Transcript Document

Microbes, Health, and Disease
 Most microbes are harmless
• Many are beneficial
• Normal microbiota (normal flora) are organisms that
routinely reside on body’s surfaces
• Some can cause disease should opportunity arise
• Weaknesses or defects in innate or adaptive defenses
can leave individuals vulnerable to invasion
– Individuals are said to be immunocompromised
– Factors include malnutrition, cancer, AIDS or other
disease, surgery, wounds, genetic defects, alcohol
or drug abuse, and immunosuppressive therapy
following procedures such as organ transplants
 Types of host-microbe relationships
• Mutualism: win/win; both partners benefit
– E.g., in large intestine, some bacteria make vitamin K
and B vitamins for host; host gives bacteria warmth
and energy sources
• Commensalism: win/0; one partner benefits, other is
unharmed
– Many microbes living on skin are neither harmful nor
helpful, but obtain food and necessities from host
• Parasitism: win/lose; one organism benefits at the
expense of the other
– All pathogens are parasites, but medical
microbiologists often reserve the word for eukaryotic
pathogens (e.g., protozoa, helminths)
The Normal Microbiota
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 Normal microbiota
• Resident microbiota
inhabit sites for
extended periods
• Transient microbiota
inhabit temporarily
• Relatively little is known
• Human Microbiome
Project aimed at
studying
https://commonfund.nih.
gov/hmp/
Nose
Staphylococcus
Corynebacterium
Throat
Streptococcus
Moraxella
Corynebacterium
Haemophilus
Neisseria
Mycoplasma
Mouth
Streptococcus
Fusobacterium
Actinomyces
Leptotrichia
Veillonella
Skin
Staphylococcus
Propionibacterium
Large intestine
Bacteroides
Escherichia
Proteus
Klebsiella
Lactobacillus
Streptococcus
Candida
Clostridium
Pseudomonas
Enterococcus
Urethra
Streptococcus
Mycobacterium
Escherichia
Bacteroides
Vagina
Lactobacillus
The Normal Microbiota
 The Protective Role of the Normal Microbiota
• Significant contribution is protection against pathogens
• Covering pathogen binding sites
• Consuming available nutrients
• Production of compounds toxic to other bacteria
• Stimulation of adaptive immune system
• Mice reared in microbe-free environment have
underdeveloped lymphoid tissue
• Important in development of oral tolerance
• Immune system learns to lessen response to many
microbes that routinely inhabit the gut as well as food
– Basis of hygiene hypothesis, which proposes
insufficient exposure to microbes can lead to allergies
The Normal Microbiota
 The Dynamic Nature of the Normal Microbiota
• Healthy human fetus sterile until just before birth
• Exposed to microbes during passage through birth canal
• These take up residence; others from food, humans,
environment soon also become established on newborn
• Composition of normal microbiota is dynamic
• Changes occur in response to physiological variations
within host (e.g., hormonal changes) and as result of
activities of host (e.g., consuming food)
Principles of Infectious Disease
 Colonization refers to microbe establishing itself
on body surface
• Term infection can be used instead of colonization to
refer to pathogen
• Can be subclinical: 0 or mild symptoms
• Infectious disease yields noticeable impairment
– Symptoms are subjective effects experienced by
patient (e.g., pain and nausea)
– Signs are objective evidence (e.g., rash, pus
formation, swelling)
• Initial infection is a primary infection
– Damage can predispose individual to developing a
secondary infection (e.g., respiratory illness
impairing mucociliary escalator)
Principles of Infectious Disease
 Pathogenicity
• A primary pathogen is a microbe or virus that causes
disease in otherwise healthy individual
• Diseases such as plague, malaria, measles, influenza,
diphtheria, tetanus, tuberculosis, etc.
