![17
stage symptoms pathogenesis
initial contact,
incubation period
(2-10 wks)
multiplication at infection
site
primary syphilis
(1-3 months)
primary chancre; enlarged nodes
(groin), spontaneous healing
(within 4-6 wks)
[silent phase (~2-10 wks)]
proliferation in regional
lymph nodes and blood
secondary syphilis
(weeks-months)
flu-like (muscle ache, headache,
fever), rash,
multiplication; lesions in
lymph nodes, joints, muscle,
skin, mucous membranes, liver
latent syphilis
(3-30 yrs)
none T. pallidum dormant
→ eventual new cell growth
tertiary syphilis neurological (paralysis, insanity)
cardiovascular (aortic lesions,
rupture; stroke)
progressive destructive disease
further dissemination,
invasion,
gumma formation (skin, bone,
joints, testes)
progression of syphilis:](https://image.slidesharecdn.com/chapter15microbialpathogenicity-210211195924/85/Chapter-15-microbial-pathogenicity-17-320.jpg)
Chapter 15 microbial pathogenicity
- 1. 1 Microbial Mechanisms of Pathogenicity
- 2. 2 Microbial Mechanisms of Pathogenicity In this chapter we will take a look at some of the specific properties of microorganisms that contribute to: – Pathogenicity: The ability of microorganism to cause disease by overcoming the defense of the host (refer to humans). – Virulence: The degree or extent of pathogenicity • To cause disease, most pathogens must: – gain access to host, – adhere to host tissues, – penetrate or evade host defenses, – and damage the host tissues. • However, some microbes do not cause diseases by directly damaging host tissue, instead disease is due to the accumulation of microbial waste products. • Also, some microbes, such as those that cause dental caries, can cause disease without penetrating the body (Streptococcus mutans)
- 3. 3 Mucous membranes, Skin, Parenteral route (direct deposition beneath the skin or membranes). 1. Mucous membranes: lining the respiratory tract, gastrointestinal tract, genitourinary tract, and conjuctiva a delicate membrane that covers the eye balls. • Respiratory tract (RT): is the easiest and frequent. Microbes are inhaled into the nose or mouth in drops of moisture and dust particles. – Diseases that are commonly contracted via the respiratory tract include the common cold, pneumonia, tuberculosis, influenza, measles, and small pox. • Gastrointestinal (GI) tract: microorganisms can gain access to GI in food and water and via contaminated fingers. Most microbes that enter the body in these ways are destroyed by hydrochloric acid (HCL) and enzymes in the stomach, or by bile and enzymes in the small intestine. Those that survive can cause disease. – Microbes in the GI tract can cause hepatitis A, typhoid fever, amoebic dysentry, giardiasis, shigellosis, and cholera (These pathogens are then eliminated with feces and can be transmitted to other host via contaminated water, food, and fingers). • Genitourinary tract: is a portal of entry for pathogens that are contracted sexually . – Some microbes can cause sexually transmitted diseases, for example, HIV, syphilis, chlamydia, gonorrhea. Portals of Entry
- 4. 4 Treponema pallidum : syphilis amoebic dysentry
- 5. 5 2. Skin: Unbroken skin is impenetrable by most microorganisms. Some microbes gain access to the body through opening in the skin, such as hair follicles, and sweat glands ducts. – In addition, larvae of the hookworm actually bore through intact skin, and some fungi grow on the keratin in skin or infect skin itself. 3. Parenteral route: other microorganisms can access to the body when they are deposited directly into the tissue beneath the skin or into mucous membranes when these barriers are penetrated or injured. – For example, punctures, injections, bites, cuts, wounds, surgery all establish parenteral routes. Portals of Entry
- 6. 6 The virulence of a microbe is often expressed as the ID50: Infectious dose for 50% of a sample population. Numbers of Invading Microbes Bacillus anthracis Portal of entry ID50 Skin (cutaneous anthrax) 10-50 endospores Inhalation 10,000-20,000 endospores Ingestion 250,000-1,000,000 endospores • These data show that cutaneous anthrax is significantly easier to acquire that either inhalation or ingestion. • A study or V. cholerae showed that the ID50 is 108 cells.
