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PATHOPHYSIOLOGY
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Chapter 8 - Part 1:
Infection and Immune Deficiencies
I. Infection
A. Normal Bacterial Flora
1. All body surfaces have bacteria that live in relationship with the human body.
2. Benefits of normal bacterial flora (commensal bacteria).

Produce enzymes that aid digestion of many molecules in the diet.

Produce antibacterial factors that prevent attachment and multiplication by pathogens.

Produce vitamins, specifically
B vitamins and vitamin K
.
3. Even normal flora can become pathogenic if the body’s defenses are breached.

Pathogenicity – situation in which the microorganism benefits at the expense of the human.

Opportunism – situation that occurs when benign microorganisms become pathogenic because of
decreased human host resistance
.
B. Factors for Infection
1. Mechanism of action – pathogens cause damage by:

Direct damage to cells.

Interference with cellular metabolism.

Release of pathogenic substances and toxins.
2. Infectivity - ability of the pathogen to invade and multiply in the individual.
3. Pathogenicity - ability of an agent to produce disease—success depends on its speed of reproduction,
extent of tissue damage, and production of toxins.
4. Virulence - potency of a pathogen measured in terms of the number of microorganisms or
micrograms of toxin required to kill a host—for example, measles is of low virulence; the rabies
virus is highly virulent.
5. Immunogenicity - ability of pathogens to induce an immune response.
6. Toxigenicity - a factor important in determining a pathogen's virulence, such as production of soluble
toxins or endotoxin.
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C. Classes of Infectious Microorganisms

There are 5 major classes of infectious organisms: viruses, bacteria, fungi, protozoa, and helminths.
1. Viruses

Intracellular parasites much smaller than bacteria (most are not visible with light microscope).

Take over the metabolic machinery of host cells and use it for their own survival and replication.

Frequently cause destruction of the infected cell.

Some contain viral DNA; others contain only RNA.
2. Bacteria

Prokaryocytes (lack a nucleus)

Can be aerobic (require oxygen) or anaerobic (do not require oxygen), motile or immotile.

Can take many forms; the most common bacterial forms are spherical (cocci), rodlike (bacilli), or
spiral (spirochetes).


Bacteria take up common stains differently, depending on the structure of their cell walls.
o
Gram-positive - stain dark purple when exposed to Gram stain; lack outer membrane.
o
Gram-negative - stain light pink when exposed to Gram stain; have an outer membrane.
There are many subclasses of bacteria that have specialized structures and mechanisms of disease
including Chlamydia, Rickettsiae, Mycoplasma, and Mycobacteria.
3. Fungi

Eukaryocytes (have a nucleus)

May take the form of yeasts (single-celled spheres) or molds (multicelled filaments or hyphae), or
both (dimorphic).

Not motile

Have thick polysaccharide cell walls that render them resistant to most antibiotics.
4. Protozoa

Eukaryocytes (have a nucleus)

Frequently motile single-celled intracellular parasites that are larger than bacteria.

Often infect the gastrointestinal tract, although infection of the liver, lungs, and central nervous
system is possible.

Protozoal infections usually occur in the presence of infected water (e.g., amoebas), venereal
transmission (e.g., Trichomonas vaginalis), ingestion (e.g., Toxoplasmosis gondii), or insect
vectors (e.g., malaria).
5. Helminths

Large parasites that can infect the gut, skin, eyes, and lymphatics.

Acquired through ingestion (e.g., pinworms or tapeworms) or through skin penetration
(hookworms, flukes).
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D. Pathogenic Defense Mechanisms
Pathogens avoid the host’s defenses (like the inflammatory and immune responses) in a number of ways:
1. Develop thick capsules that prevent phagocytosis (pneumococcus, tuberculosis, streptococcus).
2. Produce toxins that kill neutrophils.
3. Proliferate rapidly before a primary immune response can develop.
4. Hide within cells where the inflammatory and immune responses cannot reach them.
5. Cross placenta to infect fetus, whose immune system is still immature.
6. Undergo antigenic variation – change their surface proteins to evade immune response.

