Infections

Pathology Chapter 4
Prof. Abdul Jabbar N. Al-Shammari

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 Host parasite-relation ship
• Infection is the invasion of a host organism's
body tissues by disease-causing agents, their
multiplication, and the reaction of host tissues to these
organisms and the toxins they produce.
• Infectious diseases, also known as transmissible
diseases or communicable diseases, comprise
clinically evident illness (i.e., characteristic medical
signs and/or symptoms of disease) resulting from
the infection, presence and growth
of pathogenic biological agents in an
individual host organism.

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 syndrome
• A syndrome, in medicine and psychology, is the
collection of signs and symptoms that are observed in,
and characteristic of, a single condition. In medical
genetics, a syndrome refers specifically to medical
condition where the underlying genetic cause has been
identified, and the collection of symptoms is
pathogenetically related. Examples of syndromes in
medical genetics include: Down syndrome, Stickler
syndrome, and Williams syndrome. Conditions such
as Toxic shock syndrome and Acquired Immune
Deficiency Syndrome are examples of non-genetic
syndromes

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• Ibn Sina (Avicenna, 980-1037), in The Canon of
Medicine, pioneered the idea of a syndrome in
the diagnosis of specific diseases
• The concept of a medical syndrome was
further developed in the 17th century
by Thomas Sydenham

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SYMPTOM
-refers to an observable behavior or state.
-there is no implication that an underlying problem
necessarily exists or that there is a physical etiology.
-the simplest level of analyzing a presenting problem.
SYNDROME
-the next higher level of analysis
-this term is applied to a constellation of symptoms that
occur together or co-vary over time.
-the term carries no direct implications in terms of
underlying pathology.
-Whether, in fact, certain sets of symptoms co-vary with
one another is an empirical question.
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• DISORDER
-like a syndrome, refers to a cluster of symptoms,
-but the concept includes the idea that the set of
symptoms is not accounted for by a more
pervasive condition.
-As with symptom and syndrome, there is no
implication of etiology
DISEASE
-a disorder where the underlying etiology is known.
-It is the highest level of conceptual understanding.

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 Infections
• Infections are caused by infectious
agents such as viruses, viroids,
and prions, microorganisms such
as bacteria, nematodes such
as roundworms and pinworms, arthropods
such as ticks, mites, fleas, and lice,
fungi such as ringworm, and
other macroparasitessuch as tapeworms

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 Infections
• Hosts can fight infections using their immune
system. Mammalian hosts react to infections
with an innate response, often
involvinginflammation, followed by
an adaptive response.

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 Bacterial infections
• Bacterial infections are classified by the causative
agent, as well as the symptoms and medical
signs produced.
• Symptomatic infections are apparent, whereas an
infection that is active but does not produce
noticeable symptoms may be
called inapparent, silent, or subclinical. An
infection that is inactive or dormant is called
a latent infection.
• A short-term infection is an acute infection. A
long-term infection is a chronic infection

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 Primary versus opportunistic

• Among the vast varieties of microorganisms,

relatively few cause disease in otherwise healthy
individuals. Infectious disease results from the
interplay between those few pathogens and the
defenses of the hosts they infect.
• The appearance and severity of disease resulting
from any pathogen, depends upon the ability of
that pathogen to damage the host as well as the
ability of the host to resist the pathogen.

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• Clinicians therefore classify infectious
microorganisms or microbes according to the
status of host defenses - either as primary
pathogens or as opportunistic pathogens:

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 Primary pathogens
• cause disease as a result of their presence or
activity within the normal, healthy host, and their
intrinsic virulence (the severity of the disease
they cause) is, in part, a necessary consequence
of their need to reproduce and spread. Many of
the most common primary pathogens of humans
only infect humans, however many serious
diseases are caused by organisms acquired from
the environment or which infect non-human
hosts.

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 Opportunistic pathogens
• can cause an infectious disease in a host with
depressed resistance.
• Opportunistic infection may be caused by microbes
ordinarily in contact with the host, such as pathogenic
bacteria or fungi in the gastrointestinal or the upper
respiratory tract, and they may also result from
(otherwise innocuous) microbes acquired from other
hosts (as in Clostridium difficile colitis) or from the
environment as a result of traumatic introduction (as
in surgical wound infections or compound fractures).

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 Opportunistic pathogens
• An opportunistic disease requires impairment of
host defenses, which may occur as a result
of genetic defects (such as Chronic
granulomatous disease), exposure
toantimicrobial drugs
or immunosuppressive chemicals (as might occur
following poisoning or cancer chemotherapy),
exposure to ionizing radiation, or as a result of an
infectious disease with immunosuppressive
activity (such as with measles, malaria or HIV
disease).

