Unraveling the Complicated Mechanisms and Molecular Pathogenesis Underlying [Specific Disease]: A Complete Exploration of Mobile Interactions, Genetic Components, and Therapeutic Implications
Unraveling the Complicated Mechanisms and Molecular Pathogenesis Underlying [Specific Disease]: A Complete Exploration of Mobile Interactions, Genetic Components, and Therapeutic Implications
PRINCIPLES OF PATHOGENESIS
A microorganism is a pathogen whether it is able to inflicting
illness; nonetheless, some organisms are extremely pathogenic (i.e.,
they typically trigger illness), whereas others trigger illness hardly ever.
Opportunistic pathogens are those who hardly ever, if ever, trigger
illness in immunocompetent folks however could cause severe
an infection in sufferers with diminished host defenses (immunocom-
promised) and, as mentioned in Chapter 6, are frequent members
of the physique’s regular flora.
Virulence is a quantitative measure of pathogenicity and is
measured by the variety of organisms required to trigger illness.
The 50% deadly dose (LD50) is the variety of organisms wanted
to kill half the hosts, and the 50% infectious dose (ID50) is the
quantity wanted to trigger an infection in half the hosts. Organisms
with a decrease LD50 (or ID50) are stated to be extra virulent than
these with a better LD50 (or ID50) as a result of fewer organisms are
wanted to trigger loss of life or illness.
The infectious dose of an organism required to trigger dis-
ease varies enormously among the many pathogenic micro organism. For instance,
Shigella and Salmonella each trigger diarrhea by infecting the
gastrointestinal tract, however the infectious dose of Shigella is much less
than 100 organisms, whereas the infectious dose of Salmonella
is on the order of 100,000 organisms. The infectious dose of
micro organism relies upon totally on their virulence elements (e.g.,
whether or not their pili permit them to stick effectively to mucous mem-
branes, whether or not they produce exotoxins or endotoxins, whether or not
they possess a capsule to guard them from phagocytosis, and
whether or not they can survive numerous nonspecific host defenses such
as acid within the abdomen).
There are two makes use of of the phrase parasite. Inside the context
of this chapter, the time period refers back to the parasitic relationship of
the micro organism to the host cells (i.e., the presence of the bacte-
ria is detrimental to the host cells). Micro organism which can be human
pathogens could be considered, due to this fact, as parasites. Some
bacterial pathogens are obligate intracellular parasites (e.g.,
Chlamydia and Rickettsia), as a result of they’ll develop solely inside
host cells. Many micro organism are facultative parasites as a result of they
can develop inside cells, outdoors cells, or on bacteriologic media.
The opposite use of the time period parasite refers back to the protozoa and the
helminths, that are mentioned in Half VI of this ebook.
WHY DO PEOPLE GET INFECTIOUS
DISEASES?
Folks get infectious illnesses when microorganisms overpower
our host defenses (i.e., when the stability between the organism
and the host shifts in favor of the organism). The organism or its
merchandise are then current in ample quantity to induce numerous
signs, similar to fever and irritation, which we interpret
as these of an infectious illness.
From the organism’s perspective, the 2 vital determi-
nants in overpowering the host are the variety of organisms to
which the host, or particular person, is uncovered and the virulence of those
organisms. Clearly, the better the variety of organisms, the
better is the chance of an infection. You will need to understand,
nonetheless, {that a} small variety of extremely virulent organisms can
trigger illness simply as numerous much less virulent organisms
can. The virulence of an organism is decided by its potential
to supply numerous virulence elements, a number of of which had been
described beforehand.
The manufacturing of particular virulence elements additionally deter-
mines what illness the micro organism trigger. For instance, a pressure of
Escherichia coli that produces one sort of exotoxin causes watery
(nonbloody) diarrhea, whereas a distinct pressure of E. coli that
produces one other sort of exotoxin causes bloody diarrhea.
This chapter describes a number of vital examples of particular
illnesses associated to the manufacturing of assorted virulence elements.
From the host’s perspective, the 2 essential arms of our host
defenses are innate immunity and bought immunity, the latter
of which incorporates each antibody-mediated and cell-mediated
immunity. A discount within the functioning of any element of
our host defenses shifts the stability in favor of the organism and
will increase the possibility that an infectious illness will happen. Some
vital causes of a discount in our host defenses embody
genetic immunodeficiencies similar to agammaglobulinemia and
acquired immunodeficiencies similar to acquired immunodefi-
ciency syndrome (AIDS), drug-induced immunosuppression
in sufferers with organ transplants, and most cancers sufferers who
are receiving chemotherapy. Sufferers with diabetes and auto-
immune illnesses additionally might have diminished host defenses. An
overview of our host defenses is introduced in Chapters 8 and 57.
In lots of cases, an individual acquires an organism, however no
infectious illness happens as a result of the host defenses had been suc-
cessful. Such asymptomatic infections are frequent and are
usually acknowledged by detecting antibody towards the organism
within the affected person’s serum.
