pathogens enter the G.I. Tract at one end and exit at the other end.
Spread by contaminated hands & fingers or contaminated food & water
Poor personal hygiene.
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Mucus Membranes of the Genitourinary System - STD’s
Gonorrhea
Neisseria gonorrhoeae
Syphilis
Treponema pallidum
Chlamydia
Chlamydia trachomatis
HIV
Herpes Simplex II
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Mucus Membranes
D. Conjunctiva –• mucus membranes that
cover the eyeball and lines the eyelid
Trachoma• Chlamydia trachomatis
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2nd Portal of Entry: Skin
Skin - the largest organ of the body. When unbroken is an effective barrier for most microorganisms.
Some microbes can gain entrance through openings in the skin: hair follicles and sweat glands, wound …etc
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3rd Portal of Entry: Parentarel
Microorganisms are deposited into the tissues below the skin or mucus membranes
Punctures and scratches injections bites surgery
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Preferred Portal of Entry
Just because a pathogen enters your body it does not mean it’s going to cause disease.
pathogens - preferred portal of entry
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Preferred Portal of Entry
Streptococcus pneumoniae • if inhaled can cause pneumonia• if enters the G.I. Tract, no disease
Salmonella typhi • if enters the G.I. Tract can cause Typhoid Fever• if on skin, no disease
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Number of Invading Microbes
LD50 - Lethal Dose of a microbes toxin that will kill 50% of experimentally inoculated test animal
ID50 - infectious dose required to cause disease in 50% of inoculated test animals• Example: ID50 for Vibrio cholerea 108 cells
(100,000,000 cells)• ID50 for Inhalation Anthrax - 5,000 to 10,000
spores ????
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How do Bacterial Pathogens penetrate Host Defenses?
1. Adherence - almost all pathogens have a means to attach to host tissue
Binding Sites
adhesins
ligands
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Some cells use fimbriae to adhere.
Fimbriae can play a role in tissue tropism. Example - attachment of Candida to vaginal epithelial cells
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Adhesins and ligands are usually on Fimbriae Neisseria gonorrhoeae ETEC
(Entertoxigenic E. coli)
Bordetello pertussis
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Bacteria typically employ proteins known as Adhesins to attach to host tissues, which usually are located on ends of fimbriae.Alternatively, adhesins can consist of glycocalyx.
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2. Capsules Prevent phagocytosis attachment Streptococcus
pneumoniae Klebsiella pneumoniae Haemophilus
influenzae Bacillus anthracis Streptococcus mutans
K. pneumoniae
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Avoidance of Phagocytosis
Capsules are Involved in avoidance of
phagocyte-mediated recognition and
attachment.
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Cell Wall ComponentsM protein: Found on cell surface and fimbriae of Streptococcus pyogenes. Mediates attachment and helps resist phagocytosis. M-protein is heat and acid resistantWaxes [ Mycolic Acid]: In cell wall of Mycobacterium tuberculosis helps resist digestion after phagocytosis and can multiply inside WBC.
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3. Enzymes
Many pathogens secrete enzymes that contribute to their pathogenicity
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Enzymes and toxins that harm eukaryotic cells.
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A. Leukocidins
Attack certain types of WBC’s
1. Kills WBC’s which prevents phagocytosis 2. Releases & ruptures lysosomes
• lysosomes - contain powerful hydrolytic enzymes which then cause more tissue damage
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B. Hemolysins - cause the lysis of RBC’s
Streptococci
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1. Alpha (α) Hemolytic Streptococci
- secrete hemolysins that cause the incomplete lysis or RBC’s
IncompleteLysis of RBC
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2. Beta (β) Hemolytic Streptococci
- secrete hemolysins that cause the complete lysis of RBC’s
CompleteLysis of RBC
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3. Gamma (γ) Hemolytic Streptococci - do not secrete any hemolysins
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C. Coagulase - cause blood to coagulate
Blood clots protect bacteria from phagocytosis from WBC’s and other host defenses
Staphylococcus aureus - are often coagulase positive
Fibrinogen ----------------- Fibrin ( Clot)
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D. Kinases - enzymes that dissolve blood clots 1. Streptokinase - Streptococci 2. Staphylokinase - Staphylococci
Helps to spread bacteria - Bacteremia
Streptokinase - used to dissolve blood clots in the Heart (Heart Attacks due to obstructed coronary blood vessels)
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E. Hyaluronidase
Breaks down Hyaluronic acid (found in connective tissues)
“Spreading Factor” mixed with a drug to help spread the drug
through a body tissue Streptococci, Staphylococci, Clostridia and
pneumococci.