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 Koch’s postulates
• One way of proving that a given disease is
"infectious", is to satisfy Koch's
postulates (first proposed by Robert Koch),
which demands that the infectious agent be
identified only in patients and not in healthy
controls, and that patients who contract the
agent also develop the disease. These
postulates were first used in the discovery
that Mycobacteriaspecies cause tuberculosis.
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• Koch's postulates can not be applied ethically
for many human diseases because they
require experimental infection of a healthy
individual with a pathogen produced as a pure
culture. Often, even clearly infectious diseases
do not meet the infectious criteria. For
example, Treponema pallidum, the
causative spirochete ofsyphilis, cannot
be cultured in vitro - however the organism
can be cultured in rabbit testes

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 contagious disease
• Infectious diseases are sometimes called
"contagious disease" when they are easily
transmitted by contact with an ill person or
their secretions (e.g., influenza). Thus,
acontagious disease is a subset of infectious
disease that is especially infective or easily
transmitted.

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 Sepsis
• Sepsis is a serious medical condition caused by
an overwhelming immune response to
infection. Chemicals released into the blood to
fight infection trigger widespread
inflammation.
• Inflammation may result in organ damage.
• Blood clotting during sepsis reduces blood
flow to limbs and internal organs, depriving
them of nutrients and oxygen.

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• In severe cases, one or more organs fail.
In the worst cases, infection leads to a
life-threatening drop in blood pressure,
called septic shock. This can quickly lead
to the failure of several organs --
lungs, kidneys, and liver -- causing death.

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 Septicemia and Bacteriemia
• Septicemia when the bacteria are multiply and
produce their toxins in the blood.
• Bacteriemia presences of bacteria in Blood,
but not multiply.

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 MECHANISMS OF PATHOGENESIS
• Pathogenic properties of bacteria:
• microorganisms cause disease by two basic
mechanisms:
• 1) invasion of tissue
• 2) production of toxins.

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 Invasiveness:
• the ability to invade host tissues.

• Intracellular pathogens vs. extracellular

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 Invasiveness:
• pathogens:
• Intracellular pathogens generally produce
chronic disease;
• extracellular pathogens generally produce
acute disease (e.g. Mycobacterium
tuberculosis vs Streptococcus pyogenes).

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 Invasiveness:
• Adaptation: microenvironments of the host body
provide habitats for bacteria that are capable of
selective tissue invasion (e.g. Neisseria meningitidis
vs Streptococcus pneumoniae. Both inhabit the
human nasopharynx, but only the latter invades
the lower respiratory tract).
• Extracellular enzymes: Some bacteria produce
enzymes like hyaluronidase or collagenase that
degrade host tissues.

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 Toxigenicity: the production of toxins
Exotoxins:
*secreted proteins
*that are generally very toxic
* but heat labile.
* They are usually very good immunogens.
* Exotoxins are found mostly in Gram positive
organisms.

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 Endotoxins:
*complex polysaccharides (LPS)
* that are a part of the bacterial cell wall.
*They are usually poorly immunogenic.
*These toxins are released when cells
lyse,
* are generally heat stable,
*found mostly in Gram-negative bacteria.
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 Virulence:
• the combination of invasiveness and
toxigenicity producing the ability to
overcome host defenses.
•

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 Measurement of virulence:
• LD50 (% dead vs dose).
• Variability in virulence potential may be
genotypic (e.g. smooth vs rough strains of
Streptococcus pneumoniae,
• lysogeny in Corynebacterium diphtheriae)
• or phenotypic (e.g. the production of capsular
polysaccharides in the presence of rich
carbohydrates

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 TRANSMISSION OF DISEASE

Communicability: infectious disease can be transmitted either •

directly (e.g. person to person) or indirectly (e.g.
contaminated water). Factors involved in the communicability
of an infectious agent include:
Source, including dormant or latent infections (carriers). •
Number of infectious agents released from a host. •
Capability of surviving transit from host to host. •
Percentage of the host population that is susceptible to the •
agent.