- 7. 7 • Bacillus anthracis, gram-positive, endospore-forming aerobic rod • Found in soil and water • Cattle are routinely vaccinated • Treated with ciprofloxacin or doxycycline Anthrax affects human in three forms: • Cutaneous anthrax – Endospores enter through minor cut – 20% mortality Anthrax • Gastrointestinal anthrax – Ingestion of undercooked food contaminated food – 50% mortality • Inhalational anthrax – Inhalation of endospores – 100% mortality
- 8. 8 The potency of a toxin is often expressed as the LD50: Lethal dose of a toxin for 50% of a sample population. Toxin LD50 Botulinum toxin 0.03ng/kg Shiga toxin 250 ng/kg Staphylococcal enterotoxin 1350ng/kg • These data show that a much smaller dose of botulinum toxin is needed to cause symptoms. .
- 9. 9 • The attachment between the pathogen and the host is accomplished by means of surface molecules on the pathogen called adhesins or ligands that bind specifically to receptors on the cells of certain host tissue. The majority of adhesins on the microorganisms studied are glycoproteins or lipoproteins. The receptors on host cells are typically sugars, mannose. • Adhesins may be located on a microbe’s glycocalyx or on other microbial surface structures, such as pili, fimbriae, and flagella. – Streptococcus mutans (tooth decay) • Glycocalyx – Escherichia coli (gastrointestinal disease) • Fimbriae – Treponema pallidium (cause syphilis) • Used its tapered end as a hook to attach to the host cell. – Lesteria monocytogenes (causes meningitis, spontaneous abortion, stillbirths) • produces an adhesin for a specific receptor on host cells. – Neisseria gonorrhoeae (grows inside human epithelial cells and leukocytes). • Fimbriae containing adhesins and an outer membrane protein (Opa protein). Adherence
- 10. 10 – Streptococcus pyogenes • M protein (heat resistant and acid resistant protein). The M protein mediates the attachment of the bacterium to epithelial cells of the host and helps the bacterium resist phagocytosis by white blood cells. – Neisseria gonorrhoeae (grows inside human epithelial cells and leukocytes). • Fimbriae and an outer membrane protein (Opa protein). – The waxes that make up the cell wall of M. tuberculosis also increase virulence by resisting digestion by phagocytes. • In fact, M. tuberculosis can even multiply inside phagocytosis. Certain bacteria contain chemical substances that contribute to virulence.
- 11. 11 – Coagulase (produced by some member of genus Staphylococcus) • Coagulate the fibrinogen in blood. Fibrinogen is a plasma protein produced by the liver, is converted by coagulases into fibrin, the thread that form a blood clot. – Kinases (Streptococcus pyogenes) • Digest fibrin clots (successfully used to dissolve some types of blood clots in cases of heart attacks due to obstructed coronary arteries). – Hyaluronidase (Streptococci and clostridium spp.) • Hydrolyzes hyaluronic acid, a type of polysaccharide that holds together certain cells of the body, particularly cells of connective tissue and help the microorganism spread from its initial site of infection. • This digestion action is thought to be involved in the tissue blackening of infected wounds. – Collagenase (Clostridium spp.) • Hydrolyzes collagen which forms the connective tissue of muscles and other body organs and tissues. (facilitate the spread of gas gangrene). – IgA proteases (N. gonnorrhoeae and N. meningitides) • Destroy IgA antibodies (a class of antibodies that produced to defend against adherence of pathogens to mucosal surfaces) The virulence of some bacteria is thought to be aided by the production of extracellular enzymes (exoenzymes and related substance)
- 12. 12 • In the presence of antigen the body produces proteins called antibodies, which bind to the antigens and inactivate and destroy them. • However, some pathogens can alter their surface antigens, by a process called antigenic variation. Thus by the time the body mounts an immune response against a pathogen, the pathogen has already altered its antigens and is unaffected by the antibodies. • Some microbes can activate alternative genes resulting in antigenic changes. For example, • N. gonorrhoeae has several copies of the Opa-coding gene, resulting in cells with different antigens and in cells that express different antigens overtime. Example of other bacteria and protozoa that are capable of antigenic variation: • Influenzavirus, the causative agent of influenza (flu) • N. gonorrhoeae, the causative agent of gonorrhea • Trypanosma brucei gambiense, the causative agent of African trypanosomiasis (sleeping sickness). The virulence of some bacteria is thought to be aided by the Antigenic variation (Alter surface proteins)
- 13. 13 Penetration into the Host Cell cytoskeleton Salmonella entering epithelial cells. A major component of cytoskeleton is a protein called actin, which is used by some microbes to penetrate host cells and by others to move through and between host cells. • Salmonella strains and E. coli contact with the host cell plasma membrane and lead to changes in the membrane at the point of contact. The microbes produce surface proteins called invasins that rearrange nearby actin filaments of the cytoskeleton. This cause cytoplasmic structures to project from the host cell like a pedestal under the Salmonella. • Certain bacteria such as Shigella species and Listeria species can actually use actin to propel themselves through the host cell cytoplasm and from one host to another.
