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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

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