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F. Collagenase
Breaks down collagen (found in many connective tissues)
Clostridium perfringens - Gas Gangrene• uses this to spread through muscle tissue
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Severe gangrene caused by Clostridium perfringens.Source: Tropical Medicine and Parasitology, 1997
Tissue Damage Caused by Microbial Enzymes of Clostridium perfringens
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G. Necrotizing Factor
- causes death (necrosis) to tissue cells
“Flesh Eating Bacteria”
Necrotizing fasciitis
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H. Lecithinase
Destroys lecithin ( phosphatidylcholine) component of plasma membrane.
Allowing pathogen to spread Clostridium perfringens
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Summary of How Bacterial Pathogens Penetrate Host Defenses 1. Adherence 2. Capsule 3. Enzymes
• A. leukocidins B. Hemolysins• C. Coagulase D. Kinases• E. Hyaluronidase F. Collagenase• G. Necrotizing Factor H. Lecithinase
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4. Toxins Poisonous substances produced by
microorganisms toxins - primary factor - pathogenicity 220 known bacterial toxins
• 40% cause disease by damaging the Eukaryotic cell membrane
Toxemia • Toxins in the bloodstream• Toxigenicity: Capacity of microorganisms to
produce toxins.
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Two Types of Toxins
1. Exotoxins• secreted outside the bacterial cell
2. Endotoxins• part of the outer cell wall of Gram (-)
bacteria. ??
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Exotoxins versus Endotoxins
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I- Exotoxins
Mostly seen in Gram (+) Bacteria
Most gene that code for exotoxins are located on plasmids or phages
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Three Types of Exotoxins
1. Cytotoxins• kill cells e.g. Diphtheria toxin
2. Neurotoxins• interfere with normal nerve impulses.e.g.
Botulinum Toxin 3. Enterotoxins
• effect cells lining the G.I. Tract. e.g. Cholera toxin or choleragen.
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Response to Toxins
If exposed to exotoxins: antibodies against the toxin (antitoxins)
Exotoxins inactivated ( heat, formalin or phenol) no longer cause disease, but stimulate the production of antitoxin• altered exotoxins - Toxoids
Toxoids - modified toxin by heat, chemical, radiation, that have lost their toxicity. Injected to stimulate the production of antitoxins and provide immunity.
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Example: DPT Vaccine D - Diphtheria
• Corynebacterium diphtheriae
P - Pertussis• Bordetello pertussis
T - Tetanus• Clostridium tetani
DPT - Diphtheria Toxoid
Pertussis Antigen
Tetanus Toxoid
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Required Immunizations in Jordan 1. Diphtheria 2. Pertussis 3. Tetanus 4. Measles 5. Mumps 6. Rubella
• German Measles
7. Polio 9. Hepatitis B
Corynebacterium diphtheriae Bordetello pertussis Clostridium tetani Measles virus Mumps virus Rubella virus
Polio virus Hepatitis B Virus
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Most genes that code for exotoxins - plasmids or phages
Lysogenic convergence Diphtheria Cytotoxin inhibits
protein synthesis - resulting in cell death
Pseudomembrane• fibrin, dead tissue,
bacterial cells
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Lysogenic Convergence
Scarlet Fever Streptococcus pyogenes
• lysogenic convergence cytotoxin - damages blood capillaries and results in a
skin rash
• Strep Thoat with a rash
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Rash of Scarlet Fever Caused by Erythrogenic Toxins of Streptococcus pyogenes
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Diseases Caused by Staphylococcal Toxins
Scalded Skin Syndrome Toxic Shock Syndrome
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Diseases caused by Neurotoxins Botulism
• Clostridium botulinum• Gram (+), anaerobic, spore-forming rod, found in
soil
• works at the neuromuscular junction• prevents impulse from nerve cell to muscle cell• results in muscle paralysis
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Tetanus (Lock Jaw) Clostridium tetani Gram (+), spore-forming, anaerobic rod neurotoxin acts on nerves, resulting in the
inhibition of muscle relaxation tetanospasmin - “spasms” or “Lock Jaw”
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Neonatal Tetanus (Wrinkled brow and risus sardonicus)Source: Color Guide to Infectious Diseases, 1992
Muscle Spasms of Tetanus are Caused by Neurotoxin of Clostridium tetani
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Diseases caused by Enterotoxins
Cholera• Vibrio cholerae
• Gram (-) comma shaped rods
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Cholera toxin
Converts ATP into cAMP causes cells to excrete Cl- ions and inhibits
absorption of Na+ ions Electrolyte imbalance H2O leaves by osmosis H2O Loss (Diarrhea)
Two polypeptides: A (active) and B (binding). The A subunit of enterotoxin causes epithelial cells to discharge large amounts of fluids and
electrolytes.