TYPES OF BACTERIAL INFECTIONS
The time period an infection has multiple that means. One that means
is that an organism has contaminated the particular person (i.e., it has entered
the physique of that particular person). For instance, an individual could be contaminated
with an organism of low pathogenicity and never develop symp-
toms of illness. One other that means of the time period an infection is to
describe an infectious illness, similar to when an individual says, “I’ve
an an infection.” On this occasion, an infection and illness are being
used interchangeably, however you will need to understand that accord-
ing to the primary definition, the phrase an infection doesn’t need to
be equated with illness. Often, the that means will probably be obvious
from the context.
Micro organism trigger illness by two main mechanisms: (1) toxin
manufacturing and (2) invasion and irritation. Toxins fall
into two common classes: exotoxins and endotoxins. Exo-
toxins are polypeptides launched by the cell, whereas endotoxins
are lipopolysaccharides (LPS) that type an integral a part of the
cell wall of gram-negative micro organism. Endotoxins should not actively
launched from the cell and trigger fever, shock, and different general-
ized signs. Each exotoxins and endotoxins by themselves
could cause signs; the presence of the micro organism within the host
isn’t required. Invasive micro organism, however, develop to
massive numbers regionally and induce an inflammatory response
consisting of erythema, edema, heat, and ache. Invasion and
irritation are mentioned later within the part entitled “Deter-
minants of Bacterial Pathogenesis.”
Many, however not all, infections are communicable (i.e., they
are unfold from host to host). For instance, tuberculosis is com-
municable (i.e., it’s unfold from individual to individual by way of airborne
droplets produced by coughing), however botulism isn’t, as a result of
the exotoxin produced by the organism within the contaminated
meals impacts solely these consuming that meals. If a illness is extremely
communicable, the time period contagious is utilized.
An an infection is epidemic if it happens way more steadily
than regular; it’s pandemic if it has a worldwide distribution.
An endemic an infection is consistently current at a low stage in a
particular inhabitants. Along with infections that end in overt
signs, many are inapparent or subclinical and could be
detected solely by demonstrating an increase in antibody titer or by iso-
lating the organism. Some infections end in a latent state, after
which reactivation of the expansion of the organism and recur-
rence of signs might happen. Sure different infections result in a
continual provider state, wherein the organisms proceed to develop
with or with out producing signs within the host. Persistent carri-
ers (e.g., “Typhoid Mary”) are an vital supply of an infection
of others and therefore are a public well being hazard.
The dedication of whether or not an organism recovered from a
affected person is definitely the reason for the illness entails an consciousness
of two phenomena: regular flora and colonization. Members
of the conventional flora are everlasting residents of the physique and
fluctuate in sort based on anatomic web site (see Chapter 6). When
an organism is obtained from a affected person’s specimen, the query
of whether or not it’s a member of the conventional flora is vital in
deciphering the discovering. Colonization refers back to the presence of
a brand new organism that’s neither a member of the conventional flora nor
the reason for signs. It may be a troublesome medical dilemma to
distinguish between a pathogen and a colonizer, particularly in
specimens obtained from the respiratory tract, similar to throat
cultures and sputum cultures.
STAGES OF BACTERIAL PATHOGENESIS
Most bacterial infections are acquired from an exterior supply.
Nevertheless, some bacterial infections are attributable to members of
the conventional flora and, as such, should not transmitted immediately prior
to the onset of an infection.
A generalized sequence of the phases of an infection is as follows:
(1) Transmission from an exterior supply into the portal of
entry.
(2) Evasion of main host defenses similar to pores and skin or abdomen
acid.
(3) Adherence to mucous membranes, often by bacterial pili.
(4) Colonization by development of the micro organism on the web site of
adherence.
(5) Illness signs attributable to toxin manufacturing or inva-
sion accompanied by irritation.
(6) Host responses, each nonspecific and particular (immunity),
throughout steps 3, 4, and 5.
(7) Development or decision of the illness.
DETERMINANTS OF BACTERIAL
PATHOGENESIS
1. Transmission
An understanding of the mode of transmission of micro organism and
different infectious brokers is extraordinarily vital from a public
well being perspective, as a result of interrupting the chain of trans-
mission is a wonderful approach to forestall infectious illnesses. The
mode of transmission of many infectious illnesses is “human-
to-human,” however infectious illnesses are additionally transmitted from
nonhuman sources similar to soil, water, and animals. Fomites are
inanimate objects, similar to towels, that function a supply of micro-
organisms that may trigger infectious illnesses. Desk 7–1 describes
some vital examples of those modes of transmission.
Though some infections are attributable to members of the
regular flora, most are acquired by transmission from exterior
sources. Pathogens exit the contaminated affected person most steadily
from the respiratory and gastrointestinal tracts; therefore, trans-
mission to the brand new host often happens by way of airborne respiratory
droplets or fecal contamination of meals and water. Organisms
can be transmitted by sexual contact, urine, pores and skin contact,
blood transfusions, contaminated needles, or biting bugs. The
switch of blood, both by transfusion or by sharing needles
throughout intravenous drug use, can transmit numerous bacterial and
viral pathogens. The screening of donated blood for Treponema
pallidum, human immunodeficiency virus (HIV), human T-cell
lymphotropic virus, hepatitis B virus, hepatitis C virus, and
West Nile virus has enormously diminished the danger of an infection by these
organisms.
