Bacterial Pathogenicity & Infections. Stijn van der Veen

Transcription

1 Bacterial Pathogenicity & Infections Stijn van der Veen

2 Pathogenicity & Infection Pathogenicity is the ability of a microbe to gain entry to the host s tissue and bring about a physiological or anatomical change, resulting in altered health and leading to disease. Infection refers to the multiplication of a microbe in a host and the competition for supremacy taking place between them. A host whose resistance is strong remains healthy, but if the host loses the competition, disease develops.

3 Disease Disease refers to any change from the general state of good health. Infectious disease is a disease condition caused by the presence or growth of infectious microbes. Disease and infection are NOT synonymous; a host may be infected without suffering disease. Infectious disease deaths worldwide in 2008; total 15 million.

4 Disease: Communicable vs. Noncommunicable Communicable disease A disease that can be transmitted from one individual to another. Noncommunicable disease A disease that is not transmitted from one individual to another. Epidemiology The study of patterns, causes and transmission of disease.

5 Disease in the population Endemic disease A disease condition that is normally found in a certain percentage of a population. Epidemic disease A disease condition present in a greater than usual percentage of a specific population. Pandemic disease An epidemic affecting a large geographical area; often on a global scale.

6 Infections: acute vs. chronic Acute infection An infection characterized by sudden onset, rapid progression, and often with severe symptoms. Chronic infection An infection characterized by delayed onset and slow progression.

7 Infections: primary vs. secondary Primary infection An infection that develops in an otherwise healthy individual. Secondary infection An infection that develops in an individual who is already infected with a different pathogen.

8 Infections: localized vs. systemic Localized infection An infection that is restricted to a specific location or region within the body of the host. Systemic infection An infection that has spread to several regions or areas in the body of the host.

9 Infections: clinical vs. subclinical Clinical infection An infection with obvious observable or detectable symptoms. Subclinical infection An infection with few or no obvious symptoms.

10 Infections: exogenous vs. endogenous Exogenous infection An infection established by a pathogen from the environment. Endogenous infection An infection caused by a microbial member of the normal microbiota of the host. Opportunistic infection An infection caused commensals taking advantage of a shift in the delicate balance to one favoring the microbe.

11 Indigenous human microbiota Indigenous microbiota consist of microbes that established a permanent relationship with various parts of the body. This is called symbiosis. Transient microbiota is more temporary and found for a limited period. If symbiosis is beneficial for both organisms, the relationship is called mutualism. If symbiosis is only beneficial for the microbe, the relationship is called commensalism.

12 Indigenous microbiota Nutrient production / processing, e.g. vitamin K production by E. coli. Competition with pathogenic microbes. Normal development of the immune system. Indigenous microbiota is absent in: Lower respiratory tract Muscle tissue Blood & tissue fluid Cerebrospinal fluid Peritoneum Pericardium Meninges

13 Virulence The likelihood that a disease results from an infection is determined by: The virulence of the microbe The number of microbes in the infection The resistance of the host Virulence is the degree of pathogenicity of a microbe. This term is often used to describe or compare strains within a species.

14 Lethal dose (LD) & infectious dose (ID) The virulence of a microbe (or the toxicity of a toxin it produces) is often expressed as the LD 50 or ID 50. LD 50 is the number of microbes needed to kill 50% of the inoculated hosts (a test population) under standard conditions. The ID 50 is the number of microbes needed to cause disease in 50% of the test population under standard conditions. The lower the LD 50 and ID 50 of a microbe, the more virulent the microbe is.

15 Predisposing disease factors Certain predisposing factors may make the body more susceptible to disease or may alter the course of a disease. Gender Nutritional status Weather and climate Fatigue Age Habits Life style Pre-existing illness Emotional disturbance Chemotherapy

16 Stages of Infection 1. Transmission of the pathogen 2. Entry of the pathogen Portal of entry 3. Colonization (usually at the site of entry) 4. Incubation period Asymptomatic period between entry of pathogen and appearance of first symptoms 5. Prodromal (initial) symptoms 6. Invasive period Increasing severity of symptoms, fever, inflammation and swelling, tissue damage, spreading of infection. 7. Decline of infection 8. Convalescence

17 Transmission The route of transmission is dependent on the reservoir of the infection, which is the source of the infectious agent. Direct transmission Transmission from person to person, for instance by a carrier Direct transmission can be through contact of the skin or by aerosols (airborne). Indirect transmission Transmission through an intermediate source Indirect transmission can be through food, water, fomites or animal vectors.

18 Carriers, fomites & animal vectors Carriers are individuals who carries an infectious agent without manifesting symptoms, yet who can transmit the agent to another individual. Fomite are inanimate objects capable of being an intermediate in the indirect transmission of an infectious agent. Animal vectors are animals that can transmit an infectious agent to humans. Mechanical animal vectors physically transmit the infectious agent, but the agent does not incubate or grow in the animal, e.g. the transmission of bacteria sticking to the feet of flies. Biological animal vectors transmit the infectious agent and the agent must incubate or grow in the animal as part of the agent s developmental cycle, e.g. the transmission of malaria by infected mosquito s.