Antigenic drift – flu viruses undergo mutation of surface antigens H and N, allowing emergence
of a new flu strain each year

.
Antigenic shifts – major changes in antigenicity resulting from recombination of H and N genes
from different strains of viruses.
Can result in major worldwide pandemics
.
.

Gene switching – some parasites carry genes for many different surface antigens that they switch
on and off at frequent intervals.
Keeps them ahead of the adaptive immune system
.
E. Infection and Injury
1. Bacterial disease – most of the injury caused by bacteria is due to

Exotoxins – proteins that are released during cell growth from
toxins
.
gram-positive bacteria
o
Many exotoxins are directly cytotoxic and act as enzymes that affect host cells.
o
Exotoxins are immunogenic, so some vaccines (tetanus, diphtheria, and pertussis) are
.
directed against the toxin to protect the body from cellular damage.

Endotoxins – lipopolysaccharides (lipid A and lipid O) that are released from gram-negative
.
bacteria when the cell wall is injured during lysis or exposure to antibiotics.
o
Endotoxins set off a severe inflammatory response that can result in fever, endotoxic shock,
and dysfunction in many organs.
2. Viral disease
a. Viral replication
o
Viral replication depends on their ability to
o
Adsorption - the virus must be able to
o
Penetration into the cytoplasm - can occur by
envelops the virus), viral envelope
penetration
o
penetrate
bind to the surface
fusion
endocytosis
a permissive host cell.
of the host cell.
(the host cell
with the host cell wall, or
direct
of the cell membranes. The virus then sheds its protective coating (uncoating).
Replication – some viruses replicate in the cytoplasm and others replicate in the nucleus. They
use the
cell’s enzymes
to duplicate viral DNA or RNA and produce viral proteins.
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o
Assembly and release - new viruses are assembled in the cytoplasm and released from the cell so
that they can infect other cells. Release of viruses may result from
or may occur through
budding
lysis
of the host cell
of the virus from the host cell surface. This may
spare the cell from death but also renders it a persistent “factory” for viral replication.
o
Latency - some viruses remain
integrated
into the cell for many years, but
may cause active disease in the future in response to stimuli such as stress, hormonal changes,
or immunodeficiency (e.g. herpes zoster virus and shingles).
ACTIVITY 1: Antiviral drugs are designed to interfere with various steps in the virus’s life cycle.
Identify the steps in this process that you think would be easiest to disrupt and explain your reasoning.
b. Cellular effects of viruses
o
Dysfunction - DNA, RNA, or protein synthesis may be impaired.
o
Lysis - some viruses disrupt lysosomal membranes triggering apoptosis and autodigestion of
the cell.
o
Fusion - virally infected cells may fuse with healthy cells into structures called multinucleated
giant cells, or
o
syncytia
.
Antigenicity - may cause the host cell to present
foreign antigen
on its
surface, triggering an immune response against the infected cells.
o
Cancerous transformation - viruses may integrate themselves into the host DNA, causing the
cell to becomes cancerous. Uncontrolled growth of the cell may be caused by disruption of its
normal regulatory gene sequencing or because the virus itself contains a cancer-causing gene
(viral oncogenesis). Examples:
o
Hepatitis B virus, human papilloma virus
.
Secondary infection - viral infection can make tissues more susceptible to bacterial infection.
c. Immune response to viral infections
o
Viruses can often hide from the host defenses because they reproduce
o
Infected cells release
o
Because viruses must spread from cell to cell, an immune response develops which
interferon
to help neighboring cells protect themselves.
eventually cures the infection.
o
Viral infections are usually
intracellularly
self-limiting
.
.
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3. Fungal disease

Fungi can live

Fungi can adapt to the host environment and can survive in a wide variety of conditions.

Spread rapidly whenever host defenses are
anywhere
in the body (most commonly on the skin).
compromised
, such as when
commensal bacteria are lost (due to widespread use of antibiotics).