The foremost bacterial illnesses transmitted by ticks within the
United States are Lyme illness, Rocky Mountain noticed fever,
ehrlichiosis, relapsing fever, and tularemia. Of those 5 dis-
eases, Lyme illness is by far the most typical. Ticks of the
genus Ixodes transmit three infectious illnesses: Lyme illness,
ehrlichiosis, and babesiosis, a protozoan illness.
Micro organism, viruses, and different microbes can be transmitted
from mom to offspring, a course of referred to as vertical transmis-
sion. The three modes by which organisms are transmitted
vertically are throughout the placenta, inside the beginning canal throughout
beginning, and by way of breast milk. Desk 7–2 describes some medically
vital organisms which can be transmitted vertically. (Horizon-
tal transmission, in contrast, is person-to-person transmission
that’s not from mom to offspring.)
There are 4 vital portals of entry: respiratory tract,
gastrointestinal tract, genital tract, and pores and skin (Desk 7–3). Impor-
tant microorganisms and illnesses transmitted by water are
described in Desk 7–4.
The vital bacterial illnesses transmitted by meals are
listed in Desk 7–5, and people transmitted by bugs are listed in
Desk 7–6. The precise mode of transmission of every organism
is described within the subsequent part dedicated to that organism.
Animals are additionally an vital supply of organisms that
infect people. They are often both the supply (reservoir) or the
mode of transmission (vector) of sure organisms. Illnesses
for which animals are the reservoirs are referred to as zoonoses. The
vital zoonotic illnesses attributable to micro organism are listed in
Desk 7–7.
2. Adherence to Cell Surfaces
Sure micro organism have specialised buildings (e.g., pili) or pro-
duce substances (e.g., capsules or glycocalyces) that permit them
to stick to the floor of human cells, thereby enhancing their
potential to trigger illness. These adherence mechanisms are essen-
tial for organisms that connect to mucous membranes; mutants
that lack these mechanisms are sometimes nonpathogenic. For
instance, the pili of Neisseria gonorrhoeae and E. coli mediate
valves. Biofilms defend micro organism from each antibiotics and host
immune defenses similar to antibodies and neutrophils. They
additionally retard wound therapeutic, leading to continual wound infec-
tions, particularly in diabetics. Biofilms play an vital function in
the persistence of Pseudomonas within the lungs of cystic fibrosis
sufferers and within the formation of dental plaque, the precursor of
dental caries.
The manufacturing of biofilms by micro organism similar to Pseudomo-
nas is managed by the method of quorum sensing, which
permits micro organism to coordinate the synthesis of specific pro-
teins based on the density of the bacterial inhabitants.
When the focus of micro organism is low, these proteins are
not expressed; however as soon as the inhabitants reaches a vital excessive
cell density, the person members sense this and start to
synthesize these proteins, leading to phenotypic modifications that
profit the inhabitants as a complete. Examples of behaviors that
are managed by quorum sensing embody biofilm formation,
expression of virulence, and antibiotic resistance, all of which
can contribute to pathogenesis.
Overseas our bodies, similar to synthetic coronary heart valves and synthetic
joints, predispose to infections. Micro organism can adhere to those
surfaces, however phagocytes adhere poorly owing to the absence
of selectins and different binding proteins on the substitute floor
(see Chapter 8).
3. Invasion, Irritation,
& Intracellular Survival
One of many two essential mechanisms by which micro organism trigger
illness is invasion of tissue adopted by irritation. (The
inflammatory response is described in Chapter 8.) The opposite
essential mechanism, toxin manufacturing, and a 3rd mechanism,
immunopathogenesis, are described later on this chapter.
A number of enzymes secreted by invasive micro organism play a task in
pathogenesis. Among the many most distinguished are the next:
(1) Collagenase and hyaluronidase, which degrade collagen
and hyaluronic acid, respectively, thereby permitting the bacte-
ria to unfold by way of subcutaneous tissue; they’re particularly
vital in cellulitis attributable to Streptococcus pyogenes.
(2) Coagulase, which is produced by Staphylococcus aureus
and accelerates the formation of a fibrin clot from its precursor,
fibrinogen (this clot might defend the micro organism from phagocytosis
by walling off the contaminated space and by coating the organisms
with a layer of fibrin). Coagulase can be produced by Yersinia
pestis, the reason for bubonic plague. See Chapter 20 for the function
of coagulase within the pathogenesis of plague.
(3) Immunoglobulin proteases. There are a number of examples
of organisms that produce enzymes that degrade immunoglob-
ulin (Ig) A and IgG. N. gonorrhoeae, Haemophilus influenzae,
and Streptococcus pneumoniae produce IgA proteases, which
inactivate this immunoglobulin on the mucosal floor. This
results in higher adherence of those organisms to mucous mem-
branes. S. pyogenes produces an enzyme that particularly cleaves
IgG heavy chains, which reduces opsonization and complement
activation, enhancing the virulence of this organism.
Along with these enzymes, a number of virulence elements con-
tribute to invasiveness by limiting the flexibility of the host protection
mechanisms, particularly phagocytosis, to function successfully.
(1) An important of those antiphagocytic elements is the
capsule exterior to the cell wall of a number of vital pathogens
similar to S. pneumoniae and Neisseria meningitidis. The polysac-
charide capsule prevents the phagocyte from adhering to the
micro organism; anticapsular antibodies permit more practical phagocy-
tosis to happen (a course of referred to as opsonization) (see Chapter 8).