- 14. 14
- 15. 15 Sexually-transmitted diseases (STDs): disease causative agent reported cases/yr In USA bacterial gonorrhea Neisseria gonorrhoeae 350,000; true incidence much higher chlamydial infections Chlamydia trachomatis 527,000; true incidence much higher syphilis Treponema pallidum 51,600 chancroid Haemophilus ducreyi 356; true incidence much higher viral genital herpes simplex Herpes simplex virus (HSV) Around 30 million infected papillomavirus infections human papilloma virus (HPV) Around 40 million infected AIDS human immunodeficiency virus (HIV) 60,860
- 16. 16 Syphilis: Treponema pallidum: motile spirochete; cannot be grown in vitro;; strictly human pathogen transmission: direct person-person contact T. pallidum in testis
- 17. 17 stage symptoms pathogenesis initial contact, incubation period (2-10 wks) multiplication at infection site primary syphilis (1-3 months) primary chancre; enlarged nodes (groin), spontaneous healing (within 4-6 wks) [silent phase (~2-10 wks)] proliferation in regional lymph nodes and blood secondary syphilis (weeks-months) flu-like (muscle ache, headache, fever), rash, multiplication; lesions in lymph nodes, joints, muscle, skin, mucous membranes, liver latent syphilis (3-30 yrs) none T. pallidum dormant → eventual new cell growth tertiary syphilis neurological (paralysis, insanity) cardiovascular (aortic lesions, rupture; stroke) progressive destructive disease further dissemination, invasion, gumma formation (skin, bone, joints, testes) progression of syphilis:
- 18. 18 general paresis: Altered personality, emotional instability, delusions, memory loss, impaired judgement, abnormalities of eyes, speech defects congenital syphilis: • fetus susceptible after 4th month of gestation. • risk greatest if mother has primary, secondary syphilis (less if latent). ~40% of affected fetuses miscarried or stillborn • neonates may develop secondary syphilis within few weeks. • characteristic deformities (face, teeth) may appear in early childhood. treatment: • penicillin; most effective for primary, secondary syphilis. • no known antibiotic resistance problems. syphilis screening: • used to involve series of serological tests, potentially multiple blood samplings.
