HOST-PARASITE RELATIONSHIP

Microorganisms are usually found in large numbers growing in associations with higher plants
and animals. Where the relationship is not mutually beneficial, the organism which receives the
benefit is the parasite and one which serves as donor is the host. The majority of host-parasite
combinations involving microorganisms appear relatively harmless to the host. Parasitism
therefore approaches commensalism in which one species benefits from the association, the other
being unaffected. The majority of these microorganisms are included in what is called the normal
flora of the body. Parasitism sometimes elicites a violet defensive reaction. There are three
possible outcomes: the parasite may be killed, the host may be killed, or the parasite and the host
reach a sort of equilibrium and live together.

Infection & Disease: Infection is the process whereby a microorganism becomes established
upon or within an individual and thus bypass the defensive barriers of the host. Infection is not
synonymous with infectious disease. The result of an infection may not be apparent, that is, the
result of infection cannot be identified by laboratory methods. Disease is defined as a departure
from the normal state of health as when the host is visibly or sensibly injured. Thus the
recognizable interaction between the infectious agent and the host is called disease.

Pathogenicity and Virulence: The term pathogenicity and virulence are sometimes loosely used
in the same sense. Pathogenicity denotes the ability of microorganisms to cause disease.
Virulence introduces the concept of degree, i.e. virulent organisms exhibit pathogenicity when
introduced into the host in very small numbers. Thus the term pathogenic is used in a qualitative
sense.
A parasite that is capable of penetrating the normal host defense mechanism of a healthy
susceptible individual is called a primary pathogen. A secondary pathogen or an “opportunist” is
a microorganism that cannot of its own powers pass the normal defense mechanisms have been
broken as wounds, prolonged disease, old age or poisons. Microorganisms do not posses any
special powers for injury; they become established and grow because the conditions permit. If
these microorganisms make their way to the blood or deep tissues, serious infections may result.
Thus a parasite is not always a pathogen, nor a pathogen always a parasite. For eg. Clostridium
tetani the causative agent of the disease tetanus cannot invade or live in normal tissues and is
therefore not a parasite. The organism, however, lives in dead tissue and is a true saprophyte.

Virulence
It is the capacity of a given strain of microbial species to produce disease. This indicates that
avirulent strain of pathogenic microorganisms also exist. Avirulent strains of Mycobacterium
tuberculosis, Corynebacterium diphteriae, Brucella abortus, and many other pathogenic species
are known. Virulence is measured in terms of the number of microorganisms or microorganism of
toxin necessary to kill a given host when administered by a certain route. It is usually expressed
as LD50 (lethal dose) i.e the number of organisms or micrograms of toxin which must be
administered to kill 50% of the organism.

Virulence Factors

Factors responsible for the virulence of a microorganism because they influence its ability to
cause disease by affecting its invasiveness and/or its toxigenicity.

• Adhesins - promote attachment to host cells and tissues

o pili - Escherichia coli and Neisseria gonorrhoeae use these to attach to urethral
cells; Salmonella and Escherichia coli uses them to attach to intestinal cells
 o capsules - Escherichia coli uses these for attachment to intestinal cells
o type III secretion system - Escherichia coli uses this to aid attachment to
intestinal cells
o hemagglutinins - bacteria (Salmonella and Bordetella) and many viruses use
these to attach to various host cells
o spikes (peplomers) - used by viruses to attach to cells they then infect
• Invasins - promote entrance into and/or movement through tissues or cells
o fibrinolysin - enzyme produced by Staphylococcus aureus and Streptococcus
pyogenes that dissolves blood clots, thus preventing bacterial isolation and
promoting spreading
o hyaluronidase - enzyme produced by bacteria like Staphylococcus aureus and
Streptococcus pyogenes that digests connective tissue, allowing them to spread
through tissues more readily
o hemolysins - enzymes produced by bacteria like Clostridium perfringens and
Staphylococcus aureus that dissolve red blood cells, causing anemia and limiting
oxygen delivery to infected tissues
o type III secretion system - Salmonella uses this to invade intestinal cells
o hyphal extension - fungi (Aspergillis, Candida, Stachybotrys) can invade the
tissues by growing hyphal elements into them
• Evasins - protect pathogen from host defense factors, especially phagocytes
o capsules - bacteria like Haemophilus influenzae, Neisseria meningitidis and
Streptococcus pneumoniae use these to avoid phagocytosis ...
o catalase - enzyme produced by Staphylococcus aureus and other bacteria to
degrade peroxides, thus promoting survival inside phagocytes
o coagulase - enzyme produced by Staphylococcus aureus and Yersinia pestis that
promotes blood clotting (coagulation), thereby walling-off the site of infection
and protecting these bacteria from phagocytosis; this also causes the
characteristic appearance of the skin in black plague
o M protein - this surface protein is produced by Streptococcus pyogenes to inhibit
surface complement activation (which would cause opsonization)
o leukocidins - Staphylococcus aureus, Streptococcus pyogenes and other bacteria
use these to kill phagocytes by damaging their membranes
o anti-phagosomal factors - various factors allow protozoans such as Leishmania
and bacteria such as Chlamydia, Listeria, Mycobacterium, Rickettsia, and
Salmonella to survive within phagocytes.
o immune system blockades - viruses and some bacteria can produce (or trigger
the host cell to ‘]=produce) molecules that shut down the immune response to the
parasite.

