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You are watching: Disease-causing exotoxins are produced by all of the following organisms except

Baron S, editor. Medical Microbiology. Fourth edition. Galveston (TX): college of Texas clinical Branch in ~ Galveston; 1996.


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Host Susceptibility

Resistance to bacterial infections is magnified by phagocytic cells and also an intact immune system. Initial resistance is as result of nonspecific mechanisms. Specific immunity establishes over time. Susceptibility to part infections is higher in the really young and also the an extremely old and in immunosuppressed patients.


Bacterial Infectivity

Bacterial infectivity results from a disturbance in the balance between bacterial virulence and host resistance. The “objective” of bacteria is come multiply fairly than to reason disease; that is in the ideal interest of the bacteria no to kill the host.


Host Resistance

Numerous physical and chemical attributes of the organize protect versus bacterial infection. This defenses include the antibacterial factors in secretions extending mucosal surfaces and rapid rate of replacement of skin and mucosal epithelial cells. When the surface of the human body is penetrated, bacteria conference an setting virtually there is no of totally free iron essential for growth, which requires plenty of of them to scavenge because that this vital element. Bacteria invading organization encounter phagocytic cells that acknowledge them as foreign, and also through a complicated signaling mechanism including interleukins, eicosanoids, and complement, adjust an inflammatory an answer in which countless lymphoid cell participate.


Genetic and also Molecular Basis for Virulence

Bacterial virulence components may it is in encoded top top chromosomal, plasmid, transposon, or temperate bacteriophage DNA; virulence aspect genes on transposons or pleasant bacteriophage DNA may combine into the bacter chromosome.


Host-mediated Pathogenesis

In details infections (e.g., tuberculosis), tissue damages results from the toxicity mediators released by lymphoid cells rather than from bacter toxins.


Intracellular Growth

Some bacteria (e.g., Rickettsia species) can thrive only within eukaryotic bio cells, whereas rather (e.g., Salmonella species) attack cells however do not need them because that growth. Most pathogenic bacteria main point in organization fluids and also not in organize cells.


Virulence Factors

Virulence factors assist bacteria come (1) invade the host, (2) reason disease, and (3) evade host defenses. The complying with are varieties of virulence factors:

Adherence Factors: numerous pathogenic bacteria colonize mucosal web page by utilizing pili (fimbriae) come adhere to cells.

Invasion Factors: Surface components that enable the bacterium to invade organize cells have the right to be encoded on plasmids, but more often room on the chromosome.

Capsules: countless bacteria are surrounded through capsules that protect them native opsonization and also phagocytosis.

Endotoxins: The lipopolysaccharide endotoxins ~ above Gram-negative bacteria cause fever, changes in blood pressure, inflammation, lethal shock, and many various other toxic events.

Exotoxins: Exotoxins incorporate several varieties of protein toxins and enzymes developed and/or secreted from pathogenic bacteria. Major categories include cytotoxins, neurotoxins, and also enterotoxins.

Siderophores: Siderophores space iron-binding determinants that allow some bacteria to contend with the host for iron, i beg your pardon is bound come hemoglobin, transferrin, and lactoferrin.


Introduction

Infection is the intrusion of the organize by microorganisms, which then multiply in close association through the host"s tissues. Infection is differentiated from disease, a morbid procedure that does no necessarily involve infection (diabetes, for example, is a disease with no well-known causative agent). Bacteria can cause a multitude of various infections, ranging in severity indigenous inapparent to fulminating. Table 7-1 perform these varieties of infections.


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The volume of a bacter to cause condition reflects its family member pathogenicity. ~ above this basis, bacteria have the right to be organized into three major groups. Once isolated from a patient, frank or main pathogens are considered to it is in probable agents of an illness (e.g., once the reason of diarrheal condition is identified by the laboratory isolation the Salmonella spp. Indigenous feces). Opportunistic pathogens are those diverted from patients whose hold defense mechanisms have actually been compromised. They may be the agents of an illness (e.g., in patient who have actually been predisposed to urinary tract infections through Escherichia coli by catheterization). Finally, some bacteria, such as Lactobacillus acidophilus, are considered to it is in nonpathogens, because they rarely or never reason human disease. Their categorization together nonpathogens may change, however, because of the adaptability that bacteria and the detrimental result of modern-day radiation therapy, chemotherapy, and also immunotherapy ~ above resistance mechanisms. In fact, some bacteria previously taken into consideration to it is in nonpathogens space now recognized to cause disease. Serratia marcescens, for example, is a common soil bacterium that reasons pneumonia, urinary street infections, and also bacteremia in endangered hosts.

Virulence is the measure of the pathogenicity of one organism. The level of virulence is related directly to the ability of the organism to cause an illness despite host resistance mechanisms; that is impacted by plenty of variables such together the number of infecting bacteria, course of entry right into the body, certain and nonspecific organize defense mechanisms, and also virulence factors of the bacterium. Virulence can be measured experimentally by determining the number of bacteria compelled to cause pet death, illness, or lesions in a defined period after the bacteria room administered by a designated route. Consequently, calculations the a lethal sheep affecting 50 percent of a populace of pets (LD50) or an effective dose leading to a condition symptom in 50 percent the a populace of animals (ED50) are helpful in compare the loved one virulence of different bacteria.

