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Pathology of Infectious Disease

Prof. Dr. Blent Mzrak


BAU International University-Batumi

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Despite the availability of effective vaccines and antibiotics,
infectious diseases remain an important health problem
throughout the world. In the United States and other
high-income countries, infectious diseases are particularly
important causes of death among older adults and in
people who are immunosuppressed or who suffer from
debilitating chronic diseases. In the developing world,
inadequate access to medical care and malnutrition
contribute to a heavy burden of infectious diseases. In these
areas, six of the ten leading causes of death are infectious
diseases. Tragically, most of these deaths occur in children,
with respiratory and diarrheal infections taking the greatest
toll.

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How Microorganisms Cause Disease

Over the past few years, it has become evident that


humans and other animals harbor a complex ecosystem
of microbial ora (the microbiome) that has important
roles in health and disease. Most infectious diseases are
caused by pathogenic, noncommensal organisms, which
exhibit a wide range of virulence. Highly infectious
microbes produce disease in a high fraction of healthy
individuals, sometimes at doses of only a few
organisms.

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Routes of Entry of Microbes
Skin
The intact keratinized epidermis protects against
infection
by serving as a strong mechanical barrier and by
producing antimicrobial fatty acids and defensins,
small peptides that are toxic to bacteria.
Most skin infections are initiated by mechanical
injury of the epidermis.
Some pathogens penetrate the skin via an insect
or animal bite

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Gastrointestinal Tract

Most gastrointestinal pathogens are transmitted by food


or drink contaminated with fecal material. When hygiene
fails, diarrheal disease becomes rampant. The gastrointestinal tract
has several local defenses. Of these, acidic gastric
secretions are particularly important. A viscous layer of mucus
covers the gut throughout its length, protecting the surface
epithelium. Pancreatic enzymes and bile detergents can destroy
organisms with envelopes, such as certain viruses. As in the skin,
antimicrobial defensins are produce by gut epithelial cells. IgA
antibodies, produced in mucosal lymphoid tissues such as Peyer
patches and secreted into the gut lumen.
Gastrointestinal tract infections may occur when local
defenses are circumvented by a pathogen, or when they
are so weakened that even normal ora produce disease.

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Enteropathogenic pathogens may establish
symptomatic gastrointestinal disease through several
distinct mechanisms:
Adhesion and local proliferation. Examples include V.
cholerae and enterotoxigenic Escherichia coli
Adhesion and mucosal invasion. Pathogens such as
Shigella, Salmonella enterica,
Hijacking of host pathways of antigen uptake.
Ironically, multiple infectious agents, including
poliovirus, are taken up into the host through this same
pathway.

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Respiratory Tract

The microorganisms that infect the healthy respiratory


tract evade local defenses through several different mechanisms.
Some pathogenic respiratory viruses attach to and enter epithelial
cells in the lower respiratory tract and pharynx. For example,
inuenza viruses have envelope proteins called hemagglutinins that
bind to sialic acid on the surface of epithelial cells. Attachment
induces the host cell to endocytose the virus, leading to viral entry
and replication. The resulting damage to the respiratory epithelium
sets the stage for superinfection
Another important mechanism of establishing respiratory infection
is primary resistance to killing following phagocytosis. A classic
example is Mycobacterium tuberculosis.

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Urogenital Tract

Urine is sterile, and the urinary tract is protected from


infection by regular emptying during micturition. Urinary
tract pathogens (e.g., E. coli) almost always gain access via
the urethra and must be able to adhere to urothelium to
avoid being washed away. Anatomy plays an important
role in dictating risk. Obstruction of urinary ow or reux of
urine compromises normal defenses and increases susceptibility
to urinary tract infections.
From puberty until menopause the vagina is protected
from pathogens by lactobacilli, which ferment glucose to
lactic acid, producing a low pH environment that suppresses the
growth of pathogens.
The uterine cervix is covered by squamous mucosa that is also
resistant to infection.

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Vertical Transmission

Placental-fetal transmission. This is most likely to occur


when the mother is infected with a pathogen during
pregnancy. Some of the resulting infections interfere
with fetal development. Rubella infection
during the first trimester can lead to heart malformations, mental
retardation

Transmission during birth Examples include gonococcal


and chlamydial conjunctivitis.
Postnatal transmission in maternal milk. Agents transmitted in this
fashion include cytomegalovirus (CMV), human immunodeficiency
virus (HIV), and hepatitis B
virus (HBV).

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Spread and Dissemination of Microbes
Within the Body
While some disease-causing microorganisms remain
localized to the initial site of infection, others have the capacity to
invade tissues and spread to distant sites via the lymphatics, the
blood, or the nerves.
The consequences of blood-borne spread of pathogens
vary widely depending on the virulence of the organism,
the magnitude of the infection, the pattern of seeding,
and host factors such as immune status.
Other microbes cause characteristic patterns of disease
because of tropism for specifc tissues. These include
neurotropic viruses (rabies, poliovirus, varicella) and certain parasites.
Schistosoma hematobium travels to vessels in the urinary bladder and
causes cystitis.