How Host Bacterial Pathogens Damage Host Cells:

1. By using the host’s nutrients: Iron is required for the growth of most
pathogenic bacteria. In order to obtain free iron, some pathogens secrete proteins
called siderophores. When iron is needed by a pathogen, siderophores are
released into the medium where they take the iron away from iron-transport
proteins by binding the iron even more tightly. Once the iron-siderophore is
formed complex is formed, it is taken up by siderophore receptors on the
bacterial surface. Then the iron is brought into the bacterium. In some cases the
iron is released from the complex to enter the bacterium; in other cases the iron
as part of the complex. Also it is possible that some bacteria produce toxins when
 iron levels are low. The toxin kill host cells, releasing their iron, which is then
available to the bacteria.
2. Direct Damage: Once pathogen attach to the host cells, they cause direct
damage as the pathogens use the host cell for nutrients and produce waste
products. As pathogens metabolize and multiply in cells, the cells usually
rupture. Pathogens that rupture cells can spread to other tissues in greater
numbers. Some bacteria, such as E. Coli, Shigella, and Neisseria gonorrhoeae,
can induce host epithelial cells to engulf them by a process that resembles
phagocytosis. These pathogens can disrupt host cells as they pass through and
can then be extruded from the host cells by a reverse phagocytosis process,
enabling them to enter other host cells. Some bacteria can also penetrate host
cells by excreating enzymes and by their own motility; such penetration can itself
damage the host cell. Most damage by bacteria, however, is done by toxins.
3. The production of Toxins: Toxins are poisonous substances that are produced
by certain microorganisms. The capacity of microorganisms to produce toxins is
called toxogenicity. Toxins transported by the blood or lymph can cause serious
and sometimes fatal, effects. Some toxins produce fever, cardiovascular
disturbances, diarrhea and shock. Toxin can also inhibit protein synthesis,
destroy blood cells and blood vessels. The term toxemia refers to the presence of
toxins in the blood.

Toxins are of two general types:

Exotoxins: Exotoxins are produced inside some bacteria as part of their growth and
metabolism and are secreted by its bacterium into the surrounding medium or
released following lysis. Exotoxins are proteins and many enzymes that catalyze only
certain biochemical reactions. Bacteria that produce exotoxins may be gram-positive
or gram-negative. The genes for most exotoxins are carried on bacterial plasmids or
phages. Because exotoxins are soluble in body fluids, they can easily diffuse into the
blood and are rapidly transported throughout the body.

The body produces antibodies called antitoxins that provide immunity to

exotoxins. When exotoxins are inactivated by heat or formaldehyde, iodine or other
chemicals, they no longer cause the disease but can still stimulate the body to
produce antitoxins. Such altered exotoxins are called toxoids.

Exotoxins are divided into three principal types on the basis of their structure and
functions: (1) A-B toxins, (2) membrane-disrupting toxins; (3) superantigens.