Pathogenesis ad both to the system of infection and to the device by which an illness develops. The purpose of this chapter is to provide an synopsis of the many bacterial virulence components and, where possible, to indicate how they interact with host defense mechanisms and to describe their function in the pathogenesis the disease. It have to be understood that the pathogenic instrument of plenty of bacterial conditions are poorly understood, while those the others have been probed in ~ the molecule level. The relative prestige of an infectious an illness to the wellness of humans and animals walk not constantly coincide through the depth that our understanding of its pathogenesis. This details is ideal acquired by reading each the the taking place chapters on specific bacterial diseases, infectious condition texts, and also public health and wellness bulletins.


Host Susceptibility

Susceptibility to bacterial infections relies on the physiologic and also immunologic condition of the host and also on the virulence that the bacteria. Before increased quantities of particular antibodies or T cell are developed in response to invading bacter pathogens, the “nonspecific” mechanisms of organize resistance (such as polymorphonuclear neutrophils and macrophage clearance) must protect the host versus the microbes. Advancement of effective specific immunity (such together an antibody an answer to the bacterium) may require number of weeks (Fig. 7-1). The common bacterial flora the the skin and also mucosal surfaces additionally serves to defend the host versus colonization by bacterial pathogens. In most healthy and balanced individuals, bacteria native the typical flora that sometimes penetrate the body (e.g., during tooth exploit or regimen brushing that teeth) space cleared by the host"s cellular and also humoral mechanisms. In contrast, people with defective immune responses space prone to frequent, recurrent epidemic with also the the very least virulent bacteria. The best-known example of together susceptibility is acquired immune deficiency syndrome (AIDS), in which the CD4+ helper lymphocytes are significantly decimated by human being immunodeficiency virus (HIV). However, resistance mechanisms deserve to be transformed by many other processes. Because that example, aging frequently weakens both nonspecific and details defense systems so the they can no longer successfully combat the an obstacle of bacteria native the environment. Babies are additionally especially susceptible to details pathogens (such as group B streptococci since their immune systems are not yet fully developed and cannot mount a security immune response to essential bacterial antigens. In addition, some people have genetic defects of the match system or cellular defenses (e.g., inability of polymorphonuclear neutrophils to kill bacteria). Finally, a patient may develop granulocytopenia as a result of a predisposing disease, such together cancer, or immunosuppressive chemotherapy for body organ transplants or cancer.


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Figure 7-1

Serum antibody response to Salmonella typhi throughout typhoid fever and its relationship to septicemia.


Host resistance can be jeopardized by trauma and by some underlying diseases. An separation, personal, instance becomes prone to infection through a selection of bacteria if the skin or mucosa is breached, particularly in the instance of severe wounds such as burns or contaminated operation wounds. Cystic fibrosis patients, who have bad ciliary function and in turn cannot clean mucus properly from the respiratory tract, are abnormally at risk to infection through mucoid strains of Pseudomonas aeruginosa, causing serious respiratory tract distress. Ascending urinary tract infections v Escherichia coli are typical in women and also are particularly troublesome in patients v urinary tract obstructions. A range of routine clinical procedures, such as tracheal intubation and catheterization the blood vessels and also the urethra, increase the danger of bacter infection. The plastic tools used in these procedures are readily conquered by bacteria native the skin, which migrate along the exterior of the tube to infect deeper organization or get in the bloodstream. As such problem, that is standard practice to readjust catheters frequently (e.g., every 72 hrs for peripheral intravenous catheters).

Many drugs have actually been occurred to treat bacter infections. Antimicrobial agents are most effective, however, as soon as the epidemic is likewise being combated by healthy and balanced phagocytic and also immune defenses. Some factors for this instance are the bad diffusion of antibiotics into details sites (such as the prostate gland), the capability of plenty of bacteria to multiply or endure inside cell (where countless antimicrobial agents have small or no effect), the bacteriostatic quite than bactericidal action of part drugs, and the volume of part organisms to develop resistance to multiple antibiotics.

Many bacter pathogens room transmitted come the organize by a vector, typically an arthropod. Because that example, Rocky mountain spotted fever and also Lyme condition are both vectored by ticks, and also bubonic afflict is spread out by fleas. Susceptibility come these diseases depends partially on the host"s contact with the vector.


Bacterial Infectivity

Factors that are created by a virus and evoke condition are dubbed virulence factors. Instances are toxins, surface ar coats the inhibit phagocytosis, and surface receptor that bind to organize cells. Most frank (as protest to opportunistic) bacter pathogens have actually evolved certain virulence determinants that allow them to multiply in their host or vector without being killed or expelled through the host"s defenses. Many virulence factors are produced only by particular virulent strains that a microorganism. For example, only specific strains the E. Coli secrete diarrhea-causing enterotoxins.