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 Definitions:

Epidemiology: The science that studies when and where •

diseases occur and how they are transmitted.
Epidemic disease: A disease acquired by many host in a given •
area in a short time.
Endemic disease: A disease that is constantly present in •
certain population.
Infection: Is the process whereby a microorganism become •
established upon or within an individual, and thus bypasses
the defensive barrier of the host.
Pathogencity: The ability of a microorganism to cause disease. •

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 Extracellularly-Acting Toxins

• Non-Membrane Damaging
• 1. Hyaluronidase - This is also called the
spreading factor because it catalyzes the
breakdown of hyaluronic acid, the
substance that cements the human cells
together. This allows the bacterial cells to spread
through tissue causing a
condition known as cellulitis.
• 2. Coagulase- This enzyme catalyzes the
conversion of fibrinogen to fibrin with resultant
clot formation.

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 Extracellularly-Acting Toxins
• 3. Fibrinolysin - This catalyzes the conversion of
plasminogen to the fibrinolytic enzyme plasmin.
Thus it acts
opposite of coagulase. In Staphylococcus
aureus, the gene for fibrinolysin is on a
bacteriophage and is expressed
during lysogeny.
• 4. Lipase - Production of excessive amounts of
lipase allow bacteria to penetrate fatty tissue
with the consequent
formation of abscesses.

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 Extracellularly-Acting Toxins
• 5. IgA protease - Many bacteria which
colonize the mucous membranes produce an
IgA protease which degrades
secretory IgA.
• 6. Collagenase- This enzyme catalyzes the
degradation of collagen, a scleroprotein
found in tendons, nails and hair.

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 Membrane Damaging

• 1. Hemolysins - There are many different

types of hemolysins but, in each case, the
end result is lysis of the red
blood cell with resultant anemia.
• 2. Leukocidins- Again, there are many
different types of leukocidins, and some are
specific for only one type of
leukocyte. However, the end result in
lysis of leukocytes with resultant leukopenia.

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 Membrane Damaging

• 3.Phospholipase- This enzyme attacks any

cell with phospholipid in its membrane. The
result is widespread cell lysis.
Lecithinase - (phospholipase C) is an
enzyme which breaks down the lecithin in
the human cell plasma membrane,
resulting in cell lysis. It is especially
active on red blood cells. It is also called a
toxin.
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 Intracellular-Acting

• ADP-ribosyl transferases
• These promote the breakdown of
nicotinamide adenine dinucleotide (NAD)
into nicotinamide and adenine diphosphate
ribose (ADPR) and the covalent binding of the
ADPR to various proteins, thus inactivating
the bound protein.

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 Intracellular-Acting

• 1. Diphtheria toxin. Corynebacterium

diphtheriae cells lysogenized with the b-
phage produce a diphtheria toxin
which is a bipartite molecule, composed
of a B subunit which mediates binding to a
specific human cell surface
receptor and an A subunit which
possesses enzymatic (ADP-ribosyltransferase)
activity. The substrate of the
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 Intracellular-Acting

• reaction is human elongation factor 2 (EF2),

an essential part of the protein synthetic
machinery. diphtheria toxin
•
• EF2 + NAD ----> ADPR-EF2 + nicotinamide + H+
• The result of this reaction is inhibition of
protein synthesis and cell death.

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 Intracellular-Acting

• 2. Pseudomonas aeruginosa exotoxin A.

• This works in the same manner as diphtheria
toxin, i.e., it catalyzes the
ADP-ribosylation of EF-2. Human
epithelial cell death occurs.

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 Mode of action of exotoxin
• A. Exotoxin A, composed of fragments A and
B,
inhibits eukaryotic cell protein synthesis by
binding to specific receptors in the cell
membrane.

B. After fragment B binds to a cell receptor,

fragment A enters the cell.

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 Mode of action of exotoxin
C. Fragment A catalyzes the binding of •
nicotinamide adenine dinucleotide (NAD) to
Elongation Factor 2 (EF2), which is
required for translocation of nascent
polypeptide chains on eukaryotic ribosomes.
D and E. The reaction terminates in the
irreversible formation of an adenosine
diphosphate ribose. EF2 diphosphate -- EF2
complex with the release of nicotinamide
and hydrogen.
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 Mode of action of exotoxin
• 3. Pseudomonas aeruginosa exoenzyme S.
This is an ADP-ribosyl transferase whose
substrate is unknown. However
EF-2 is not the substrate. It also causes
human epithelial cell death.

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 Mode of action of exotoxin
• 4. Cholera toxin. Vibrio cholerae growing in the intestine
secretes an exotoxin composed of 5 B subunits, an A
subunit and an A2 subunit. On exposure to small
bowel epithelial cells, each B subunit binds to a receptor
on the
gut epithelium. Following binding the A and A2
moieties migrate through the epithelial cell membrane.
The A
subunit is an ADP-ribosyl transferase that catalyzes
the transfer of ADPR from NAD to a guanosine
triphosphate
(GTP)-binding protein that regulates adenylate cyclase
activity.