The vaccines towards S. pneumoniae, H. influenzae, and N. men-
ingitidis comprise capsular polysaccharides that induce protecting
anticapsular antibodies.
(2) A second group of antiphagocytic elements are the cell wall
proteins of the gram-positive cocci, such because the M protein of the
group A streptococci (S. pyogenes) and protein A of S. aureus.
The M protein is antiphagocytic, and protein A binds to the Fc
portion of IgG and prevents the activation of complement.
These virulence elements are summarized in Desk 7–8.
(3) Leukocidins are pore-forming toxins that degrade the
cell membrane of neutrophils and macrophages. The Panton-
Valentine leukocidin produced by S. aureus is an efficient instance.
Micro organism could cause two kinds of irritation: pyogenic and
granulomatous. In pyogenic (pus-producing) irritation,
neutrophils are the predominant cells. A few of the most impor-
tant pyogenic micro organism are the gram-positive and gram-negative
cocci listed in Desk 7–8. In granulomatous irritation,
macrophages and helper T cells predominate. Probably the most impor-
tant organism on this class is Mycobacterium tuberculosis.
No bacterial enzymes or toxins that induce granulomas have
been recognized. Slightly, it seems that bacterial antigens stimu-
late the cell-mediated immune system, leading to sensitized
T-lymphocyte and macrophage exercise. Phagocytosis by mac-
rophages kills many of the micro organism, however some survive and develop
inside the macrophages within the granuloma.
Intracellular survival is a vital attribute of sure
micro organism that enhances their potential to trigger illness. These
micro organism are referred to as “intracellular” pathogens and generally
trigger granulomatous lesions. The perfect-known of those micro organism
belong to the genera Mycobacterium, Legionella, Brucella, and
Listeria. The perfect-known fungus is Histoplasma. These organ-
isms could be cultured on microbiologic media within the laboratory
and due to this fact should not obligate intracellular parasites, which
distinguishes them from Chlamydia and Rickettsia. The intra-
mobile location gives a protecting area of interest from antibody and
neutrophils that operate extracellularly.
Intracellular micro organism use a number of completely different mechanisms to
permit them to outlive and develop inside cells. These embody
(1) inhibition of the fusion of the phagosome with the lysosome,
which permits the organisms to keep away from the degradative enzymes
within the lysosome; (2) inhibition of acidification of the phago-
some, which reduces the exercise of the lysosomal degradative
enzymes; and (3) escape from the phagosome into the cyto-
plasm, the place there are not any degradative enzymes. Members of the
genera Mycobacterium and Legionella are recognized to make use of the primary
and second mechanisms, whereas Listeria species use the third.
The invasion of cells by micro organism depends on the interac-
tion of particular bacterial floor proteins referred to as invasins and
particular mobile receptors belonging to the integrin household of
transmembrane adhesion proteins. The motion of micro organism
into the cell is a operate of actin microfilaments. As soon as inside
the cell, these micro organism usually reside inside cell vacuoles such
as phagosomes. Some stay there, others migrate into the
cytoplasm, and a few transfer from the cytoplasm into adjoining
cells. An infection of the encircling cells on this method permits
the micro organism to evade host defenses. For instance, Listeria
monocytogenes aggregates actin filaments on its floor and is
propelled in a “sling-shot” style, referred to as actin rockets, from
one host cell to a different.
The “Yops” (Yersinia outer-membrane proteins) produced
by a number of Yersinia species are vital examples of bacterial
virulence elements that act primarily after invasion of human cells
by the organism. An important results of the Yops are to
inhibit phagocytosis by neutrophils and macrophages and to
inhibit cytokine manufacturing (e.g., tumor necrosis issue [TNF]
manufacturing) by macrophages. For instance, one of many Yops of
Y. pestis (Yop J) is a protease that cleaves sign transduction pro-
teins required for the induction of TNF synthesis. This inhibits
the activation of our host defenses and contributes to the flexibility
of the organism to trigger bubonic plague.
The genes that encode many virulence elements in micro organism
are clustered in pathogenicity islands positioned on the bacterial
chromosome or plasmids. For instance, in lots of micro organism, the
genes encoding adhesins, invasins, and exotoxins are adjoining
to one another on these islands. Nonpathogenic variants of those
micro organism would not have these pathogenicity islands. It seems that
these massive areas of the bacterial genome had been transferred as a
block by way of conjugation or transduction. Pathogenicity islands are
discovered in lots of gram-negative rods, similar to E. coli, Salmonella,
Shigella, Pseudomonas, and Vibrio cholerae, and in gram-positive
cocci, similar to S. pneumoniae.
After micro organism have colonized and multiplied on the portal
of entry, they could invade the bloodstream and unfold to different
components of the physique. Receptors for the micro organism on the floor of
cells decide, largely, the organs affected. For instance,
sure micro organism or viruses infect the mind as a result of receptors for
these microbes are positioned on the floor of mind neurons. The
blood–mind barrier, which limits the flexibility of sure medication to
penetrate the mind, isn’t regarded as a determinant of micro-
bial an infection of the mind. The idea of a blood–mind barrier
primarily refers back to the lack of ability of hydrophilic (charged, ionized)
medication to enter the lipid-rich mind parenchyma, whereas lipo-
philic (lipid-soluble) medication enter effectively.