Virulence components should never ever be thought about independently of the host"s defenses; the clinical food of a disease often depends on the communication of virulence factors with the host"s response. One infection starts when the balance in between bacterial pathogenicity and also host resistance is upset. In essence, we live in an setting that favors the microbe, simply because the growth rate that bacteria much exceeds that of most eukaryotic cells. Furthermore, bacteria space much more versatile 보다 eukaryotic cell in substrate utilization and biosynthesis. The high mutation rate of bacteria merged with their brief generation time results in rapid selection of the best-adapted strains and also species. In general, bacteria are much much more resistant come toxic components in the environment than eukaryotes, an especially when the significant barriers of standard scale (skin and also mucous membranes) space breached.

From a helpful standpoint, bacteria deserve to be claimed to have actually a single objective: come multiply. Only a few of the vast variety of bacterial varieties in the atmosphere consistently cause an illness in a provided host. Native a teleologic standpoint, it is no in the finest interest that the virus to death the host, due to the fact that in most cases the death of the host means the fatality of the pathogen. The most highly progressed or adjusted pathogens are the ones that obtain the essential nutritional substances for growth and dissemination with the smallest expenditure that energy and also least damages to the host. Because that example, Rickettsia akari, the etiologic agent of rickettsialpox, reasons a mild, self-limited infection consisting of headache, fever, and also a papulovesicular rash. Other members of the rickettsial group, such as R. Rickettsii, the certified dealer of Rocky mountain spotted fever, elicit much more severe, life-threatening infections. Some bacteria that are poorly adapted to the hold synthesize virulence factors (e.g., tetanus and also diphtheria toxin) so potent that they threaten the life that the host.


Host Resistance

Although easily damaged, the skin represents one of the many important obstacles of the body to the microbial world, which has a diverse array of bacteria in enormous numbers. Fortunately, most bacteria in the setting are relatively benign to people with normal immune systems. However, patients who are immunosuppressed, together as individuals receiving cancer chemotherapy or have AIDS, opportunistic microbial pathogens can develop life-threatening infections. Normally, microbes in the setting are prevented indigenous entering the human body by the skin and mucous membranes. The outermost surface ar of the skin consists of squamous cell epithelium, largely made up of dead cell that are sloughed off as new cells space formed listed below them. In enhancement to the skin barrier, mucous membranes of the respiratory, gastrointestinal, and also urogenital solution represent various other portals with which bacteria can gain accessibility to the body. Favor the squamous epithelial cells of the skin, the mucosal epithelial cells divide rapidly, and also as the cells mature, castle are propelled laterally towards the intestinal lumen and shed. The entire procedure is reported to require only 36-48 hours for complete replacement the the epithelium, i m sorry diminishes the number of bacteria linked with the epithelium. The skin surface is a dry, acidic environment, and the temperature is less than 37° C. The pores and crevices the the skin also are conquered by the “normal bacter flora”, which ensure competition for pathogens to which the skin is exposed. Similarly, the mucous layer that covers the epithelia contains hostile substances to microbial colonization. Protective level of lysozyme, lactoferrin, and lactoperoxidase in the rubber either death bacteria or restrict their growth. In addition, the mucus consists of secretory immunoglobulins (predominantly sIgA) synthesized by plasma cell resident in the submucosal tissue during the common course that life, individuals build local antibodies specific for a selection of minister bacteria the colonize mucosal surfaces.

Another device of restricting growth of bacteria that penetrate the skin and mucous membrane is competition for iron. Typically, the quantity of free iron in tissues and blood easily accessible to bacteria is very low, since plasma transferrin binds basically all steel in the blood. Similarly, hemoglobin in the erythrocytes binds iron. Without cost-free iron, bacterial development is restricted unless the bacteria synthesize siderophores or receptors for iron containing molecules that compete for transferrin-bound iron. Such siderophores piece iron from transferrin and also present it to the bacteria, which allows them come grow. The phagocytic cells of the human body patrol the blood and tissues for foreign substances, including bacteria. This task is assumed primarily by polymorphonuclear neutrophils; however, monocytes, macrophages, and eosinophils also participate. After ~ phagocytosis, this bacterial cells typically are killed unless their numbers are extreme or they own virulence factors, that permit them to endure the lysosomal enzymes and acidic pH. In some instances, the bacteria kill the phagocyte or multiply in ~ the macrophage, escaping the enemy extracellular environment. Once inflammation occurs, phagocytic cells, along with lymphocytes, play vital role in innate immunity to bacter infections. Throughout the communication of bacter cells through macrophages, T cells, and B cells, particular antibody responses and/or cell-mediated immunity construct to protect versus reinfection.