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 Mode of action of exotoxin
• The ADP-ribosylation of GTP binding protein
inhibits the GTP turnoff reaction and
causes a sustained increase in adenylate
cyclase activity which results in
excess secretion of isotonic fluid into the
intestine with resulting diarrhea.

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 Mode of action of exotoxin
• 5. Labile toxin (LT) of Escherichia coli. This toxin is
identical to that of cholera toxin. The ability to
produce it is
mediated by a plasmid.
• 6. Bordetella pertussis toxin. During an episode of
whooping cough, the B. pertussis cell produces an
exotoxin
composed of an A portion and 4 B portions. The
A subunit is an ADP-ribosyl transferase which elevates
cAMP but in a way different from cholera toxin. It
ribosylates a 41,000 MW membrane protein which
specifically
binds guanine nucleotide (the G1 protein).
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 Non-Ribosylating Toxins

• 1. Shiga toxin. Species of Shigella carry the

gene for shiga toxin on the chromosome. This
toxin has an A subunit
and 5 B subunits. The A subunit can be
divided into A1 and A2 subunits. The A1
moiety binds to the 60S human
ribosome which inhibits protein
synthesis. The toxin has a multiplicity of
effects; it is neurotoxic, cytotoxic and
enterotoxic.
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 Non-Ribosylating Toxins
• 2. Anthrax toxin. Bacillus anthracis produces
an exotoxin composed of three distinct
proteins: protective antigen,
edema factor and lethal factor. The
protective antigen is the binding protein, the
edema factor is an adenyl
cyclase and the lethal factor has an
unknown function but is thought to be
enzymatic. Dermal necrosis is the result
of the toxin action.
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 Non-Ribosylating Toxins
• 3. Tetanus toxin. Clostridium tetani produces
an endopeptidase that cleaves
synaptobrevins: this interferes with
vesicle formation at the myoneural
junction and the neural-neural junction in the
spinal cord. The result is muscle
spasm. The tetanus toxin serologically
cross-reacts with the botulinum toxin.

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 Non-Ribosylating Toxins
• A. Neurotransmission is controlled by the balance
between excitatory and inhibitory neurotransmitters.
B. The inhibitory neurotransmitters (e.g., GABA,
glycine) prevent depolarization of the postsynaptic
membrane and conduction of theelectrical signal.

C. Tetanospasmin does not interfere with

production or storage of GABA or glycine, but rather
their release (presynaptic activity).
D. In the absence of inhibitory neurotransmitters,
excitation of the neuroaxon is unrestrained.

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 Non-Ribosylating Toxins
• 4. Botulinum toxin. Clostridium botulinum produces
an endopeptidase that blocks the release of
acetylcholine at the myoneural junction.
Muscle paralysis is the result. the botulinum
toxin, like tetanus toxin, cleaves synaptobrevin
thus interfering with vesicle formation. This
toxin is used clinically in the treatment of dystonias
(Dystonia is a neurological movement disorder, in
which sustained muscle contractions cause twisting
and repetitive movements or abnormal postures).

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5. Pyocyanin. Pseudomonas aeruginosa produces this
non-enzyme protein which binds to the flavoproteins
of the cytochrome system. It interferes with
terminal electron transport causing an energy deficit
and cell death.

6. Adenylate cyclase. Bordetella pertussis produces a

calmodulin-independent adenylate cyclase which
inhibits and/or kills white blood cells.

7. NAD glycohydrolase. Shigella flexneri, upon being

phagocytized, produces a NAD glycohydrolase which
rapidly depletes the phagocyte of NAD, thus blocking
cellular metabolism and bacterial cell killing.

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Toxins with Undefined Mechanism of
Action
1. Trachea toxin. Bordetella pertussis tracheal cytotoxin kills cilia-
bearing cells.
2. b-toxin. Clostridium difficile produces a beta toxin which causes a
necrotic enteritis.
3. Exfoliating toxin. Staphylococcus aureus produces an exfoliating
toxin which causes a sloughing of skin (scalded
skin syndrome).
4. Toxic shock syndrome toxin. Staphylococcus aureus produces this
toxin which has an undefined mode of action but
is mediated through induction of interleukin-1. It causes
hypotension, rash, fever and desquamation of skin.
5. Erythrogenic toxin. Streptococcus pyogenes produces this toxin
which is similar to toxic shock syndrome toxin.
6. Mycolactone. Mycobacterium ulcerans produces this toxin which
causes skin and muscle necrosis.

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 End of chapter •

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