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Release from the Body and
Transmission of Microbes
Infectious microbes use a variety of exit strategies
to ensure their transmission from one host to the
next. Depending on the location of of infection,
release may be accomplished by skin shedding,
coughing, sneezing, voiding of urine or feces, during
sexual contact, or through insect vectors.
Most pathogens are transmitted from person to
person by respiratory, fecal-oral, or sexual routes.

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Host-Pathogen Interactions
Host Defenses against Infection
The outcome of infection is determined by the
virulence of the microbe and the nature of the
host immune response, which may either
eliminate the infection or, in some cases,
exacerbate or even be the principal cause of tissue
damage.
The host has a large and complex armamentarium
of defenses against pathogens, including physical
barriers and components of the innate and adaptive
immune systems .

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Immune Evasion by Microbes

Most pathogenic microbes have developed one or


more strategies that allow them to evade host
defenses
Antigenic variation. This is an important
mechanism for escape from antibody-mediated
host defenses. To escape recognition, microbes
have many strategies that allow them to change
their coats by expressing different surface
antigens.

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Resistance to antimicrobial peptides
Resistance to killing by phagocytes.
Evasion of apoptosis and manipulation of host cell
metabolism.
Resistance to cytokine-, chemokine- and complement-
mediated host defense
Evasion of recognition by CD4+ helper T cells and CD8+
cytotoxic T cells
Another strategy exploits immunoregulatory
mechanisms to downregulate anti-microbial T cell
responses
The ultimate means of avoiding the immune system is
to lie low by establishing a state of latent infection in
which few if any viral genes are expressed

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Injurious Effects of Host Immunity

As mentioned earlier, while generally beneficial, the host


immune response to microbes can sometimes be the
major cause of tissue injury.
Damage to hepatocytes following hepatitis B virus and
hepatitis C virus infection is mainly due to the effects of
the immune response on infected liver cells rather than
cytopathic effects of the virus.
Inammation elicited by microbes also underlies a wide
variety of chronic inammatory disorders as well as some
forms of cancer.

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Infections in People with
Immunodeficiencies
Inherited or acquired defects in innate and adaptive
immunity often impair only part of the
immune system, rendering the affected individual
susceptible to specific types of infections.
Antibody deficiencies, as seen in patients with X-linked
agammaglobulinemia, lead to increased susceptibility
to infections by extracellular bacteria
Complement defects
Defects in neutrophil function
Defects in Toll-like receptor (TLR) signaling pathways
T-cell defects lead to susceptibility to intracellular
pathogens, particularly viruses and some parasites.

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Host Damage

Infectious agents establish infection and damage tissues by


three mechanisms:

They can contact or enter host cells and cause cell


death directly, or cause changes in cellular metabolism and
proliferation that can eventually lead to transformation.

They may release toxins that kill cells at a distance,


release enzymes that degrade tissue components, or
damage blood vessels and cause ischemic necrosis.

They can induce host immune responses that, though


directed against the invader, cause additional tissue
damage.

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Mechanisms of Viral Injury

Viruses can directly damage host cells by entering them


and replicating at the hosts expense. The predilection for
viruses to infect certain cells and not others is called tropism.
A major determinant of tissue tropism is the presence of
viral receptors on host cells.
For example, HIV glycoprotein gp120 binds to CD4 on T cells
and to the chemokine receptors CXCR4 (mainly on T cells) and
CCR5 (mainly on macrophages) , while Epstein-Barr
virus binds to complement receptor 2 (also known as CR2
or CD21) on B cells.

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Once viruses are inside host cells, they can
damage or kill the cells by a number of
mechanisms :
Direct cytopathic effects. Some viruses kill cells
by preventing synthesis of critical host
macromolecules (e.g., host cell DNA, RNA, or
proteins), or by producing degradative enzymes
and toxic proteins
Anti-viral immune responses. Host
lymphocytes can recognize and destroy virus-
infected cells
Transformation of infected cells

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Mechanisms of Bacterial Injury

Bacterial Virulence. Bacterial damage to host tissues


depends on the ability of the bacteria to adhere to
host cells, to invade cells and tissues, or to deliver
toxins.
Pathogenic bacteria have virulence genes that encode
proteins that confer these properties.
Mobile genetic elements such as plasmids and
bacteriophages can transmit functionally important
genes to bacteria, including genes that inuence
pathogenicity and drug resistance.

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Bacterial Adherence to Host Cells

Adhesins are bacterial surface proteins that bind


bacteria to host cells or extracellular matrix.
Pili are filamentous proteins on the surface of
bacteria that act as adhesins

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Virulence of Intracellular Bacteria

After bacteria enter the host cell, their fate (and that of
the infected cell) varies greatly depending on the
organism.
Shigella and E. coli inhibit host protein synthesis, replicate
rapidly, and lyse the host cell within hours. Most bacteria
are killed within macrophages when the phagosome
fuses with an acidic lysosome to form a phagolysosome,
but certain bacteria elude this host defense.
For example, M. tuberculosis blocks fusion of the
lysosome with the phagosome, allowing it to proliferate
unchecked within the macrophage.