Cause serious systemic infection, especially in immunocompromised individuals who have
decreased phagocytic and T lymphocyte function →
o
opportunistic infection
.
Examples: Candida albicans (thrush, vaginal and systemic infections), Pneumocystis carinii
(pneumonia)

Do not respond to most antibiotics because they have

Vaccines are

Antifungal drugs are
not
thick polysaccharide walls
effective.
toxic
to host cells.
F. Clinical Manifestations of Infectious Disease

Variable, depending on the pathogen.

May be directly caused by the pathogen or indirectly caused by its products.

Fever – occurs when the set point for body temperature is raised in the hypothalamus (involves
prostaglandins). This can be due to either exogenous pyrogens (from pathogens) or endogenous
pyrogens (like IL-1, interferon, and tumor necrosis factor-alpha).
G. Countermeasures against Pathogenic Disease
1. Vaccines - induce a primary immune response, thus priming the immune system so that exposure to
the actual organism in the future is met with a vigorous and effective defense.

Inactivated or weakened, but antigenically similar material is used to make vaccine.

This could be an attenuated organism (live but weakened), dead organisms, a recombinant viral
protein, bacterial antigens, or toxins.

Attenuated viruses can cause life-threatening infections in immunocompromised individuals.

Some individuals fail to mount an adequate immune response to certain vaccines, either for
genetic reasons or because they are taking drugs that suppress their immune system.
2. Antimicrobials – substances that kill or inhibit the growth of bacteria, viruses, fungi, or parasites.

Antibiotics - used in the management of bacterial infections.
o
Different antibiotics are effective against different bacteria.
o
Modes of action - inhibit synthesis of cell wall, damage cytoplasmic membrane, alter
metabolism of nucleic acid, inhibit protein synthesis, or modify energy metabolism.

Antivirals - because viruses reproduce inside the host cell, it has been more difficult to develop
safe and effective antivirals.
o

Research into HIV has lead to new antivirals that can also treat other types of viruses.
Antifungals are frequently highly toxic and have many side effects.
.
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ACTIVITY 2: Why is it easier to develop effective drugs against bacteria than to develop effective
antiviral or antifungal agents?
H. Pathogenic Adaptations
1. Development of drug resistance - one of the most serious challenges to effective management of
infectious disease.
o
Occurs when microorganisms undergo a mutation of genes that renders them resistant to available
antimicrobials.
2. Antigenic changes (see above)
3. Suppression of immune response (see below)
II. Deficiencies in Immunity
A. Overview

Immunodeficiency is the failure of mechanisms of self-defense to function in their normal capacity.

Primary (congenital) immunodeficiencies are caused by
disrupt lymphocyte development or problems during
genetic defects
that
prenatal development

Secondary (acquired) immunodeficiencies are caused by

The clinical hallmark of immunodeficiency is
disease
.
or other physiologic alterations.
recurrent infections
, both by
common pathogens and by microorganisms that do not normally cause disease (opportunistic infections).


The type of infection usually reflects the immune system defect:
o
T cell defects result in more
o
B cell or complement defects result in primarily
fungal
and
viral
bacterial
infections.
infections.
Management of immunodeficient individuals requires constant vigilance for the early signs of
infection and rapid administration of antimicrobials.
B. Primary (Congenital) Immune Deficiencies

Most are the result of a single gene defect.