Genetic and Molecular Basis because that Virulence

Virulence determinants in bacteria might be encoded top top chromosomal DNA, bacteriophage DNA, plasmids, or transposons in either plasmids or the bacterial chromosome (Fig. 7-2; Table 7-2). Because that example, the capacity of the Shigella varieties to invade cells is a building encoded in part on a 140-mega-dalton plasmid. Similarly, the heat-labile enterotoxin (LTI) that E. Coli is plasmid encoded, conversely, the heat-labile toxin (LTII) is encoded ~ above the chromosome. Various other virulence components are acquired by bacteria adhering to infection through a details bacteriophage, which integrates the genome right into the bacter chromosome by the process of lysogeny (Fig. 7-2). Pleasant bacteriophages often serve as the communication of toxin production in pathogenic bacteria. Examples include diphtheria toxin manufacturing by Corynebacterium diphtheriae, erythrogenic toxin development by Streptococcus pyogenes, Shiga-like toxin synthetic by E. Coli, and also production of botulinum toxin (types C and also D) by Clostridium botulinum. Various other virulence components are encoded ~ above the bacter chromosome (e.g., cholera toxin, Salmonella enterotoxin, and also Yersinia intrusion factors).


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The transport of gene for antibiotic resistance among bacteria is a far-reaching medical problem, although nobody of this properties in reality confers increased virulence to the bacterium. Rather, they carry out the chance for resistant bacteria to proliferate and produce various other virulence components in patient who are being treated with an unreasonable antibiotic. Resistance factors are discussed completely in thing 5.

An attractive question regarding most bacterial protein toxin is the objective they offer for the bacteriophage or the bacterium delivering them. Numerous bacterial toxins space enzymes. Because that example, cholera toxin, diphtheria toxin, Pseudomonas exotoxin A, and pertussis toxin all are NAD+ glycohydrolases that additionally act as ADP-ribosyltransferases. The toxic result of these bacterial enzyme on the hold is integral to the pathogenesis of the bacterial infections, yet the function of the enzymes in the normal bacterial physiology is no known. Of every the protein toxins synthesized by pathogenic bacteria, there are few instances in i beg your pardon the duty of the protein to the bacterium is known. It would be unlikely for the bacter or infecting bacteriophage to expend the power necessary come synthesize these relatively high-molecular-weight and facility molecules if they offered it no advantage. Frequently the toxicity of this substances is “unintentional” as far as the bacteria are concerned, given that the major goal of the microorganisms is to acquire nutrients and multiply rather than to damage the host.


Host-mediated Pathogenesis

The pathogenesis of many bacterial infections cannot be separated from the organize immune response, for lot of the tissue damage is brought about by the host an answer rather than by bacter factors. Classic examples of organize response-mediated pathogenesis are seen in diseases such together Gram-negative bacter sepsis, tuberculosis, and tuberculoid leprosy. The tissue damages in this infections is led to by toxic determinants released indigenous the lymphocytes, macrophages, and also polymorphonuclear neutrophils infiltrating the site of epidemic (Fig. 7-3). Often the host solution is so extreme that hold tissues are destroyed, enabling resistant bacteria come proliferate. In lepromatous leprosy, in contrast, the lack of a cellular response to Mycobacterium leprae enables the bacteria to main point to such huge numbers in the skin the they end up being tightly packed and also replace healthy tissue. The molecular basis for this details immune anergy is poorly understood.


Figure 7-3

Generalized mechanisms of bacter pathogenesis. Bacteria-induced toxicity or host-mediated damage.


Intracellular Growth

In general, bacteria that can enter and survive within eukaryotic cells space shielded from humoral antibodies and also can be eliminated only through a moving immune response. However, this bacteria should possess devoted mechanisms to safeguard them from the harsh impacts of the lysosomal enzyme encountered within the cabinet (see Ch. 1). Pathogenic bacteria deserve to be grouped into three category on the communication of their invasive properties for eukaryotic cells (Fig. 7-4; Table 7-3). Although part bacteria (e.g., Rickettsia, Coxiella, and also Chlamydia) flourish only inside organize cells, rather (e.g., Salmonella, Shigella, and Yersinia) are facultative intracellular pathogens, invading cells as soon as it provides them a selective benefit in the host.


Figure 7-4

Examples the pathogenic bacteria, indicating their preferred growth step within the host. (ETEC:enterotoxigenic E. Coli)


Some bacteria endure the intracellular milieu by developing phospholipases come dissolve the phagocytic vesicle surrounding them. This shows up to be the case for R. Rickettsii, i beg your pardon destroys the phagosomal membrane v which the lyosoms fuse. Legionella pneumophila, i m sorry prefers the intracellular environment of macrophages for growth, appears to induce its own uptake and blocks lysosomal combination by undefined mechanisms. Other bacteria have advanced to the suggest that they favor the low-pH setting within the lysosomal granules, as may be the situation for Coxiella burnetii, a highly resistant member of the rickettsial group. Salmonella and Mycobacterium varieties also show up to be very resistant come intracellular death by phagocytic cells, however their instrument of resistance are not yet totally understood. Certainly, the volume of bacteria to survive and also multiply within organize cells has good impact top top the pathogenesis of the particular infections.