A-B toxins: A-B toxins also called type III toxins, were the first toxins, were the first
toxins to be studied intensively and are so named because they consist of two parts
designated A and B, toxins. The A part is the active (enzyme) component, and the B
part is the binding component. An example of an A-B toxin is the diphtheria toxin
which is illustrated ad follows:

1. In the first step, the A-B toxin is released from the bacterium.

2. The B part binds to a surface receptor on the host cell, usually a carbohydrate.
Following binding, the A-B toxin is transported across the plasma membrane into the
host cell cytoplasm.
3. Within the cell, the A-B components separate. The A part inhibit protein synthesis
and kills the host cell while the part B part is released from the cell.

Membrane-Disrupting Toxins: Membrane-disrupting toxins, also called type II

toxins, cause lysis of host cells by disrupting their plasma membrane. Some do this
by forming protein channels in the plasma membrane; others disrupt the
phospholipids portion of the membrane. The cell-lysing exotoxin of Staphylococcus
aureus is an example of an exotoxin that forms protein channels, whereas that of
Clostridium perfringens is an example of an exotoxins that disrupts the
phospholipids. Membrane disrupting toxins that kill phagocytic leukocytes are called
leukocidinds. They act by forming protein channels. Leukocidins are also active
against macrophages, phagocytes present in tissues. Most leukocidins are produced
by staphylococci, Streptococci and Pneumonococci. Membrane-disrupting toxins
that destroy erythrocytes, also by forming protein channels, are called hemolysins.
Hemolysins produced by Streptococci are called Streptolysins. One kind, called
streptolysin are called streptolysins. Another kind of Streptolysin is called
Streptolysin S because it is stable in an oxygen environment.

Superantigens: Superantigens or type I toxins, are antigens that provoke a very

intense immune response. They are bacterial proteins. Superantigens stimulate the
proliferation of immune cells called T-cells. In response to superantigens, T cells are
stimulated to release enormous amount of chemicals called cytokines. Cytokines are
small protein hormones that stimulate or inhibit many normal cell functions.
Bacterial superantigens include the staphylococci toxins that cause food poisoning
and toxic shock syndrome.

Exotoxins are named on the basis of several characteristics. For example,

neurotoxins attack nerve cells, cardiotoxins attack heart cells, heptatoxins attack liver
cells, leukotoxins attack leucocytes, enterotoxins attack the lining of the
gastrointestinal tract, and cytotoxins attack a wide variety of cells.

Diphtheria Toxin: Corynebacterium diphtheria produces the diphtheria toxin only

when it is infected by a lysogenic phage carrying the tox gene. This cytotoxin inhibits
protein synthesis in eukaryotic cells.

Erythrogenic toxins: Streptococcus pyogenes has the genetic material to synthesize

three types of cytotoxins, designated A, B, and C. These erythrogenic toxins damage
the plasma membranes of blood capillaries under the skin and produce a red skin
rash. Scarlet fever, caused by S. pyogenes exotoxins, is named for this characteristics
rash.

Botulinum Toxin: Botulinum toxin is produced by Clostridium botulinum.

Botulinum toxin is an A-B neurotoxin; it acts at the neuromuscular junction and
prevents the transmission of impulses from the nerve cell to the muscle. The toxin
accomplishes this by binding to the nerve cell and inhibiting the release of a
neurotransmitter called acetylcholine. As a result, botulinum toxin causes paralysis in
which the muscle tone is lacking. C. botulinum produces several different types of
botulinum toxin, and each possess a different potency.
 Tetanus toxin: Clostridium tetani produces tetani neurotoxin, also known as
tetanospasmin. This A-B toxin reaches the central nervous system and binds to nerve
cells that control the contraction of various skeletal muscles. The binding of
tetanospasmin blocks this relaxation pathway. The result is uncontrollable muscle
contrations, producing the convulsive symptoms of tetanus or “lock-jaw”.

The action of an exotoxin: Mechanism of action of diphtheria toxin

Enterotoxin - Escherichia coli, Staphylococcus aureus, Vibrio cholerae and other

bacteria produce this toxin, which causes intestinal cells to pump water and salts
(electrolytes) from the bloodstream into the intestine, causing diarrhea that leads to
dehydration, shock, and even death in the worst cases.

Vibrio Enterotoxin: Vibrio cholerae produces an enterotoxin called cholera toxin.