Usually become apparent from recurrent or persistent infections suffered by infants beyond six
months of age.
ACTIVITY 3: Why are primary immunodeficiencies not apparent until a child is about six months old?
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1. B lymphocyte deficiencies

Usually result in decreased levels of
antibody
, but do not affect T cell function.
a. Selective IgA deficiency - characterized by a lack of IgA production; results from an inability of
plasma cells to class-switch to IgA (but they can still make other antibody types).
o
Secretory immune system is compromised - results in infections of the
GI tract,
lungs & sinuses
o
.
Often accompanied by chronic intestinal candidiasis, autoimmune diseases, and allergy.
b. Bruton agammaglobulinemia - results from defects in the bursal-equivalent tissue necessary for
B cell
development.
o
Children with this disorder have absent or very low levels of all of the immunoglobulin types.
o
Highly prone to all types of infection, especially those by
o
Frequently experience otitis media, pharyngitis, pneumonia, and septicemia.
encapsulated
microorganisms.
2. T lymphocyte deficiencies

Because helper T cells are needed for many B cell responses, antibody levels are often
a. DiGeorge syndrome – results from congenital thymic aplasia (absence of
or hypoplasia and diminished
o
parathyroid
low
thymus
.
gland)
gland development.
T-cell number and function are severely compromised, resulting in numerous
fungal
infections (especially of the GI tract) and bacterial and viral pneumonias.
o
Parathyroid dysfunction leads to hypocalcemia and tetany.
o
Abnormal facial development is also common.
3. Combined deficiencies – affect both B and T cells.
a. Severe combined immunodeficiency disease (SCID) - caused by a failure of
stem cell
.
development into mature lymphocytes.
o
Most children with SCID have
very few
T and B lymphocytes, but they do have
normal numbers of neutrophils and macrophages.
o
SCID can also arise from inherited enzymatic defects in adenosine deaminase (ADA) that
result in the accumulation of toxic purines within rapidly dividing cells such as lymphocytes.
o
Children with this disorder lack both
cellular
and
humoral
immunity
and are highly susceptible to infections from viruses, bacteria, fungi, and parasites.
b. Bare lymphocyte syndrome - characterized by an inability of macrophages and lymphocytes to
express
HLA (MHC) class I or II antigens.
o
Very severe form of SCID - immune system cannot present foreign antigens to lymphocytes.
o
Causes failure of the
children before they reach
entire
immune system and results in fatal infections for most
5 years
of age.
c. Wiskott-Aldrich syndrome - X-linked recessive disorder characterized by decreased IgM production.
o
Impairs ability to defend against encapsulated bacteria (Streptococcus pneumoniae and
Haemophilus influenza), as well as many viruses.
o
Platelet dysfunction also occurs, leading to
bleeding
problems.
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4. Complement deficiencies
a. C3 deficiency – most severe. Often results in life threatening infections by encapsulated bacteria.
b. Deficiencies of terminal components (C5 – C9) – increase risk of Neisseria infections.
5. Phagocyte deficiencies

Often associated with inadequate opsonization of encapsulated bacteria, resulting in severe
infections of these (see C3 deficiency above).

Phagocytosis can also be impaired by inadequate numbers of phagocytes, especially neutrophils.

Phagocyte activity can also be defective because of an inability to kill organisms intracellularly.
o
These defects most commonly involve cytoplasmic granule formation (e.g., Chediak-Higashi
syndrome) or deficiencies in lysosomal enzymes such as myeloperoxidase (e.g., chronic
granulomatous disease).
C. Secondary (Acquired) Immune Deficiencies
1. Causes - caused by superimposed conditions, not genetically encoded.

Stress, trauma, malnutrition, malignancy, and infection.

Many medications can suppress immune function, especially those drugs used for the treatment of
cancer, inflammation, or transplant rejection.

Secondary immunodeficiencies are more common than primary immunodeficiencies.
2. Acquired Immunodeficiency Syndrome (AIDS)
a. Overview
o
Acquired dysfunction of the immune system caused by a retrovirus (HIV) that infects and
destroys CD4+ lymphocytes (helper T cells).
o
HIV (Human Immunodeficiency Virus) - virus responsible for AIDS
o
AIDS (Acquired Immune Deficiency Syndrome) - term used to refer to the disease syndrome
occurring in individuals who are HIV positive and who develop opportunistic infections,
tumors or other symptoms of AIDS.
b. Transmission - through body fluids via sexual contact, sharing of needles, contaminated blood
transfusions, and passage from mother to child at birth or through breast milk.
c. HIV Infection of Host Cells – HIV binds to cells with the CD4 receptor, which is located on Th
cells, macrophages, and a few others.
o
Impairs function of these cells, especially helper T cells.
o
Inserts into DNA of these cells and can remain latent for many years.
d. Clinical Course of HIV Infection
o
Early-stage disease – 1-6 weeks after infection patients may present with mild symptoms
resembling influenza, such as night sweats, swollen lymph glands, diarrhea, or fatigue.