• Opportunistic pathogen (opportunist) causes disease
only when body’s innate or adaptive defenses are
compromised or when introduced into unusual
location
• Can be members of normal microbiota or common in
environment (e.g., Pseudomonas)
• Virulence refers to degree of pathogenicity
• Virulence factors are traits that allow microorganism
to cause disease
Principles of Infectious Disease
 Characteristics of Infectious Disease
• Communicable or contagious diseases easily spread
• Infectious dose is number of microbes necessary to
establish infection
• ID50 is number of cells that infects 50% of population
• Shigellosis results from ~10–100 ingested Shigella
• Salmonellosis results from as many as 106 ingested
Salmonella enterica serotype Enteritidis
– Difference partially reflects their ability to survive
stomach acid
Principles of Infectious Disease
 Course of Infectious Disease
• Incubation period: time between infection and onset
• Varies considerably: few days for common cold to years
for Hansen’s disease (leprosy)
• Depends on growth rate, host’s condition, infectious dose
• Illness: signs and symptoms of disease
• Convalescence: recuperation, recovery from disease
• Carriers may harbor and
spread infectious agent Incubation period Illness Convalescence
for long periods of time in Acute. Illness is short term because the pathogen is eliminated by the host
defenses; person is usually immune to reinfection.
absence of signs or
Incubation period
Illness (long lasting)
symptoms
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Chronic. Illness persists over a long time period.
Incubation period
Illness
Convalescence
Latent. Illness may recur if immunity weakens.
Latency
Recurrence
Primary Pathogen
Carrier
Commensalism
Virulence
Viremia
Infection
Toxemia
Hygiene hypothesis
Bacteremia
Signs
Mutualism
Colonization
Chronic infection
Latent infection
Subclinical
Systemic infection
Symbiosis
Symptoms
Incubation period
Parasitism
Acute infection
Opportunist
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 Koch’s Postulates
• Criteria Robert Koch used to
establish that Bacillus anthracis
causes anthrax
1 The microorganism must be present in every case of the
disease, but not in healthy hosts.
2 The microorganism must be grown in pure culture from
diseased hosts.
3 The same disease must be produced when a pure culture
of the microorganism is introduced into susceptible hosts.
4 The same microorganism must be recovered from the
experimentally infected hosts.
 Koch’s Postulates - Limitations
• Some organisms cannot be grown in laboratory medium
(e.g., causative agent of syphilis)
• Infected individuals do not always have symptoms (e.g.,
cholera, polio)
• Some diseases are polymicrobial (e.g., periodontal
disease)
• Suitable animal hosts not always available for testing
Mechanisms of Pathogenesis
 Several general patterns
•
•
•
•
Produce toxins that are ingested
Colonize mucous membranes, produce toxins
Invade host tissues, avoid defenses
Invade host tissues, produce toxins
• Goal of the pathogen is to multiply inside the host, then
exit to find a new host
• Pathogens and hosts generally evolve toward balanced
pathogenicity
• Pathogen becomes less virulent and host becomes more
resistant
Establishing Infection
 Adherence
• Pathogen has to attach to a receptor on a host cell
• Adhesins on bacterial pili
• Spikes on viruses
• Generally specific for certain receptors on certain cells
 Colonization
•
Must access iron
•
•
Must get around secretory IgA (antibody on mucus
membrane surface)
•
•
Some bind their own, some can break it off of host
proteins
Some make IgA proteases to break IgA
Must compete with normal microbiota for space and
nutrients
Courtesy of Chihiro Sasakawa, University of Tokyo
Establishing Infection
 Delivering Effector Proteins to Host Cells
• Secretion systems in Gram-negatives
• Several types discovered; some can inject molecules other
than proteins
• Type III secretion system Effector
Bacterial
(injectisome)
cytoplasm
– Effector proteins
induce changes
(e.g., altering of cell’s
Bacterial
periplasm
cytoskeleton structure)
– Can induce uptake
of bacterial cells
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Host cell
Courtesy of Chihiro Sasakawa, University of Tokyo
Invasion—Breaching the Anatomical Barriers
 Penetrating the Skin
• Generally through wounds or insect bites
 Penetrating Mucous Membranes
• Entry point for most pathogens
• Directed Uptake by Cells
• Pathogen induces cells to
engulf via endocytosis
– Salmonella uses type III
secretion system to inject
effector proteins; actin
molecules rearrange, yield
membrane ruffling
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Ruffle
M-cell surface
10 µm
Bacterial cell
Courtesy of Mark A. Jepson, from Trends in Microbiology v6, issue 1:359-365, 1 Sept 1998,
"Studying M cells and their role in infection"; M.A. Jepson and M.A. Clark, Elsevier Press
 Exploiting Antigen-Sampling Processes
• Mucosal-associated lymphoid tissue (MALT) samples
microbes
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3 Within an epithelial cell, Shigella cells cause
the host actin to polymerize. This propels
the bacterial cell, sometimes with enough
force to push it into the next cell.