Two vital illnesses, diphtheria and pseudomembra-
nous colitis, are characterised by inflammatory lesions referred to as
pseudomembranes. Pseudomembranes are thick, adherent, gray-
ish or yellowish exudates on the mucosal surfaces of the throat in
diphtheria and on the colon in pseudomembranous colitis. The
time period pseudo refers back to the irregular nature of those membranes in
distinction to the conventional anatomic membranes of the physique, similar to
the tympanic membrane and the placental membranes.
4. Toxin Manufacturing
The second main mechanism by which micro organism trigger illness is
the manufacturing of poisons. A comparability of the primary options of
exotoxins and endotoxins is proven in Desk 7–9.
Exotoxins
Exotoxins are produced by a number of gram-positive and gram-
unfavourable micro organism, in distinction to endotoxins, that are current
solely in gram-negative micro organism. The important attribute
of exotoxins is that they’re secreted by the micro organism, whereas
endotoxin is a element of the cell wall. Exotoxins are poly-
peptides whose genes are steadily positioned on plasmids or
lysogenic bacterial viruses (bacteriophages). Some vital
exotoxins encoded by bacteriophage DNA are diphtheria toxin,
cholera toxin, and botulinum toxin.
Exotoxins are among the many most poisonous substances recognized. For
instance, the deadly dose of tetanus toxin for a human is estimated
to be lower than 1 μg. As a result of some purified exotoxins can repro-
duce all facets of the illness, we are able to conclude that sure bac-
teria play no different function in pathogenesis than to synthesize the
exotoxin. Exotoxin polypeptides are good antigens and induce
the synthesis of protecting antibodies referred to as antitoxins, a few of
that are helpful within the prevention or remedy of illnesses such
as botulism and tetanus. When handled with formaldehyde (or
acid or warmth), the exotoxin polypeptides are transformed into tox-
oids, that are utilized in protecting vaccines as a result of they keep
their antigenicity however have misplaced their toxicity.
Many exotoxins have an A–B subunit construction; the A (or
energetic) subunit possesses the poisonous exercise, and the B (or bind-
ing) subunit is accountable for binding the exotoxin to particular
receptors on the membrane of the human cell. The binding of
the B subunit determines the precise web site of the motion of the
exotoxin. For instance, botulinum toxin acts on the neuromus-
cular junction as a result of the B subunit binds to particular receptors
on the floor of the motor neuron on the junction. Essential
exotoxins which have an A–B subunit construction embody diphtheria
toxin, tetanus toxin, botulinum toxin, cholera toxin, and the
enterotoxin of E. coli (Determine 7–1).
The A subunit of a number of vital exotoxins acts by catalyz-
ing the addition of adenosine diphosphate ribose (ADP-ribose)
to the goal protein within the human cell (ADP-ribosylation).
The modification of goal proteins with ADP-ribose typically
inactivates it however may also hyperactivate it, both of which
could cause the signs of illness. For instance, diphtheria
toxin and Pseudomonas exotoxin A ADP-ribosylate elongation
factor-2 (EF-2), a necessary issue required for eukaryotic pro-
tein synthesis. This modification inactivates EF-2, freezing the
translocation complicated, and ends in the inhibition of protein
synthesis. Alternatively, cholera toxin and E. coli toxin
ADP-ribosylate Gs protein, thereby activating it. This causes an
enhance in adenylate cyclase exercise, a consequent enhance in
the quantity of cyclic adenosine monophosphate (AMP), and
the manufacturing of watery diarrhea. Pertussis toxin is an interest-
ing variation on the theme. It ADP-ribosylates Gi
protein and
inactivates it. Inactivation of the inhibitory G proteins activates
adenylate cyclase, inflicting a rise within the quantity of cyclic
AMP, which performs a task in inflicting the signs of whooping
cough.
Exotoxins are launched from micro organism by specialised struc-
tures referred to as secretion techniques. Some secretion techniques trans-
port the exotoxins into the extracellular house, however others
transport the exotoxins immediately into the mammalian cell. These
that transport the exotoxins immediately into the mammalian cell
are particularly efficient as a result of the exotoxin isn’t uncovered to
antibodies within the extracellular house.
A number of lessons of bacterial secretion techniques (six and count-
ing) have been recognized, however the sort III secretion system
(additionally referred to as an injectosome) is especially vital in viru-
lence. This secretion system is mediated by a needlelike projec-
tion (generally referred to as a “molecular syringe”) and by transport
FIGURE 7–1 Mode of motion of diphtheria toxin. The toxin binds
to the cell floor by way of its binding subunit, and the energetic subunit
enters the cell. The energetic subunit is an enzyme that catalyzes the
addition of ADP-ribose (ADP-R) to elongation factor-2 (EF-2). This
inactivates EF-2, and protein synthesis is inhibited.
pumps within the bacterial cell membrane. The significance of the
sort III secretion system is illustrated by the discovering that the
strains of Pseudomonas aeruginosa which have this secretion
system are considerably extra virulent than these that don’t.