The early stage, with or without symptoms, may last as long as 10 years without treatment.

During this period the virus is actively proliferating in lymph nodes.

Infected individuals may not test positive for HIV for many months after infection.
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o
Progression of HIV to AIDS – After infection with HIV the immune system attempts to
control the infection.

Cytotoxic T cells destroy virus infected cells, including Th cells, keeping the viral load low.

As the Th cell numbers drop, the Tc cells become less effective.

When the Th level drops below 200/mm3 the Tc cells are no longer effectively stimulated
and the amount of virus detectable in the blood begins to rise rapidly.
o
AIDS – a patient is diagnosed with AIDS if they have antibodies against HIV (test
seropositive), and have atypical or opportunistic infections and cancers (like Kaposi’s
sarcoma), as well as indications of debilitating chronic disease (e.g., wasting syndrome,
recurrent fevers).

New cases of AIDS are commonly diagnosed by decreased CD4+ T cell (Th) numbers
(less than 200/mm3; normal = 800-1000/mm3).

The average time from infection to development of AIDS is about 10 years without
treatment. With treatment this can be extended, perhaps indefinitely.

Death is usually due to overwhelming infections (without treatment) or side effects of
therapy (with HAART).
e. Treatment
o
Highly Active Antiretroviral Therapy (HAART) – consists of a combination of drugs,
including reverse transcriptase inhibitors and protease inhibitors to slow viral proliferation in
the body.
ACTIVITY 4: Answer the following questions.
1. Which of the primary immunodeficiencies does AIDS most closely resemble? Why?
2. What are the benefits of giving antiretrovirals drugs as a combination rather than individually?
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Chapter 8, Part 1 - ANSWER KEY TO ACTIVITIES
ACTIVITY 1: Antiviral drugs are designed to interfere with various steps in the virus’s life cycle.
Identify the steps in this process that you think would be easiest to disrupt and explain your reasoning.
1) Drugs could block adsorption to the targets, for example by using monoclonal antibodies that
attach to the adsorption sites and mask them.
2) Viral replication could be blocked by using artificial nucleotides that prevent elongation of the
DNA or RNA (AZT, zidovudine) or by interfering with viral enzymes (reverse transcriptase
inhibitors).
3) Assembly of viral particles could be inhibited by using substances that prevent normal
processing of the viral proteins (protease inhibitors).
ACTIVITY 2: Why is it easier to develop effective drugs against bacteria than to develop effective
antiviral or antifungal agents?
1) Since bacteria are prokaryotes it is easier to develop drugs that target bacterial processes, but do
not affect eukaryotic processes.
2) Bacteria often replicate outside of cells, where drugs can more easily reach them. Viruses divide
inside cells where they are less accessible.
ACTIVITY 3: Why are primary immunodeficiencies not apparent until a child is about six months old?
This is after passive immunity from mother (in the form of antibodies that cross the placenta and
those transmitted through breast feeding) runs out.
ACTIVITY 4: Answer the following questions.
1. Which of the primary immunodeficiencies does AIDS most closely resemble? Why?
It is most similar to a T cell deficiency (like DiGeorge syndrome) since the lack of T cells makes the
individual more susceptible to fungal infections and pneumonia due to opportunistic infection.
2. What are the benefits of giving antiretrovirals drugs as a combination rather than individually?
The drugs are given together to avoid development of resistance by the AIDS virus. It also would
affect more steps in the viruses replication cycle at the same time, and so be more likely to prevent
replication.