1. Pathogenesis Chapter 7

2. ● A microorganism is a pathogen if it is capable of causing disease. ● Opportunistic pathogens are those that cause serious infection in immuno- compromised patients. ● These opportunists are frequent members of the body’s normal flora. ● Virulence is a measure of pathogenicity and is measured by the number of organisms required to cause disease. ● The 50% lethal dose (LD 50 ) is the number of organisms needed to kill half the hosts, and the 50% infectious dose (ID 50 ) is the number needed to cause infection in half the hosts. ● Organisms with a lower LD 50 (or ID 50 ) are said to be more virulent than those with a higher LD 50 (or ID 50 ) because fewer organisms are needed to cause death or disease. ● The infectious dose of an organism required to cause disease varies greatly among the pathogenic bacteria. 2

3. ● For example, Shigella and Salmonella both cause diarrhea by infecting the GI tract, but the infectious dose of Shigella is less than 100 organisms, whereas the infectious dose of Salmonella is on the order of 100,000 organisms. ● The infectious dose of bacteria depends primarily on their virulence factors (e.g., pili, exotoxins or endotoxins) WHY DO PEOPLE GET INFECTIOUS DISEASES? 3 ● People get infectious diseases when microorganisms overpower our host defenses. ● The organism or its products are then present in sufficient amount to induce various symptoms, such as fever and inflammation. ● From the organism’s perspective, the two critical determinants are the number of organisms to which the host is exposed and the virulence of these organisms.

4. 4 ● It is important to realize that a small number of highly virulent organisms can cause disease just as a large number of less virulent organisms can. ● From the host’s perspective, the two main arms of host defenses are innate immunity and acquired immunity. ● A reduction in the functioning of any component of host defenses increases the chance that an infectious disease will occur. ● Some causes of a reduction in host defenses include genetic immunodeficiencies such as agammaglobulinemia, acquired immunodeficiencies such as AIDS, diabetes, and drug-induced immunosuppression in patients with organ transplants, with autoimmune diseases, and in cancer patients who are receiving chemotherapy. ● In many instances, a person acquires an organism, but no infectious disease occurs because the host defenses were successful. Such asymptomatic infections are recognized by detecting antibody against the organism in the patient’s serum.

5. 5 TYPES OF BACTERIAL INFECTIONS ● Bacteria cause disease by two major mechanisms: (1) toxin production and (2) invasion and inflammation. ● Toxins fall into two general categories: exotoxins and endotoxins. ● Exotoxins are polypeptides released by the cell, whereas endotoxins are lipopolysaccharides (LPS), which form an integral part of the cell wall. ● Endotoxins occur only in gram-negative rods and cocci, are not actively released from the cell, and cause fever, shock, and other generalized symptoms. ● Both exotoxins and endotoxins by themselves can cause symptoms; the presence of the bacteria in the host is not required. ● Invasive bacteria, on the other hand, grow to large numbers locally and induce an inflammatory response consisting of erythema, edema, warmth, and pain.

6. 6 ● Many, but not all, infections are communicable. ● For example, tuberculosis is communicable, but botulism is not. ● If a disease is highly communicable, the term contagious is applied. ● An infection is epidemic if it occurs much more frequently than usual; it is pandemic if it has a worldwide distribution. ● An endemic infection is constantly present at a low level in a specific population. ● Some infections result in a latent state, after which reactivation of the growth of the organism and recurrence of symptoms may occur. ● Certain other infections lead to a chronic carrier state, in which the organisms continue to grow with or without producing symptoms in the host.

7. 7 STAGES OF BACTERIAL PATHOGENESIS ● A generalized sequence of the stages of infection is as follows: 1. Transmission from an external source into the portal of entry. 2. Evasion of primary host defenses such as skin or stomach acid. 3. Adherence to mucous membranes, usually by bacterial pili. 4. Colonization by growth of the bacteria at the site of adherence. 5. Disease symptoms caused by toxin production or invasion accompanied by inflammation. 6. Host responses, both nonspecific and specific (immunity), during steps 3, 4, and 5. 7. Progression or resolution of the disease. 1. Transmission ● Sources of infectious diseases are human, soil, water, and animals. ● Fomites, such as towels, that serve as a source of infectious diseases. ● Table 1 describes some important examples of these modes of transmission.