Different medically vital gram-negative rods that make the most of
injectosomes embody Shigella species, Salmonella species, E. coli,
and Y. pestis.
The mechanisms of motion of the vital exotoxins
produced by toxigenic micro organism are described within the following
dialogue and summarized in Tables 7–10, 7–11, and seven–12.
The primary location of signs of illness attributable to bacterial
exotoxins is described in Desk 7–13.
Gram-Constructive Micro organism
The exotoxins produced by gram-positive micro organism have a number of
completely different mechanisms of motion and produce completely different medical
results. Some vital exotoxins embody diphtheria toxin,
which inhibits protein synthesis by inactivating EF-2; tetanus
toxin and botulinum toxin, that are neurotoxins that forestall
the discharge of neurotransmitters; and poisonous shock syndrome toxin
(TSST), which acts as a superantigen inflicting the discharge of huge
quantities of cytokines from helper T cells and macrophages. The
mechanisms of motion and the medical results of exotoxins pro-
duced by gram-positive micro organism are described subsequent.
(1) Diphtheria toxin, produced by Corynebacterium diph-
theriae, inhibits protein synthesis by ADP-ribosylation of EF-2
(Determine 7–1).1
The ensuing loss of life of the affected cells results in two promi-
nent signs of diphtheria: pseudomembrane formation in
the throat and myocarditis.
The exotoxin exercise relies on two features mediated
by completely different domains of the molecule. The toxin is synthesized
as a single polypeptide that’s unhazardous as a result of the energetic web site
of the enzyme is masked. This molecule is cleaved and modi-
fied to yield two energetic polypeptides. Fragment A, derived from
the amino-terminal finish of the exotoxin, yields an enzyme that
catalyzes the switch of ADP-ribose from nicotinamide adenine
dinucleotide (NAD) to EF-2, inhibiting protein synthesis. Frag-
ment B, derived from the carboxy-terminal finish, binds to recep-
tors on the outer membrane of eukaryotic cells and mediates
transport of fragment A into the cells.
Because the micro organism synthesize and secrete the full-length exo-
toxin, the carboxy-terminal finish binds to host cell membrane
receptors. The toxin is transported throughout the cell membrane,
triggering cleavage and modification that end in energetic frag-
ment A, which then targets and inactivates EF-2. The precise-
ity for this protein is because of a novel amino acid, a modified
histidine referred to as diphthamide, that’s current solely on EF-2. Since
all eukaryotic cells perform protein synthesis, there isn’t any tis-
sue or organ specificity. Prokaryotic and mitochondrial protein
synthesis should not affected as a result of a distinct, nonsusceptible
elongation issue is concerned. The enzyme exercise is remarkably
potent; a single molecule of fragment A will kill a cell inside
a number of hours. Different organisms whose exotoxins act by ADP-
ribosylation are E. coli, V. cholerae, and Bordetella pertussis.
The tox gene, which codes for this exotoxin, is carried by
a lysogenic bacteriophage referred to as beta phage. Because of this, solely
C. diphtheriae strains lysogenized by this phage trigger diph-
theria. (Nonlysogenized C. diphtheriae could be discovered within the
throat of some wholesome folks.) This is a vital instance
of lysogenic conversion, the method by which micro organism purchase
new traits when lysogenized by a bacteriophage (see Chapter 4).
Regulation of exotoxin synthesis is managed by the interplay
of iron within the medium with a tox gene repressor synthesized by
the bacterium. Because the focus of iron will increase, the iron-
repressor complicated inhibits the transcription of the tox gene.
(2) Tetanus toxin, produced by Clostridium tetani, is a
neurotoxin that forestalls launch of an inhibitory neurotrans-
mitter concerned in muscle rest. When the inhibitory neu-
rons are nonfunctional, the excitatory neurons are unopposed,
resulting in muscle spasms and a spastic paralysis. Tetanus toxin
(tetanospasmin) consists of two polypeptide subunits
encoded by plasmid DNA. The heavy chain of the polypeptide
binds to gangliosides within the membrane of the neuron; the sunshine
chain is a protease that degrades the protein(s) accountable for
the discharge of the inhibitory neurotransmitters (γ-aminobutyric
acid [GABA] and glycine). The toxin launched on the web site of the
peripheral wound might journey both by retrograde axonal trans-
port or within the bloodstream to the anterior horn and interstitial
neurons of the spinal twine. Inhibiting the discharge of the GABA
and glycine results in convulsive contractions of the voluntary
muscle mass, finest exemplified by spasm of the jaw and neck muscle mass
(“lockjaw”).
(3) Botulinum toxin, produced by Clostridium botulinum, is
a neurotoxin that blocks the discharge of a distinct neurotrans-
mitter, acetylcholine, on the synapse of the neuromuscular junc-
tion, producing a flaccid paralysis. Roughly 1 μg is deadly
for people; it is without doubt one of the most poisonous compounds recognized. The
toxin consists of two polypeptide subunits held collectively by
disulfide bonds. One of many subunits binds to a receptor on the
neuron; the opposite subunit is a protease that degrades the
protein(s) accountable for the discharge of acetylcholine. There are
six serotypes of botulinum toxin (A–F), with toxins A, B, E, and
F being an important for human illness. Some serotypes
are encoded on a plasmid, some on a temperate bacteriophage,
and a few on the bacterial chromosome.