Most bacterial pathogens carry out not attack cells, proliferating instead in the extracellular environment enriched by human body fluids. Several of these bacteria (e.g., V. Cholerae and also Bordetella pertussis) carry out not even penetrate body tissues, but, rather, adhere come epithelial surfaces and cause disease by secreting potent protein toxins. Return bacteria such together E. Coli and P. Aeruginosa room termed noninvasive, they commonly spread quickly to various tissues once they gain access to the body. All bacteria can at some allude be taken into consideration intracellular when they end up being ingested through polymorphonuclear neutrophils and macrophages, yet these organisms space not renowned because that their volume to survive the intracellular environment or come induce their own uptake by most hold cells.


Specific Virulence Factors

The virulence determinants of bacteria have the right to be divided into a variety of functional types. These are debated in the following sections:


Adherence and also Colonization Factors

To cause infection, numerous bacteria must very first adhere come a mucosal surface. Because that example, the alimentary street mucosa is continually cleansed by the release of mucus from goblet cells and also by the peristaltic circulation of the gut contents over the epithelium. Similarly, ciliated cells in the respiratory tract sweep mucus and bacteria upward. In addition, the sales of epithelial cells at these surfaces is reasonably rapid. The minister epithelial cell monolayer is continually replenished, and the cells are moved from the crypts to the villar tips in around 48 hours. To develop an infection at such a site, a bacterium must adhere to the epithelium and also multiply before the mucus and also extruded epithelial cells are swept away. To attain this, bacteria have advanced attachment mechanisms, together as chili (fimbriae), that recognize and attach the bacteria to cell (see Ch. 2). Colonization factors (as they are often called) are created by plenty of bacterial pathogens and also constitute critical part that the pathogenic device of this bacteria. Some instances of piliated, adherent bacter pathogens space V. Cholerae, E. Coli, Salmonella spp., N. Gonorrheae, N. Meningitidis, and Streptococcus pyogenes.


Invasion Factors

Mechanisms that enable a bacterium to attack eukaryotic cell facilitate entry in ~ mucosal surfaces. Few of these invasive bacteria (such as Rickettsia and also Chlamydia species) space obligate intracellular pathogens, however most space facultative intracellular pathogens (Fig. 7-4). The certain bacterial surface determinants that mediate intrusion are not known in most instances, and often, multiple gene commodities are involved. Some Shigella invasion factors are encoded on a 140 megadalton plasmid, which, as soon as conjugated into E. Coli, gives these noninvasive bacteria the volume to invade cells. Other intrusion genes have additionally recently been established in Salmonella and Yersinia pseudotuberculosis. The mechanisms of intrusion of Rickettsia, and also Chlamydia types are no well known.


Capsules and Other surface Components

Bacteria have evolved countless structural and also metabolic virulence determinants that improve their survival price in the host. Capsule development has lengthy been recognized as a protective mechanism for bacteria (see Ch. 2). Encapsulated strains of many bacteria (e.g., pneumococci) are much more virulent and much more resistant to phagocytosis and intracellular death than space nonencapsulated strains. Biology that reason bacteremia (e.g., Pseudomonas) are much less sensitive than many other bacteria to killing by fresh person serum containing complement components, and also consequently are referred to as serum resistant. Serum resistance might be related to the amount and composition of capsular antigens as well as to the framework of the lipopolysaccharide. The relationship in between surface structure and also virulence is important additionally in Borrelia infections. Together the bacteria encounter an increasing details immune solution from the host, the bacterial surface ar antigens are altered by mutation, and the progeny, which are no longer known by the immune response, express renewed virulence. Salmonella typhi and some that the paratyphoid organisms carry a surface ar antigen, the vi antigen, assumed to enhance virulence. This antigen is created of a polymer of galactosamine and uronic acid in 1,4-linkage. Its duty in virulence has not been defined, however antibody to it is protective.

Some bacteria and also parasites have actually the ability to survive and also multiply inside phagocytic cells. A classic example is Mycobacterium tuberculosis, whose survival seems to count on the structure and also composition the its cabinet surface. The parasite Toxoplasma gondii has the remarkable capability to block the combination of lysosomes v the phagocytic vacuole. The hydrolytic enzymes contained in the lysosomes are unable, therefore, to add to the destruction of the parasite. The mechanism(s) whereby bacteria such together Legionella pneumophila, Brucella abortus, and also Listeria monocytogenes remain unharmed within phagocytes space not understood.