 Example: Shigella
• Causes Shigellosis
• Fecal-oral transmission
• Causes diarrhea, blood
and/or mucus in feces
Lumen of the intestine
Mucous
membrane
Shigella
M cell
Tissue
Macrophages
2 Shigella cells attach to the
base of the epithelial cells
and induce these cells to
engulf them.
1 Macrophages in the Peyer’s patches engulf material that
passes through M cells. Shigella cells survive and
replicate, causing the phagocytes to undergo apoptosis.
http://cmgm.stanford.edu/theriot/movies.htm#Hits
Avoiding the Host Defenses
 Hiding Within a Host Cell
• Allows avoidance of complement proteins, phagocytes,
and antibodies
 Avoiding Killing by Complement System Proteins
• Serum resistant bacteria resist complement
• Neisseria gonorrhoeae hijacks
host system, binds complement
a Host cell surface
regulatory proteins to avoid
C3b is quickly inactivated when it attaches to the surface.
activation of membrane attack
Complement
Other
C3b attaches to host cell
regulatory
complement
surface; complement regulatory
complex
protein
proteins
proteins inactivate it.
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C3b
Host cell surface
Avoiding Death by Phagocyte
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1 Prevent encounters
with phagocytes
• C5a peptidase
• Cytolytic toxins
C5a
Microbes
2 Avoid recognition
and attachment
• Capsules
• M protein
• Fc receptors
Pseudopod
C3b
Phagocyte
Lysosomes
C3b
Phagosome
Phagolysosome
C3b receptors
on phagocyte
Digestive
enzymes
3 Survive within phagocytes
• Escape from the phagosome
• Prevent phagosomelysosome fusion
• Survive within the phagosome
 Avoiding Destruction by Phagocytes (continued…)
• Avoiding Recognition and Attachment
• Capsules and M protein: interfere with opsonization; some
bind host’s regulatory proteins that inactivate C3b
– E.g., Streptococcus pneumoniae, Streptococcus
pyogenes
• Fc receptors: bind Fc region of antibodies
– E.g., Staphylococcus aureus, Streptococcus pyogenes
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Bacterium
Fab region of the antibody
(binds to antigen)
Antibody
Fc receptor on
bacterium (binds
the Fc region of
an antibody)
Fc region of the antibody
(phagocytes recognize
and bind this region as
an initial step in phagocytosis)
 Avoiding Destruction by Phagocytes (continued…)
• Surviving Within Phagocytes
• Escape from phagosome: prior to fusion with lysosomes
– Listeria monocytogenes produces molecule that forms
pores in membrane; Shigella species lyse phagosome
• Prevent phagosome-lysosome fusion: avoid destruction
– Salmonella sense ingestion by macrophage, produce
protein that blocks fusion process
• Survive within phagolysosome: few can survive destructive
environment
– Coxiella burnetii (Q fever) can withstand; delays
lysosome fusion, allows time to equip itself to survive
 Avoiding Destruction by Phagocytes
(continued…)
• Avoiding Antibodies
• IgA protease: cleaves IgA (a type of
antibody)
• Antigenic variation: alter structure of
surface antigens, stay ahead of adaptive
immune recognition
• Mimicking host molecules: cover surface
with molecules similar to those found in
host cell, appear to be “self”
http://andtheghostssosilver.blogspot.co
m/2009_06_01_archive.html
Damage to the Host
 Direct or indirect effects
• Direct (e.g., toxins produced)
• Indirect (e.g., immune response)
• Damage may help pathogen to exit and spread
• Vibrio cholerae induces watery diarrhea, up to 20
liters/day, which can contaminate water supplies
• Bordetella pertussis triggers severe coughing, pathogens
released into air
Direct Damage: Toxins
 Exotoxins: proteins with damaging effects
• Secreted or leak into tissue following bacterial lysis
• Foodborne intoxication results from consumption
• Destroyed by heating; most exotoxins are heat-sensitive
• Can act locally or systemically
• Proteins, so immune system can generate antibodies
• Many are fatal before immune response mounted
• Vaccines critical
• Antitoxin is made of neutralizing antibodies
• Neurotoxins damage nervous system
• Enterotoxins cause intestinal disturbance
• Cytotoxins damage variety of cell types
 Exotoxins (continued…)
• A-B toxins have two parts
• A subunit is toxic, usually an enzyme
• B subunit binds to cell, dictates cell type to be infected
– Can use B subunit to make vaccines
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Active subunit
Binding subunit
A
B
Binding site
1 B subunit binds to a
specific molecule
on the host cell.