(4) Two exotoxins are produced by Clostridium difficile, each
of that are concerned within the pathogenesis of pseudomembra-
nous colitis. Exotoxin A is an enterotoxin that causes watery
diarrhea. Exotoxin B is a cytotoxin that damages the colonic
mucosa and causes pseudomembranes to type. Exotoxins A
and B are glucosyltransferases that modify goal sign trans-
duction proteins (Rho GTPases), which interferes with their
sign transduction operate. Glucosylation by exotoxin B
causes disaggregation of actin filaments within the cytoskeleton,
resulting in apoptosis and cell loss of life.
(5) A number of toxins are produced by Clostridium perfringens
and different species of clostridia that trigger fuel gangrene. A complete
of seven deadly elements and 5 enzymes have been characterised, however
no species of Clostridium makes all 12 merchandise. The perfect char-
acterized is the alpha toxin, which is a lecithinase that hydro-
lyzes lecithin within the cell membrane, leading to destruction of
the membrane and widespread cell loss of life. The opposite 4
enzymes are collagenase, protease, hyaluronidase, and deoxyri-
bonuclease (DNase). The seven deadly toxins are a heteroge-
neous group with hemolytic and necrotizing exercise. Sure
strains of C. perfringens produce an enterotoxin that causes
watery diarrhea. This enterotoxin acts as a superantigen comparable
to the enterotoxin of S. aureus (described beneath).
(6) Three exotoxins are produced by Bacillus anthracis, the
agent of anthrax: edema issue, deadly issue, and protecting anti-
gen. The three exotoxins affiliate with one another, however every
element has a definite operate. Edema issue is an adenyl-
ate cyclase that raises the cyclic AMP focus inside the
cell, leading to lack of chloride ions and water and consequent
edema formation within the tissue (see Desk 7–12). Deadly issue is
a protease that cleaves a phosphokinase required for the sign
transduction pathway that controls cell development. Lack of the
phosphokinase ends in the failure of cell development and conse-
quent cell loss of life. Protecting antigen binds to a cell floor
receptor and types pores within the human cell membrane that
permit edema issue and deadly issue to enter the cell. The identify
protecting antigen relies on the discovering that antibody towards
this protein protects towards illness. The antibody blocks the
binding of protecting antigen, thereby stopping edema issue
and deadly issue from coming into the cell.
(7) TSST is a superantigen produced primarily by sure
strains of S. aureus but in addition by sure strains of S. pyogenes.
TSST binds on to class II main histocompatibility (MHC)
proteins on the floor of antigen-presenting cells (macro-
phages) with out intracellular processing. This complicated interacts
with the T-cell receptor of many helper T cells, leading to
activation of those T cells (see the dialogue of superantigens in
Chapter 58). This causes the discharge of huge quantities of inter-
leukins, particularly interleukin-1, interleukin-2, and TNF. These
cytokines produce lots of the indicators and signs of poisonous
shock.
(8) Staphylococcal enterotoxin can be a superantigen, however
as a result of it’s ingested, it acts regionally on the lymphoid cells lining
the small gut. The enterotoxin is produced by S. aureus in
the contaminated meals and causes meals poisoning, often
inside 1 to six hours after ingestion. The primary signs are
vomiting and watery diarrhea. The distinguished vomiting seen in
meals poisoning is attributable to cytokines launched from the lym-
phoid cells stimulating the enteric nervous system, which acti-
vates the vomiting heart within the mind.
(9) Exfoliatin is a protease produced by S. aureus that causes
scalded pores and skin syndrome. Exfoliatin cleaves desmoglein, a protein
within the desmosomes of the pores and skin, ensuing within the detachment of
the superficial layers of the pores and skin. Exfoliatin can be referred to as epider-
molytic toxin.
(10) Panton-Valentine (PV) leukocidin is a pore-forming
exotoxin produced by methicillin-resistant strains of S. aureus
(MRSA). It destroys white blood cells, pores and skin, and subcutaneous
tissue. The 2 subunits of the toxin assemble within the cell mem-
brane to type a pore by way of which cell contents exit into the
extracellular house.
(11) Erythrogenic toxin, produced by S. pyogenes, causes the
rash attribute of scarlet fever. Its mechanism of motion is
much like that of TSST (i.e., it acts as a superantigen). The DNA
that codes for the toxin resides on a temperate bacteriophage.
Nonlysogenic micro organism don’t trigger scarlet fever, though they
could cause pharyngitis.
Gram-Destructive Micro organism
The exotoxins produced by gram-negative micro organism even have
a number of completely different mechanisms of motion and produce completely different
medical results. Two essential exotoxins are the entero-
toxins of E. coli and V. cholerae (cholera toxin), which induce
a rise within the quantity of cyclic AMP inside the enterocyte,
leading to watery diarrhea (see Desk 7–12). The mechanisms
of motion and the medical results of exotoxins produced by gram-
unfavourable micro organism are described subsequent.