19 Portal of entry The portal of entry is the avenue by which pathogens gain entrance to the host Mucous membranes Respiratory tract Gastrointestinal tract Urogenital system Conjunctiva of the eye Skin Parenteral route

20 Colonization After gaining entrance, pathogens need to colonize the host tissues, which is usually at the site of entry. The initial step in colonization of host tissues is attachment. Attachment can be specific or non-specific Specific attachment is dependent on the interaction between an adhesin (ligand) and its receptor. Non-specific attachment is mediated by Van der Waals and electrostatic forces and hydrogen bonding.

21 Incubation period After pathogens gain access to the host and are able to establish attachment to host tissue, the incubation period starts. The incubation period is the time between entry of the host and the appearance of primary symptoms. The length of the incubation period varies greatly and is dependent on several factors: Number of invading organisms Generation time Virulence Level of host resistance Location of entry

22 Prodromal phase The prodromal phase is the period of first onset of symptoms For many diseases it is characterized by indistinct general symptoms like: Nausea Headache Muscle ache For some diseases the initial symptoms are clearly recognizable.

23 Invasive phase The invasive or acute phase is the stage when signs and symptoms are of greatest intensity. Increasing severity of symptoms Fever, Inflammation and swelling Tissue damage Spreading of infection The length of this phase is quite variable and is dependent on: Body s response to the pathogen Virulence of the pathogen

24 Decline of infection & convalescence When symptoms start to subdue, the period of decline starts. Sweating is common to release excess heat and waste products. When the host start to recover, the period of convalescence start. During this period, the body s systems return to normal.

25 Overview of bacterial infections

26 Bacterial pathogenicity

27 Portal of entry: respiratory tract Respiratory Tract Microbes inhaled into mouth or nose in droplets of moisture or dust particles Easiest and most frequently used portal of entry.

28 Respiratory diseases Pneumonia Streptococcus pneumonia, Haemophilus influenzae, Staphylococcus aureus, Mycoplasma pneumoniae, Legionella pneumophila Tuberculosis Mycobacterium tuberculosis Diphtheria Corynebacterium diphtheriae Whooping cough Bordetella pertussis

29 Portal of entry: gastrointestinal tract Pathogens gain entrance of the gastrointestinal (G.I.) tract through contaminated food or water, or dirty hands. Most microbes that enter the G.I. tract are generally eliminated by the gastric acid, bile, and antibacterial enzymes in the small intestine.

30 GI tract diseases Campylobacteriosis Campylobacter sp. Salmonellosis Salmonella sp. Escherichia coli infections EHEC, ETEC, EIEC, EPEC Gastritis / peptic ulcers Helicobacter pylori Shigellosis Shigella sp. Cholera Vibrio cholerae Clostridium sp. / Staphylococcus aureus

31 Fecal - Oral diseases Pathogens enter the G.I. tract at one end and exit at the other end. Spread by contaminated hands, food, and water. Poor personal hygiene.

32 Portal of entry: urogenital system Sexually transmitted diseases/infections (STD/STI) Diseases that are spread by sex, including vaginal intercourse and oral or anal sex. The risk of spreading of the disease is great due to the lack of primary symptoms (particularly in women). Urinary tract infections (UTI) Infection of the lower urinary tract is known as cystitis or bladder infection. Infection of the upper urinary tract is called pyelonephritis or kidney infection.

33 Urogenital tract diseases Sexually transmitted diseases Gonorrhea Neisseria gonorrhoeae Syphilis Treponema pallidum Chlamydia Chlamydia trachomatis Urinary tract infections Escherichia coli Staphylococcus saprophyticus

34 Portal of entry: conjunctiva Conjunctiva are the mucus membranes that cover the eyeball and lines of the eyelid. The conjunctiva are generally sterile places. Conjunctiva infections include: Staphylococcus aureus Neisseria gonorrhoeae Chlamydia trachomatis

35 Portal of entry: skin The skin is the largest organ of the body. When unbroken the skin is an effective barrier for most microbes. Some microbes can gain entrance through openings in the skin, e.g. hair follicles and sweat glands.

36 Portal of entry: parenteral Microbes are directly deposited into the tissues below the skin or mucus membranes. Punctures and scratches Injections Bites Surgery Examples include: Tetanus (Clostridium tetani) from rusty nails Lyme disease (Borrelia burgdorferi) from tick bites Staphylococcus infections from surgery Etc.