8. 8 Table 1: Important Modes of Transmission

9. 9 ● Organisms can also be transmitted by respiratory and gastrointestinal tracts, sexual contact, urine, skin contact, blood transfusions, contaminated needles, or biting insects. ● The transfer of blood, either by transfusion or by sharing needles during intravenous drug use, can transmit various bacterial and viral pathogens. ● Bacteria, viruses, and other microbes can also be transmitted from mother to offspring, a process called vertical transmission. ● The three modes by which organisms are transmitted vertically are across the placenta, within the birth canal during birth, and via breast milk. ● Table 7–2 describes some medically important organisms that are transmitted vertically. ● (Horizontal transmission, by contrast, is person-to-person transmission that is not from mother to offspring.)

10. 10 ● There are four important portals of entry: respiratory tract, gastrointestinal tract, genital tract, and skin. ● Animals are also an important source of organisms that infect humans. ● They can be either the source (reservoir) or the mode of transmission (vector) of certain organisms. ● Diseases for which animals are the reservoirs are called zoonoses.

11. 11 TABLE 2: Vertical Transmission of Some Important Pathogens

12. 12 TABLE 3: Portals of Entry of Some Common Pathogens

13. 13 TABLE 4: Transmission of Important Waterborne Diseases

14. 14 TABLE 5: Bacterial Diseases Transmitted by Foods

15. 15 TABLE 6: Bacterial Diseases Transmitted by Insects

16. 16 TABLE 7: Zoonotic Diseases Caused by Bacteria

17. 17 2. Adherence to Cell Surfaces ● Certain bacteria have specialized structures (e.g., pili, capsules or glycocalyces) that allow them to adhere to the surface of human cells, thereby enhancing their ability to cause disease. ● The various molecules that mediate adherence to cell surfaces are called adhesins. ● After the bacteria attach, they often form a protective matrix called a biofilm consisting of various polysaccharides and proteins. ● Biofilms form especially on foreign bodies such as prosthetic joints, prosthetic heart valves, and intravenous catheters, but they also form on native structures such as heart valves. ● Biofilms protect bacteria from both antibiotics and host immune defenses. ● They also retard wound healing resulting in chronic wound infections, especially in diabetics.

18. 18 ● Biofilms play an important role in the formation of dental plaque, the precursor of dental caries. ● The production of biofilms by bacteria is controlled by the process of quorum sensing. ● In quorum sensing, the bacteria grow in a nonaggressive manner until a quorum is sensed (i.e., a certain density of bacteria has been reached), at which point the synthesis of new bacterial virulence factors (e.g., biofilms) that contribute to pathogenesis occurs. 3. Invasion, Inflammation, & Intracellular Survival ● Several enzymes secreted by invasive bacteria play a role in pathogenesis. Among the most prominent are the following: 1. Collagenase and hyaluronidase, which degrade collagen and hyaluronic acid, respectively, thereby allowing the bacteria to spread through subcutaneous tissue.

19. 19 2. Coagulase, which is produced by Staphylococcus aureus and accelerates the formation of a fibrin clot from fibrinogen (this clot may protect the bacteria from phagocytosis by walling off the infected area and by coating the organisms with a layer of fibrin). 3. Immunoglobulin A (IgA) protease, which degrades IgA, allowing the organism to adhere to mucous membranes, and is produced by some bacteria. 4. Leukocidins, which can destroy both neutrophilic leukocytes and macrophages 4. Toxin Production ● The second major mechanism by which bacteria cause disease is the production of toxins. Exotoxins ● Exotoxins are produced by several gram-positive and gram-negative bacteria, in contrast to endotoxins, which are present only in gram-negative bacteria.

20. 20 ● Exotoxins are secreted by the bacteria, whereas endotoxin is a component of the cell wall. ● Some important exotoxins are diphtheria toxin, cholera toxin, and botulinum toxin. ● Many exotoxins have an A–B subunit structure; the A subunit possesses the toxic activity, and the B subunit is responsible for binding the exotoxin to specific receptors on the membrane of the human cell. ● The A subunit of several important exotoxins acts by ADP-ribosylation (i.e., the A subunit is an enzyme that catalyzes the addition of [ADP-ribose] to the target protein in the human cell). ● The addition of ADP-ribose to the target protein often inactivates it but can also hyperactivate it, either of which can cause the symptoms of disease. Endotoxins ● Endotoxins are integral parts of the cell walls of both gram-negative rods and cocci, in contrast to exotoxins, which are actively released from the cell.