(1) The warmth-labile enterotoxin produced by E. coli causes
watery, nonbloody diarrhea by stimulating adenylate cyclase
exercise in cells within the small gut (Determine 7–2). The ensuing
enhance within the focus of cyclic AMP causes excretion of
the chloride ion, inhibition of sodium ion absorption, and sig-
nificant fluid and electrolyte loss into the lumen of the intestine. The
heat-labile toxin, which is inactivated at 65°C for half-hour, is
an AB toxin. The B subunit confers specificity to the enterocytes
within the small gut by binding to a ganglioside receptor in
the cell membrane. This allows the A subunit to enter the cell
the place it ADP-ribosylates its goal Gs protein. This locks the
Gs protein within the “on” place, which constitutively stimulates
adenylate cyclase to synthesize cyclic AMP. This in flip acti-
vates cyclic AMP–dependent protein kinase, an enzyme that
phosphorylates ion transporters within the cell membrane, ensuing
within the lack of water and ions from the cell. A lot of the genes
for the heat-labile toxin and for the heat-stable toxin (described
subsequent) are carried on plasmids.
Along with the labile toxin, there’s a heat-stable toxin,
which is a polypeptide that’s not inactivated by boiling for 30
minutes. The warmth-stable toxin impacts cyclic guanosine mono-
phosphate (GMP) somewhat than cyclic AMP. It stimulates guanyl-
ate cyclase and thus will increase the focus of cyclic GMP,
which inhibits the reabsorption of sodium ions and causes
diarrhea.
(2) Shiga toxin is an exotoxin produced primarily by strains
of E. coli with the O157:H7 serotype. These enterohemorrhagic
strains trigger bloody diarrhea and are the reason for outbreaks
related to consuming undercooked meat, particularly hamburger
in fast-food eating places. The toxin is called for a really comparable
toxin produced by Shigella dysenteriae. The toxin inactivates
protein synthesis by eradicating adenine from a particular web site on
the 28S rRNA within the massive subunit of the human ribosome.
Shiga toxin is encoded by a temperate (lysogenic) bacterio-
phage. When E. coli Shiga toxin enters the bloodstream, it may possibly
trigger hemolytic-uremic syndrome (HUS). Shiga toxin binds to
receptors on the kidney and on the endothelium of small blood
vessels. Inhibition of protein synthesis ends in loss of life of these
Lively subunit
ADP-R
ENTEROCYTE
GUT LUMEN
Cholera
toxin
Binding subunit Gs
protein
Adenylate
cyclase
cAMP Protein
kinase
Water and
electrolytes
Water, chloride,
bicarbonate
Diarrhea
FIGURE 7–2 Mode of motion of Escherichia coli and Vibrio cholerae enterotoxins. The enterotoxin (e.g., cholera toxin) binds to the floor
of the enterocyte by way of its binding subunit. The energetic subunit then enters the enterocyte. The energetic subunit is an enzyme that catalyzes the
addition of ADP-ribose (ADP-R) to the GS regulatory protein. This prompts adenylate cyclase to overproduce cyclic adenosine monophosphate
(AMP). As a consequence, cyclic AMP–dependent protein kinase exercise will increase, and water and electrolytes go away the enterocyte, inflicting
watery diarrhea.
cells, resulting in renal failure and microangiopathic hemolytic
anemia. Sure antibiotics, similar to ciprofloxacin, can enhance
the quantities of Shiga toxin produced by E. coli O157, which
predisposes to HUS.
(3) The AB enterotoxins produced by V. cholerae, the agent
of cholera (see Chapter 18), and Bacillus cereus, a reason behind
diarrhea, act in a way much like that of the heat-labile toxin
of E. coli (see Determine 7–2).
(4) Pertussis toxin, produced by B. pertussis, the reason for
whooping cough, is an exotoxin that catalyzes the switch of
ADP-ribose from NAD to an inhibitory G protein. Inactivation
of this inhibitory regulator has two results: one is to stimulate
adenylate cyclase exercise, resulting in a rise in cyclic AMP
focus inside the affected cells (see Desk 7–12). This
ends in edema and different modifications within the respiratory tract,
resulting in the cough of whooping cough. It additionally inhibits the sig-
nal transduction pathway utilized by chemokine receptors. This
causes the marked lymphocytosis seen in sufferers with pertus-
sis. The toxin inhibits sign transduction by all chemokine
receptors, leading to an lack of ability of lymphocytes emigrate to
and enter lymphoid tissue (spleen, lymph nodes). As a result of they
don’t enter tissue, there is a rise of their quantity within the
blood (see the dialogue of chemokines in Chapter 58).
Endotoxins
Endotoxins are integral components of the cell partitions of each gram-
unfavourable rods and cocci, in distinction to exotoxins, that are
actively launched from the cell (see Desk 7–9). As well as,
endotoxins are lipopolysaccharides (LPS), whereas exotoxins
are polypeptides; the enzymes that produce the LPS are encoded
by genes on the bacterial chromosome, somewhat than by plasmid
or bacteriophage DNA, which often encodes the exotoxins.
The toxicity of endotoxins is low compared with that of
exotoxins. All endotoxins produce the identical generalized results
of fever and shock, though the endotoxins of some organisms
are more practical than these of others (Determine 7–3). Endotox-
ins are weakly antigenic; they induce protecting antibodies so
poorly that a number of episodes of toxicity can happen. No toxoids