Endotoxins

Endotoxin is consisted of of toxic lipopolysaccharide materials of the external membrane of Gram-negative bacteria (see Ch. 2). Endotoxin exerts extensive biologic results on the host and may be lethal. Due to the fact that it is omnipresent in the environment, endotoxin have to be removed from all medical supplies destined for injection or use during surgical procedures. The ax endotoxin was coined in 1893 by Pfeiffer to differentiate the class of toxic substances released after lysis of bacteria native the toxicity substances (exotoxins) secreted by bacteria. Few, if any, various other microbial products have been as generally studied together bacterial endotoxins. Maybe it is ideal that a molecule v such important biologic results on the host, and one created by so countless bacterial pathogens, need to be the subject of extreme investigation.


Structure that Endotoxin

Figure 7-5 illustrates the simple structure the endotoxin. Endotoxin is a molecular facility of lipid and also polysaccharide; hence, the alternating name lipopolysaccharide. The facility is secured come the outer membrane through ionic and also hydrophobic forces, and its strong an adverse charge is neutralized by Ca2+ and also Mg2+ ions.


The structure of endotoxin molecule from Salmonella spp. And also E. Coli is recognized in detail. Enough data on endotoxin from other Gram-negative organisms have actually been gathered to reveal a typical pattern v genus and species diversity. Although all endotoxin molecules are comparable in chemical structure and biologic activity, part diversity has actually evolved. Purified endotoxin appears as big aggregates. The molecular complex can be split into three areas (Fig. 7-5): (1) the O-specific chains, i m sorry consist the a variety of repeating oligosaccharide residues, (2) the core polysaccharide that develops the backbone of the macromolecule, and (3) lipid A, composed usually of a glucosamine disaccharide v attached long-chain fatty acids and also phosphate. The polysaccharide portions are responsible because that antigenic diversity, conversely, the lipid A moiety confers toxicity. Dissociation that the complex has revealed the the polysaccharide is necessary in solubilizing the toxicity lipid A component, and in the activities it can be replaced by transport proteins (e.g., bovine serum albumin).

Members that the family members Enterobacteriaceae exhibit O-specific chain of various lengths, vice versa, N. Gonorrhoeae, N. Meningitidis, and also B. Pertussis contain only core polysaccharide and also lipid A. Part investigators working on the latter develops of endotoxin choose to call them lipooligosaccharides come emphasize the chemical distinction from the endotoxin of the enteric bacilli. Nevertheless, the biologic activities of every endotoxin preparations are essentially the same, through some being much more potent than others.


Biologic activity of Endotoxin

The biologic impacts of endotoxin have actually been extensively studied. Purified lipid A (conjugated come bovine serum albumin) and also endotoxin elicit the same biologic responses. Table 7-4 lists few of the biologic impacts of endotoxin. The an ext pertinent toxic impacts include pyrogenicity, leukopenia adhered to by leukocytosis, enhance activation, depression in blood pressure, mitogenicity, induction that prostaglandin synthesis, and also hypothermia. These occasions can finish in sepsis and lethal shock. However, it need to be provided from Table 7-4 that no all impacts of endotoxin room necessarily detrimental; several induce responses potentially valuable to the host, assuming the stimulation is no excessive. This include:


1.

mitogenic impacts on B lymphocytes that boost resistance come viral and bacterial infections

2.

induction the gamma interferon manufacturing by T lymphocytes, i beg your pardon may improve the antiviral state, promote rejection that tumor cells, and activate macrophages and also natural killer cells

3.

activation of the enhance cascade through the development of C3a and also C5a

4.

induction that the development of interleukin-1 by macrophages and also interleukin-2 and also other mediators through T lymphocytes.

Current research concentrates on exploiting some of the potential useful effects that “nontoxic” endotoxin derivatives and holds promise for advancement of future therapy regimens for stimulating the immune response. For example, the toxicity of endotoxin is mostly attributed come lipid A, attached to a polysaccharide carrier. The toxicity of lipid A is markedly reduced after hydrolysis the a phosphate team or deacylation the one or an ext fatty mountain from the lipid A molecule. Clinical trials room in progress to check a monophosphoryl lipid A because that its potential of inducing short dose yongin to endotoxin. Tolerance to endotoxin can be achieved by pretreatment that an animal with short doses of endotoxin or a detoxified lipid A derivative before an obstacle with high doses of endotoxin. Speculative studies have demonstrated the induction of tolerance to endotoxin to reduce the dangerous effects of endotoxin. The is hoped the these reasonably nontoxic lipid A derivatives may be useful in to reduce the severity of bacterial sepsis in which bacterial endotoxin produce a life-threatening clinical course.