21. 21 ● Endotoxins are lipopolysaccharides (LPS), whereas exotoxins are polypeptides. ● The toxicity of endotoxins is low in comparison with that of exotoxins. ● All endotoxins produce the same generalized effects of fever and shock. ● Endotoxins are weakly antigenic; they induce protective antibodies so poorly that multiple episodes of toxicity can occur. ● Septic shock is one of the leading causes of death in intensive care units and has an estimated mortality rate of 30% to 50%. ● The endotoxins of gram-negative bacteria are the best-established causes of septic shock, but surface molecules of gram-positive bacteria can also cause septic shock. ● Two features of septic shock are interesting: 1. Septic shock is different from toxic shock. In septic shock, the bacteria are in the bloodstream, whereas in toxic shock, it is the toxin that is circulating in the blood.

22. 22 ● The clinical importance of this observation is that in septic shock, blood cultures are usually positive, whereas in toxic shock, they are usually negative. 2. Septic shock can cause the death of a patient even though antibiotics have killed the bacteria in the patient’s blood (i.e., the blood cultures have become negative). ● This occurs because septic shock is mediated by cytokines, such as TNF and IL-1, which continue to act even though the bacteria that induced the cytokines are no longer present. ● The biologic effects of endotoxin include fever, hypotension, and DIC.

23. 23 Table 8: Main Features of Exotoxins and Endotoxins

24. 24 5. Immunopathogenesis ● In certain diseases, such as rheumatic fever and acute glomerulonephritis, it is not the organism itself that causes the symptoms of disease but the immune response to the presence of the organism. ● For example, in rheumatic fever, antibodies are formed against the M protein of S. pyogenes, which cross-react with joint, heart, and brain tissue. ● Inflammation occurs, resulting in the arthritis, carditis, and chorea that are the characteristic findings in this disease.

25. 25 BACTERIAL INFECTIONS ASSOCIATED WITH CANCER ●The fact that certain viruses can cause cancer is well established, but the observation that some bacterial infections are associated with cancers is just emerging. ● Several documented examples include : 1. The association of Helicobacter pylori infection with gastric carcinoma and gastric mucosal-associated lymphoid tissue (MALT) lymphoma. 2. The association of Campylobacter jejuni infection with MALT lymphoma of the small intestine. ● Support for the idea that these cancers are caused by bacteria comes from the observation that antibiotics can cause these cancers to regress if treated during an early stage.

26. 26 TYPICAL STAGES OF AN INFECTIOUS DISEASE ● A typical acute infectious disease has four stages: 1.The incubation period, which is the time between the acquisition of the organism (or toxin) and the beginning of symptoms. 2.The prodrome period, during which nonspecific symptoms such as fever, malaise, and loss of appetite occur. 3.The specific-illness period, during which the overt characteristic signs and symptoms of the disease occur. 4.The recovery period, also known as the convalescence period, during which the illness abates and the patient returns to the healthy state.

27. 27 DID THE ORGANISM ISOLATED FROM THE PATIENT ACTUALLY CAUSE THE DISEASE? ● This is the problem that Robert Koch faced in 1877 when he was among the first to try to determine the cause of an infectious disease. ● His approach led to the formulation of Koch’s postulates, which are criteria that he proposed must be satisfied to confirm the causal role of an organism. ● These criteria are as follows: 1. The organism must be isolated from every patient with the disease. 2. The organism must be isolated free from all other organisms and grown in pure culture in vitro. 3. The pure organism must cause the disease in a healthy, susceptible animal. 4. The organism must be recovered from the inoculated animal.

28. 28 ● In some infections, no organism is isolated from the patient, and the diagnosis is made by detecting a rise in antibody titer to an organism. ● For this this purpose, the titer (amount) of antibody in the second or late serum sample should be at least four times the titer (amount) of antibody the first or early serum sample. End of Chapter