2
Toxin is taken up
by endocytosis.
3 Toxin subunits separate
allowing the A subunit
to enter the cytoplasm.
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 Superantigens:
simultaneously bind
MHC class II and Tcell receptor
• T-cell interprets this
as antigen
recognition
• Toxic effect is from
massive cytokine
release from
nonspecific TH
activation
• Include toxic shock
syndrome toxin
(TSST) and
several
by S.
aureus, S.
pyogenes
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Antigen-presenting cell
Antigen-presenting cell
MHC class II
molecule
Peptide
recognized by
T-cell receptor
Peptide not
recognized by
T-cell receptor
Superantigen
T-cell
receptor
Helper T cell
a
Helper T cell
Helper T cell that recognizes peptide is b Helper T cell that does not recognize
activated; it proliferates and releases
peptide is activated because of superantigen;
cytokines.
it proliferates and releases cytokines.
Adapted from Arousing the Fury of the Immune System, 1998 Howard Hughes Medical Institute.
Please note that due to differing
operating systems, some animations
will not appear until the presentation is
viewed in Presentation Mode (Slide
Show view). You may see blank slides
in the “Normal” or “Slide Sorter” views.
All animations will appear after viewing
in Presentation Mode and playing each
animation. Most animations will require
the latest version of the Flash Player,
which is available at
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 Endotoxin
• Endotoxin is lipopolysaccharide (LPS)
• Lipid A triggers inflammatory response
– When localized, response helps clear bacteria
– When systemic, causes widespread response: septic
shock or endotoxic shock
• Lipid A typically released
following cell lysis
• Phagocytosis, MAC
formation, certain
antibiotics
• Activates innate and
adaptive defenses
• Toll-like receptors
• Heat-stable; autoclaving
does not destroy
http://faculty.ccbcmd.edu/courses/bio141/le
cguide/unit4/innate/u1fig10b.html
 Damaging Effects of the Immune Response
• Inflammation
• Phagocytic cells can release enzymes and toxic products
• Adaptive Immunity
• Antigen-antibody complexes can form, settle in kidneys
and joints, and activate complement system leading to
inflammation
• Cross-reactive antibodies: may bind to body’s own
tissues, promote autoimmune response
– E.g., acute rheumatic fever following S. pyogenes
infection
Mechanisms of Viral Pathogenesis
 Avoiding Immune Responses
• Avoiding the Antiviral Effects of Interferons
• Viruses may block expression of host genes or block
activation of enzymes
• Antibodies and Viruses
• Move cell to cell or cause cell fusion to avoid antibodies
• Modify surface antigens, outpace body’s capacity to
produce effective antibodies
– RNA virus replicases, HIV reverse transcriptase lack
proofreading ability; mutations are common
 Avoiding Immune Responses (continued…)
• Regulating Host Cell Death
• Prevent or delay apoptosis, control regulatory protein p53
• Block MHC class I presentation (NK cells get around this)
• Present “counterfeit” MHC class I molecules
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1 Virus
Peptide from
normal protein
MHC class I
molecule
2
Fake MHC
class I molecule
3
4
TC cell
Viral
genome
NK
cell
Virus infects cell.
Viral genome directs the cell
to make fake MHC class I
molecules that cannot
present peptides from
cytoplasmic proteins.
Because of the fake MHC class I
molecules, neither TC cells nor
NK cells can recognize that the
cell is infected.
Infected cell survives and
carries the viral genome.