- 19. 19 Gonorrhea: Neisseria gonorrhoeae: gram negative diplococci, nonmotile, fastidious; most strains susceptible to cold, drying; humans transmission: direct person-person contact symptoms: may be mild, absent (especially in females) • incubation period: 2-7 days male: urethritis, painful urination, thick, pus-containing penile discharge female: increased vaginal discharge, painful urination, abdominal pain, menstrual abnormalities . pathogenesis: - attachment to epithelia: urethra, cervix, pharynx, conjunctiva - avoidance of phagocytosis & host immune response (due to hypervariable surface antigens) - capable of invading of host cells treatment: penicillin resistance is a problem, especially in Asia cephalosporins, fluoroquinones, azithromycin vaccine - much effort, little success (hypervariability of surface proteins, intracellular mode)
- 20. 20 Chlamydia trachomatis • obligate intracellular parasite; infection mimics gonorrhea in several ways symptoms: 7-14 d post-exposure male: thin, grey-white penile discharge, testicular pain female: increased vaginal discharge, may be painful urination, vaginal bleeding, abdominal pain inclusion conjunctivitis: - eye infection in neonates tissue damage: • attaches to sperm (like N. gonorrheae) • testicular damage, fallopian tube damage may lead to sterility treatment: early use of azithromycin, tetracycline, erythromycin will prevent serious complications • condom use is effective in prevention
- 21. 21 How bacterial pathogens damage host cells? • If the pathogen overcomes the host defense, the microorganism can damage host cells in four ways: • By using the host’s nutrients • By causing direct damage in the immediate vicinity of the invasion • By producing toxins, transported by blood and lymph • By inducing hypersensitivity reactions
- 22. 22 Using the host’s nutrients • Iron is required for the growth of most pathogenic bacteria. • The concentration of free iron in human body is fairly low because iron in human body is tightly bound to iron-transport proteins, such as lactoferrin, transferrin, and ferritin, as well as hemoglobin; • In order to obtain free iron, some pathogens produce protein called siderophores. • When iron is needed by a pathogen, siderophores are released into the medium where they take the iron away from iron-transport proteins. Once the iron-siderophore complex is formed, it is taken up by a siderophores receptors on the bacterial surface. Then the iron is brought into the bacterium. • Some pathogens have receptors that bind directly to iron-transport proteins and hemoglobin.
- 23. 23 Direct Damage • Once pathogen attach to host cells, they can cause direct damage as the pathogens use the host cell for nutrients and produce waste products. • As pathogen metabolize and multiply in cells, the cells usually rupture and the pathogens spread to other tissue. (Many viruses, intercellular bacteria, protozoa that grow in host cells are released when the host cell rupture). • Some bacteria such as E. coli, Shigella, Sallmonella, and Nisseria gonorrhoeae, can induce host epithelial cells to engulf them by a process that resembles phagocytosis. These pathogen can disrupt host cells. • Other bacteria can penetrate host cells by excreting enzymes and by their motility; such penetration can itself damage the host cell.
- 24. 24 The production of toxins • Toxins: Are poisonous substances that are produced by certain microorganisms and that contribute to pathogenicity. • Toxigenicity: Ability of microorganisms to produce a toxin Toxins transported by the blood or lymph can cause serious, and sometimes fatal effects. Some toxins produce fever, cardiovascular disturbances, diarrhea, and shock. Toxins can also inhibit protein synthesis, destroy blood cells and blood vessels, and disrupt the nervous system by causing spasms. • Toxemia: Presence of toxins in the host's blood • Antitoxin: Antibodies against a specific toxin (Antibodies produced by the body provide immunity to exotoxins). • Toxoid: Inactivated toxin used in a vaccine. (When exotoxins inactivated by heat or by formaldehyde, iodine, or other chemicals, they no longer cause the disease but can still stimulate the body to produce antitoxins).
- 25. 25 Endotoxins: are lipopolysacchrides Toxins are of two general types, based on their position relative to the microbial cell: Exotoxins and endotoxins. Exotoxins: are proteins
- 26. 26 Exotoxin Source Mostly Gram + Metabolic product By-products of growing cell Chemistry Protein Fever? No Neutralized by antitoxin Yes LD50 Small The genes for most exotoxins are carried on bacterial phages or plasmids. Found on phages, toxin genes for: Diphtheria, Botulism, Scarlet fever, Toxic streptococci (“flesh-eating”) Toxin genes found on plasmids: E. coli toxin causes diarrhea, S. aureus toxin causes “scalded skin syndrome”. • Because exotoxins are soluble in body fluid, they can easily diffuse into the blood and are rapidly transported throughout the body. • Exotoxins are disease-specific, because it is the exotoxins that produce the specific signs and symptoms of the disease (not a bacterial infection).