Endotoxin, which mostly accumulates in the liver following injection the a sublethal dose by the intravenous route, deserve to be devastating since of its ability to affect a variety of cell and also host proteins. Kupffer cells, granulocytes, macrophages, platelets, and lymphocytes all have a cell receptor on your surface dubbed CD14, which binding endotoxin. Endotoxin binding come the CD14 receptor ~ above macrophages is intensified by communication with a host protein made in the liver (i.e., LPS-binding protein). The extent of involvement of every cell kind probably relies on the level the endotoxin exposure. The results of endotoxin on together a wide variety of host cells an outcome in a complicated array of host responses that can culminate in the serious condition gram-negative sepsis, which frequently leads come shock and death. The impacts of endotoxin on organize cells are well-known to wake up prostaglandin synthesis and to activate the kallikrein system, the kinin system, the match cascade via the different pathway, the clotting system, and also the fibrinolytic pathways. As soon as these normal organize systems room activated and operate the end of control, that is not surprising the endotoxin can be lethal. Although that is complicated to understand the instrument of every the cell responses and the myriad sequelae that the cabinet mediators released fairly indiscriminately in the host adhering to exposure to endotoxin, it does it seems to be ~ clear the the organize cellular an answer to endotoxin, rather than a straight toxic impact of endotoxin, dram the significant role in causing tissue damage (Fig. 7-3).


Detection that Endotoxin in clinical Solutions

Endotoxin is omnipresent in the environment. It is discovered in most deionized-water currently in hospitals and laboratories, because that example, and also affects practically every biology assay system ever before examined. It has tendency to be a scapegoat for all biologic troubles encountered in the laboratory, and, numerous times, this call is deserved. Since of the pyrogenic and destructive properties, extreme care must be taken to prevent exposing patients to clinical solutions containing endotoxin. Even though all supplies should be sterile, services for intravenous management can come to be contaminated v endotoxin-containing bacteria after sterilization as a result of not correct handling. Furthermore, water offered in the ready of such solutions have to be filtered with ion exchange resins to remove endotoxin, because it is not removed by one of two people autoclave sterilization or filtration with bacterial membrane filters. If endotoxin-containing options were provided in together medical actions as renal dialysis, heart bypass machines, blood transfusions, or operation lavage, the patient would suffer prompt fever add by a rapid and also possibly lethal alterations in blood pressure.

Solutions for person or veterinary usage are all set under carefully controlled conditions to ensure sterility and also to eliminate endotoxin. Representative samples of every manufacturing batch room checked because that endotoxin by among two procedures: the Limulus lysate check or the rabbit pyrogenicity test. The hare pyrogenicity check is based upon the exquisite sensitivity of rabbits to the pyrogenic impacts of endotoxin. A sample that the systems to be tested typically is injected intravenously into the ear veins of adult rabbits when the rectal temperature of the animal is monitored. Careful monitoring that the temperature responses gives a sensitive and also reliable indicator of the visibility of endotoxin and, importantly, one measure of the safety of the solution for usage in patients.

The Limulus lysate test is much more common and less expensive. This test, i m sorry is based on the capacity of endotoxin to induce gelation the lysates the amebocyte cell from the horseshoe crab Limulus polyphemus, is simple, fast, and also sensitive (about 1 ng/ml). That is so sensitive, however, that trace quantities of endotoxin in regular deionized water frequently obscure the results. It deserve to be used for quick detection of particular Gram-negative epidemic (e.g., the cerebrospinal fluid); however, blood consists of inhibitors that avoid gelation. Check kits are commercially available. The amebocyte is the single phagocytic immune cell of the horseshoe crab, and the gelation reaction is believed to be connected in sequestering invading Gram-negative bacteria.


Exotoxins

Exotoxins, unequal the lipopolysaccharide endotoxin, room protein toxins released native viable bacteria. They type a course of poisons that is amongst the most potent, every unit weight, the all toxicity substances. Most of the higher molecular-sized exotoxin protein are warmth labile; however, plenty of low molecular-sized exotoxins space heat-stable peptides. Unequal endotoxin, i m sorry is a structural component of every Gram-negative cells, exotoxins are produced by part members the both Gram-positive and Gram-negative genera. The functions of this exotoxins because that the bacteria are usually unknown, and the gene for most have the right to be deleted through no noticeable effect on bacterial growth. In contrast to the comprehensive systemic and immune-system effects of endotoxin top top the host, the site of activity of many exotoxins is an ext localized and is limit to particular cell types or cell receptors. Tetanus toxin, for example, affects just internuncial neurons. In general, exotoxins are excellent antigens that elicit particular antibodies called antitoxins. Not all antitoxin to exotoxins space protective, yet some reaction with important binding web page or enzymatic website on the exotoxin, resulting in finish inhibition that the toxic task (i.e., neutralization).

Exotoxins can be grouped right into several category (e.g., neurotoxins, cytotoxins, and also enterotoxins) based upon their biologic impact on organize cells. Neurotoxins are best exemplified by the toxins produced by Clostridium spp., because that example, the botulinum toxin formed by C. Botulinum. This potent neurotoxin acts upon motor neurons by preventing the relax of acetylcholine in ~ the myoneural junctions, thereby staying clear of muscle excitation and producing flaccid paralysis. The cytotoxins constitute a larger, much more heterogeneous grouping with a vast array of hold cell specificities and also toxic manifestations. One cytotoxin is diphtheria toxin, i beg your pardon is developed by Corynebacterium diphtheriae. This cytotoxin inhibits protein synthetic in numerous cell types by catalyzing the ADP-ribosylation the elongation aspect II, which blocks elongation that the farming peptide chain.