Subunit binds to epithelial cells, and subunit A causes cells to secrete large amounts
of fluids and electrolytes. Normal muscular contractions are disturbed, leading to
severe diarrohea that may be accompanied by vomiting.

Staphylococcal Enterotoxin: Staphylococcus aureus produces an enterotoxin that

effects the intestine in the same way as cholera toxin. A strain of S. aureus also
produces enterotoxins that result in the symptoms associated with the toxic shock
syndrome.

Exotoxins produced by various pathogenic bacteria

Bacterial species Disease Toxin Mode of action

Corynbacterium Diphtheria Diphtheric toxin Inhibition of protein

diphtheriae synthesis and the
synthesis of cytochrome
b; produces necrosis of
heart muscle, kidney and
liver.

Clostridium tetani Tetanus Tetanospasmin Causes muscle spasm

resulting in rigidity of
jaws
Clostridium Botulism Neurotoxin Causes paralysis
botulinum specially of respiratory

Clostridium Gas-gangrene ά- toxin Produces necrosis and

perfrigens haemolysis

Clostridium novyi
Staphylococcus Food poisoning Enterotoxin Stimulates centre of gas
aureus motility.Vomiting
commonly result
Streptococcus Scarlet fever Erythrogenic toxin Produce red rash
pyogenes

Vibrio cholerae Cholera Enterotoxin Causes massive

hypersecretion of water
and chloride and result in
diarrhea and acidosis.
Shigella dysentriae Dysentry Neurotoxin Causes paralysis and
haemorrhage

Yersinia pestis Plague Plague toxin Inhibits mitochondrial

respiration

Endotoxins – Endotoxins are the lipopolysaccharide (LPS) portion of the outer membrane of
gram-negative bacterial cell walls which is released when the bacteria disintegrate
and causes fever and/or endotoxin shock, depending on its concentration in the
bloodstream.

Endotoxins are released when gram-negative bacteria die and their cell walls undergo
lysis, thus liberating the endotoxin. Antibiotics used to treat diseases caused by gram-
negative bacteria can lyse the bacterial cells; this reaction releases endotoxin and may
lead to an immediate worsening of the symptoms, but the condition usually improves
as the endotoxin breaks down. All endotoxins produce the same signs and symptoms,
 regardless of the species of microorganism, although not to the same degree. These
includes chills, fever, weakness, generalized aches and in some cases, shock and even
death.

Another consequence of endotoxins is the activation of blood-clotting proteins,

causing the formation of small blood clots. These blood clots obstruct capillaries and
the resulting decreased blood supply induces the death of tissues. This condition is
referred to as disseminated intravascular clotting.

The fever (pyrogenic response) caused by endotoxins is believed to occur as:

• When gram –negative are ingested by phagocytes

• Degraded in vacuoles, the LPS of the bacterial cell wall are released. These endotoxins
cause macrophages to produce a cytokinin called interleukin-1, formely called
endogenous pyrogen
• Which is carried via the blood to the hypothalamus, a temperature control centre in the
brain
• IL-1 induces the hypothalamus to relase lipids called prostaglandins, which reset the
thermostat in the hypothalamus at a higher temperature. The result is a fever.

Bacterial cell wall caused by lysis or antibiotics can also produce fever by this
mechanism. Both aspirin and acetaminophen reduce fever by inhibiting the synthesis of
prostaglandis.

Shock refers to any life-threatening loss of blood pressure. Shock caused by bacteria is
called septic shock. Gram-negative bacteria cause endotoxin shock. Like fever, the shock
produced by endotoxins is related to the secretion of a cytokinin by macrophages. Phagocytosis
of gram-negative bacteria causes the phagocytes to secrete a polypeptide called tumor necrosis
factor (TNF) is damage to blood capillaries; their permeability is increased, and they lose large
amounts of fluid. The result is a drop in blood pressure that results in shock. Low blood pressure
has serious effects on the kidneys, lungs and gastro-intestinal tract.

It is important to have a sensitive test to identify the presence of endotoxins in drugs,

medical devices, and body fluids. One such laboratory test is called the Limulus amoebocyte
lysate (LAL) assay, which can detect even minute amounts of endotoxin.

Mechanism by which endotoxins cause fever

Exotoxins and Endotoxins