- 27. 27 Exotoxins are divided into three principle types on the basis of their structure and function: 1. A-B toxins or type III toxins 2. Membrane-disrupting toxin or type II toxins 3. Superantigens or type I toxins. 1. A-B toxins: - Are consists of two parts designated A and B, both of which are polypeptides. - Most exotoxins are A-B toxin. An example of A-B toxin is the diphtheria toxin, which illustrated in the figure. Exotoxins
- 28. 28 2. Membrane-disrupting toxins or type II toxins: – Causes Lysis of host cells by disrupting their plasma membrane: • Some do this by making protein channels in the plasma membrane (e.g., leukocidins, hemolysins). Example, Staphylococcus aureus . • Others disrupting phospholipid bilayer. Example, Clostridium perfringens. – Contribute to virulence by killing host cells especially phagocytes. Membrane-disrupting toxins that kill phagocytic leukocytes (WBC) are called leukocidins. • Most leukocidins are produced by staphylococci, streptococci, and pneumococci. Membrane-disrupting toxins that destroy erythrocytes (RBC) are called hemolysins. • Important producers of hemolysins include staphylococci and streptococci. Hemolysins produced by streptococci are called streptolysins. Cont’d Exotoxins
- 29. 29 3. Superantigens or type I toxins: – They are bacterial protein – Superantigen stimulate the proliferation of immune cells called T cells. These cells are types of WBC that act against foreign organisms and tissues and regulate the activation and proliferation of other cells of the immune system. – In resposne to superantigens, T cells are stimulated to release enormous amounts of chemical called cytokines from host cells. Cytokines are small protein hormone that stimulate or inhibit many normal function. – The excessively high levels of cytokines released by the T cells enters the bloodstream and give rise to a number of symptoms, including fever, nausea, vomiting, diarrhea, and sometimes shock, and even death. – Bacterial superantigens include staphylococcal toxins that cause food poising and toxic shock syndrome. Exotoxins
- 30. 30 Exotoxins are named on the basis of several characteristics. One is the type of the host cell that is attached: – Neurotoxins: attack nerve cells – Hepatotoxins: attack liver cells – Cardiotoxins: attack heart cells – Leukotoxins: attack leukocytes – Enterotoxins: attack the lining of the gastrointestinal tract – Cytotoxins : attack a wide variety of cell Some exotoxins are named for the disease with which they are associated: – Diphtheria toxins: cause of diphtheria – Tetanus toxins: cause of tetanus Other exotoxins are named for the specific bacterium that produces them: – Botulinum toxin: Clostridium botulinum – Vibrio entertoxin: Vibrio cholerae
- 31. 31 Exotoxins Species Exotoxin Corynebacterium diphtheriae A-B toxin. Inhibits protein synthesis. Streptococcus pyogenes Membrane-disrupting. Erythrogenic. Clostridium botulinum A-B toxin. Neurotoxin C. tetani A-B toxin. Neurotoxin Vibrio cholerae A-B toxin. Enterotoxin Staphylococcus aureus Superantigen. Enterotoxin.
- 32. 32 Endotoxins • Endotoxins are part of the outer portion of the cell wall of Gram –ve bacteria. • The lipid portion of the lipopolysaccharides, called lipid A, is the endotoxins. Thus, endotoxins are lipopolysaccharides, whereas exotoxins are proteins. • Endotoxins are released when Gram-ve bacteria are lysed, or during bacterial multiplication. Endotoxins exert their effects by stimulating macrophages to release cytokines in very high concentrations. At these levels, cytokines are toxic. Endotoxins give rise to a number of symptoms, including chills, fever, weakness, generalized aches, and sometimes shock, and even death, and can also induce miscarriage. Another consequence of endotoxins is the activation of blood-clotting proteins, causing formation of small blood clots and as a result induces the death of the tissue. This condition is referred to as disseminated intravascular clotting.
- 33. 33 Endotoxins The fever (pyrogenic response) caused by endotoxins is believed to occur as depicted in fig below. Bacterial cell death caused by lysis or antibiotics can also produce fever by this mechanism. Both aspirin and acetaminophen reduce fever by inhibiting the synthesis of prostaglandins.
- 34. 34 Endotoxins Source Gram–ve bacteria Metabolic product Present in LPS of outer membrane Chemistry Lipid Fever? Yes Neutralized by antitoxin No LD50 Relatively large
- 35. 35 • Respiratory tract – Coughing, sneezing • Gastrointestinal tract – Feces, saliva • Genitourinary tract – Urine, vaginal secretions • Skin • Blood – Biting, needles/syringes Portals of Exit