Enterotoxins wake up hypersecretion of water and electrolytes from the minister epithelium and thus create watery diarrhea. Part enterotoxins are cytotoxic (e.g., shiga-like enterotoxin from E. Coli), while others perturb eukaryotic bio cell functions and also are cytotonic (e.g., cholera toxin). Enterotoxins additionally can disturb common smooth muscle contraction, causing abdominal cramping and decrease transit time for water absorb in the intestine. Enterotoxigenic E. Coli and V. Cholerae create diarrhea after attaching to the minister mucosa, where they fancy enterotoxins. Neither virus invades the human body in considerable numbers, other than in the situation of E. Coli species that have got an intrusion plasmid. Importantly, cholera toxin and E. Coli heat-labile enterotoxins I and II cause ADP-ribosylation of cell proteins in a manner comparable to diphtheria toxin, except that the main target is the regulation protein (Gs_) that adenylate cyclase, result in raised levels of cyclic 3′,5′-adenosine monophosphate (cAMP) (see Ch. 25). In contrast, the organisms responsible because that shigellosis (Shigella dysenteriae, S. Boydii, S. Flexneri, and also S. Sonnei) permeate the mucosal surface of the colon and also terminal ileum come proliferate and cause ulcerations the bleed into the intestinal lumen. Despite causing considerable ulceration of the mucosa, the pathogens rarely go into the bloodstream. The Shiga enterotoxin produced by Shigella types and the Shiga-like enterotoxin elaborated by numerous isolates the E. Coli inhibit protein synthetic in eukaryotic bio cells. The is not clear exactly how this cytotoxic enterotoxin causes hypersecretion that water and also electrolytes from the minister epithelium. This enterotoxins different from those secreted by V. Cholerae and also E. Coli in that the Shiga toxins space cytotoxic and lethal, whereas the cholera toxin-like enterotoxins room not. The last enterotoxins reason no structural damages to cells, and are explained as cytotonic. The taking place inflammatory an answer to the invading bacteria and/or your toxins appears to activate neurologic manage mechanisms (e.g., prostaglandins, serotonin) that typically regulate water and also electrolyte transport.


Siderophores

Both animals and bacteria require iron because that metabolism and growth, and the regulate of this minimal resource is regularly used as a tactic in the conflict between microorganism and host. Animals have progressed mechanisms the “withholding” steel from tissue fluids in an effort to border the development of invading bacteria. Back blood is a rich source of iron, this steel is not readily obtainable to bacteria due to the fact that it is not free in solution. Many of the steel in blood is bound either to hemoglobin in erythrocytes or come transferrin in plasma. Similarly, the iron in milk and other secretions (e.g., tears, saliva, bronchial mucus, bile, and also gastrointestinal fluid) is bound to lactoferrin. Some bacteria refer receptors because that eukoyotic iron-binding proteins (e.g., transferrin-binding external membrane proteins on the surface ar of Neisserira spp.). Via these specialized receptors iron salvation is facilitated, giving the esssential aspect for bacter growth.

Other bacteria have evolved elaborate mechanisms to extract the stole from hold proteins (Fig. 7-6). Siderophores room substances created by plenty of bacteria (and some plants) to capture iron native the host. The lack of iron triggers transcription of the gene coding for the enzymes that synthesize siderophores, and also for a set of surface protein receptor that acknowledge siderophores transferring bound iron. The binding constants the the siderophores for iron space so high that even iron bound to transferrin and also lactoferrin is confiscated and taken up by the bacterial cells. An example of a bacter siderophore is enterochelin, i m sorry is created by Escherichia and also Salmonella species. Classic experiments have demonstrated that Salmonella mutants that have lost the volume to synthesize enterochelin shed virulence in an assay that lethality in mice. Injection the purified enterochelin along with the Salmonella mutants restores virulence come the bacteria. Therefore, siderophore production by plenty of pathogenic bacteria is considered critical virulence mechanism.


Figure 7-6

Competition between host cells and also bacterial pathogens because that iron, showing the importance of siderophores. Since totally free iron is scarce in organization fluids and blood, bacterial siderophores compete effectively for Fe3+ bound come lactoferrin and also transferrin. (more...)


Epilogue

Many components determine the outcome of the bacterium-host relationship. The hold must live in an atmosphere filled with a diverse population of microorganisms. Since of the magnitude of the infectious-disease problem, us strive to know the herbal immune instrument of the organize so that future improvements in resistance to bacterial infections might be possible. Similarly, substantial research efforts are being expended come identify and characterize the virulence components of pathogenic bacteria and also hence allow us to interrupt the pathogenic instrument of virulent bacteria. The access of an array of antibiotics and vaccines has listed the medical profession with an effective tools to control or cure many infections. Unfortunately, this drugs and vaccines have eliminated no bacterial disease from the human being or animal populations, and also bacterial infections and drug resistance remain a serious medical problem.


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