Microbial Mechanisms of Pathogenicity

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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 hosts 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
  agents 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
diseaseVirulence - degree of pathogenicity

• Many properties that determine a microbes
  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
Damage to host tissues
Production and delivery of various factors
Attachment to host tissues
Replication and evasion of immunity
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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 -
STDs
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 its 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 Components M protein Found on cell
surface and fimbriae of Streptococcus pyogenes.
Mediates attachment and helps resist
phagocytosis. M-protein is heat and acid
resistant Waxes 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 WBCs
• 1. Kills WBCs 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 RBCs
Streptococci
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1. Alpha (a) Hemolytic Streptococci - secrete
hemolysins that cause the incomplete lysis or
RBCs
Incomplete Lysis of RBC
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2. Beta (ß) Hemolytic Streptococci - secrete
hemolysins that cause the complete lysis of RBCs
Complete Lysis of RBC
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3. Gamma (?) Hemolytic Streptococci - do not
secrete any hemolysins
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C. Coagulase - cause blood to coagulate

• Blood clots protect bacteria from phagocytosis
  from WBCs 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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Tissue Damage Caused by Microbial Enzymes of
Clostridium perfringens
Severe gangrene caused by Clostridium
perfringens. Source Tropical Medicine and
Parasitology, 1997
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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

• Corynebacterium diphtheriae
• Bordetello pertussis
• Clostridium tetani
• Measles virus
• Mumps virus
• Rubella virus
• Polio virus
• Hepatitis B Virus

• 1. Diphtheria
• 2. Pertussis
• 3. Tetanus
• 4. Measles
• 5. Mumps
• 6. Rubella
• German Measles
• 7. Polio
• 9. Hepatitis B

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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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Muscle Spasms of Tetanus are Caused by Neurotoxin
of Clostridium tetani
Neonatal Tetanus (Wrinkled brow and risus
sardonicus) Source Color Guide to Infectious
Diseases, 1992
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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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Vibrio Enterotoxin Causes Profuse Watery Diarrhea
Rice-water stool of cholera. The A subunit of
enterotoxin causes epithelial cells to discharge
large amounts of fluids and electrolytes. Source
Tropical Medicine and Parasitology, 1995
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EHEC (Enterohemorrhagic E. coli)

• E. coli (0157H7)
• 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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More on Toxins
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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 bodys 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
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.
Incubation period is the interval between
exposure and illness onset.
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