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Severe cases, 12 - 20 liters of liquid lost in a day
Untreated cases - Mortality Rate about 50%
Mortality may be reduced to about 1%• administering fluids and electrolytes
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Rice-water stool of cholera. The A subunit of enterotoxin causesepithelial cells to discharge large amounts of fluids and electrolytes.Source: Tropical Medicine and Parasitology, 1995
Vibrio Enterotoxin Causes Profuse Watery Diarrhea
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EHEC (Enterohemorrhagic E. coli) E. coli (0157:H7) enterotoxin causes a hemolytic inflammation
of the intestines results in bloody diarrhea
• Toxin• alters the 60S ribosomal subunit
• inhibits Protein Synthesis
• Results in cell death
• lining of intestine is “shed”
• Bloody Diarrhea (Dysentary)
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Mor
e on
Tox
ins
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II- Endotoxins• Part of outer membrane surrounding gram-negative
bacteria.
• Endotoxin is lipid portion of lipopolysaccharides (LPS), called lipid A.
• Effect exerted when gram-negative cells die and cell walls undergo lysis, liberating endotoxin.
• All produce the same signs and symptoms:
• Chills, fever, weakness, general aches, blood clotting and tissue death, shock, and even death. Can also induce miscarriage.
• Fever: Pyrogenic response is caused by endotoxins.
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Exotoxins vs. Endotoxins
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Endotoxin is LPS
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Endotoxins (Continued)• Endotoxins do not promote the formation of
effective antibodies.• Organisms that produce endotoxins include:
• Salmonella typhi
• Proteus spp.
• Pseudomonas spp.
• Neisseria spp.
• Medical equipment that has been sterilized may still contain endotoxins.
• Limulus amoebocyte assay (LAL) is a test used to detect tiny amounts of endotoxin.
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Events leading to fever:• Gram-negative bacteria are digested by
phagocytes.
• LPS is released by digestion in vacuoles, causing macrophages to release interleukin-1 (IL-1).
• IL-1 is carried via blood to hypothalamus, which controls body temperature.
• IL-1 induces hypothalamus to release prostaglandins, which reset the body’s thermostat to higher temperature.
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Microbial Mechanisms of Pathogenicity: How Microorganisms Cause Disease
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III. B. The Normal Flora of Humans
Types of Symbiosis• Mutualism
• A symbiotic relationship in which both species benefit
• Commensalism
• A symbiotic relationship in which one species benefits, and the other species is neither helped nor harmed
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III. B. The Normal Flora of Humans
Types of Symbiosis (cont.)• Parasitism
• A symbiotic relationship in which one species benefits, and the other species is harmed
• Generally, the species that benefits (the parasite) is much smaller than the species that is harmed (the host)
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III. B. The Normal Flora of Humans
Normal flora is present in • skin
• upper respiratory tract
• oral cavity
• intestine, especially large intestine
• vaginal tract
Very little normal flora in eyes & stomach
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III. B. The Normal Flora of Humans
Notably absent in most all internal organs• Absent in:
• lower respiratory tract
• muscle tissue
• blood & tissue fluid
• cerebrospinal fluid
• peritoneum
• pericardium
• meninges
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III. B. The Normal Flora of Humans
Benefits of the normal flora • Nutrient production/processing
eg Vitamin K production by E. coli
• Competition with pathogenic microbes
• Normal development of the immune system
Normal flora and opportunistic infections
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III. C. Generalized Stages of Infection
1. Entry of Pathogen • Portal of Entry
2. Colonization • Usually at the site of entry
3. Incubation Period• Asymptomatic period
• Between the initial contact with the microbe and the appearance of the first symptoms
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III. C. Generalized Stages of Infection
4. Prodromal Symptoms• Initial Symptoms
5. Invasive period• Increasing Severity of Symptoms
• Fever
• Inflammation and Swelling
• Tissue Damage
• Infection May Spread to Other Sites
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III. C. Generalized Stages of Infection
6. Decline of Infection
5. Convalescence
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Course of Infectious Disease
Incubation period is the interval
between exposure and illness onset.
Convalescence is a time of
recuperation and recovery from
illness.
Depending on various factors an individual may still be infectious during
either incubation or convalescence.
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