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Bacterial Toxins

Any bacterial substance that contributes


to illness can be considered a toxin. Toxins are
classified as endotoxins, which are
components of the bacterial cell,
and exotoxins, which are proteins that are
secreted by the bacterium.

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Bacterial endotoxin

Endotoxin is a lipopolysaccharide (LPS) in


the outer membrane of Gram-negative bacteria
that both stimulates host immune responses and
injures the host.
High levels of endotoxin play a pathogenic role in
septic shock, disseminated intravascular
coagulation (DIC), and adult respiratory distress
syndrome, mainly through induction of
excessive levels of cytokines such as TNF, IL-1, and
IL-12

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Exotoxins

Exotoxins are secreted bacterial proteins that cause cellular injury and
disease.

Enzymes. Bacteria secrete a variety of enzymes (proteases, hyaluronidases,


coagulases, fibrinolysins)

Toxins that alter intracellular signaling or regulatory pathways.

Neurotoxins produced by Clostridium botulinum and Clostridium tetani


inhibit release of neurotransmitters, resulting in paralysis.

Superantigens are bacterial toxins that stimulate very


large number of T lymphocytes. Superantigens made by S. aureus and S.
Pyogenes cause toxic shock syndrome (TSS)

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Sexually Transmitted Infections

A variety of organisms can be transmitted through sexual


contact. The presence of an STI in children, unless acquired
during birth, strongly suggests sexual abuse.
STIs may become established and spread from the urethra,
vagina, cervix, rectum, or oral pharynx.

Infection with one STI-associated organism increases the risk


for additional STIs.

The microbes that cause STIs can be spread from a pregnant


woman to the fetus and cause severe damage to the fetus or
child.

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Spectrum of Inammatory Responses
to Infection
Many pathogens produce similar reaction patterns, and
few features are unique or pathognomonic for
a particular microorganism. Moreover, sometimes the
nature of the interaction between the microorganism and
the host determines the histologic features of the
inammatory response. Thus, pyogenic bacteria, which
normally evoke vigorous leukocyte responses, may cause
rapid tissue necrosis with little leukocyte exudation in a
profoundly neutropenic host.

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Suppurative (Purulent) Inammation

This pattern is characterized by increased vascular


permeability and leukocytic infltration,
predominantly of neutrophils. The neutrophils are
attracted to the site of infection by release of
chemoattractants from the pyogenic (pus-
forming) bacteria that evoke this response,
mostly extracellular gram-positive cocci and gram-
negative rods. Masses of dying and dead
neutrophils and liquefactive necrosis of the tissue
form pus.

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Mononuclear and Granulomatous
Inammation
Diffuse, predominantly mononuclear, interstitial
infiltrates are a common feature of all chronic
inammatory processes, but when they develop
acutely, they often are a response to viruses,
intracellular bacteria, or intracellular parasites. In
addition, spirochetes and helminths provoke
chronic inammatory responses. Which
mononuclear cell predominates within the
inammatory lesion depends on the host immune
response to the organism.

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Cytopathic-Cytoproliferative Reaction

These reactions are usually produced by viruses.


The lesions are characterized by cell necrosis or
cellular proliferation, usually with sparse
inammatory cells. Some viruses replicate within
cells and make viral aggregates that are visible as
inclusion bodies (e.g., herpesviruses or
adenovirus) or induce cells to fuse and form
multinucleated cells called polykaryons (e.g.,
measles virus or herpesviruses).

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Tissue Necrosis

Clostridium perfringens and other organisms


such as C. diphtheriae that secrete powerful
toxins cause such rapid and severe necrosis
(gangrenous necrosis) that tissue damage is the
dominant feature. The parasite E. histolytica
causes colonic ulcers and liver abscesses
characterized by extensive tissue destruction
with liquefactive necrosis and little
inammatory infltrate.

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Chronic Inammation and Scarring

Many infections elicit chronic inammation, which can


lead either to complete healing or to extensive scarring.
For example, chronic HBV infection may cause cirrhosis of
the liver, in which dense fibrous septae surround nodules
of regenerating hepatocytes with complete loss of normal
liver architecture and consequent changes in blood ow..
Sometimes the exuberant scarring response is the major
cause of dysfunction (e.g., the pipestem fibrosis of the
liver or fibrosis of the bladder wall caused by
schistosomal
eggs

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Special Techniques for Diagnosing
Infectious Agents
The gold standards for diagnosis of infections are culture,
biochemical or serologic identifcation, and, in some
cases, molecular diagnosis, depending on the organism
in question.
Some infectious agents or their products can
be directly observed in hematoxylin and eosinstained
sections. Many infectious agents, however, are best visualized
by special stains that identify organisms on the basis of
particular characteristics of their cell wall or coatGram, acid-
fast, silver, mucicarmine, and Giemsa stainsor by staining
with specific antibodies

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Nucleic acid amplifcation tests, such as
polymerase chain reaction (PCR) and
transcription-mediated amplification, are
increasingly being used for rapid identification
of microbes. These molecular diagnostic assays
have become routine for diagnosis of gonorrhea,
chlamydial infection, tuberculosis, and herpes
encephalitis.

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