37 Preferred portal of entry Just because a pathogen enters your body it does not mean it s going to cause disease. Pathogens have a preferred portal of entry. For instance: Streptococcus pneumoniae When inhaled can cause pneumonia When it enters the G.I. tract, no disease Salmonella typhi When it enters the G.I. tract it can cause typhoid fever. When it is on the skin, no disease

38 Bacterial mechanisms of pathogenicity

39 Virulence factors Attachment to host tissues Production and delivery of various factors Replication and evasion of immunity Damage to host tissues

40 Adherence Many pathogens adhere to host cells at their preferred portal of entry because they contain specific adhesins. Adhesins are proteins or sometime cabohydrates that are located on the bacterial cell surface and are able to interact directly with structures on the host cell surface, thereby mediating attachment. Adhesins are often associated with bacterial pili, flagella, or capsules.

41 Adhesins Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Salmonella sp., ETEC, and many other bacterial pathogens have ligands on the tip of pili that are able to directly adhere to structures on the surface of epithelial cells. Streptococcus mutans adheres to the surfaces of tooth enamel via an extracellular polysaccharide that it secretes. Streptococcus pyogenes binds to fibronectin on the surface of epithelial cells via a cell wall protein called M-protein and via lipoteichoic acids in the cell wall. Etc.

42 Capsule Capsule contributes to virulence of pathogens Mediates adherence Protects against phagocytosis Protects against antimicrobial compounds secreted by host cells, such as antimicrobial peptides and ROS. Examples include: Neisseria meningitidis Streptococcus pneumoniae Klebsiella pneumoniae Haemophilus influenzae Bacillus anthracis Streptococcus mutans

43 Type III secretion system syringe-like multi-protein structure able to penetrate host cells and deliver effectors (mostly small proteins or toxins) directly into the host cytosol. The effectors modulate host functions or stimulate uptake into non-phagocytic cells. Similar in structure to type II secretion systems and type IV pili. Found in some gram negative bacteria.

44 Actin polymerization Some bacteria recruit actin to provide the force for intracellular movement. Means to escape autophagy, which is an intracellular antimicrobial resistance mechanism. Means to move between cells. Examples Listeria monocytogenes Shigella sp.

45 Bacterial cloaking S. aureus produces protein A and S. pyogenes produces Protein G which bind the Fc portion of IgG Binding of IgG to the bacterial cell surface provides protection against phagocytosis.

46 Leukocidins Leukocidins are enzymes that destroy circulating white blood cells (WBC) such as neutrophils and macrophages, which are immune cells designed to phagocytize and destroy pathogens. Leukocidins destroy the cell membrane of WBC and trigger the release and rupture of lysosomes. Lysosomes contain powerful hydrolytic enzymes which then cause more tissue damage. Example: Staphylococcus aureus Streptococcus pyogenes Streptococcus pneumoniae

47 Coagulase Coagulase catalyses the formation of blood clots from Fibrinogen proteins in the human blood. Blood clots protect bacteria from phagocytosis by WBC s and other host defenses. Example: Staphylococcus aureus

48 Kinase Kinases have the ability to dissolve blood clots used as a defense by the body to restrict and isolate an infected area. Kinases help bacteria to spread and cause bacteremia Examples: Streptokinase - Streptococcus sp Staphylokinase - Staphylococcus aureus

49 Hyaluronidase Hyaluronidase breaks down hyaluronic acid, which is a polysaccharide that connects cells in tissues. It is called the spreading factor because it enhances penetration of bacteria into tissues. Examples: Streptococcus sp. Staphylococcus aureus Clostridia sp.

50 Hemolysins Hemolysins combine with the membranes of red blood cells, causing it to lyse. Lysing of red blood cells provide pathogens with the iron from hemoglobin, which is required for many metabolic processes. α, β, and γ hemolyses Example: Streptococcus sp Staphylococcus aureus

51 Collagenase Collagenase breaks down collagen, which is found in many connective tissues. Collagenase allows pathogens to spread through muscle tissue. Example: Clostridium perfringens - Gas Gangrene

52 Overview of enzymatic virulence factors

53 Toxins Toxins are poisonous substances produced by some microbes that is important for pathogenicity. There are 220 known bacterial toxins and 40% cause disease by damaging the eukaryotic cell membrane. The capacity to produce toxins is called toxigenicity. Toxemia refers to symptoms caused by toxins in the blood. There are two basic types of toxins Exotoxins Endotoxins

54 Exotoxins Most exotoxins are produced by gram positive bacteria. Exotoxins are soluble in body fluids and are transported rapidly throughout the body. Exotoxins are frequently encoded from genes that are carried on plasmids or in lysogenic bacteriophages. Exotoxins are among the most lethal toxins known to man. For example, 1 mg of the botulinum toxin can kill 1 million guinea pigs.

55 Toxoids Exotoxins are disease specific and are frequently the main cause of the disease. The host can produce anti-toxins (antibodies) which can provide immunity against the effects of the toxin. Exotoxins can be inactivated by heat, formaldehyde, iodine or other substances to produce toxoids. Toxoids can be used for vaccination to produce antitoxin antibodies.

56 Exotoxin structure Many have an A (toxic effect)/b (binding) structure

57 Botulinum toxin Botulinum toxin produced by Clostridium botulinum. This toxin is unique in that it is not released until the death of the microorganism. It acts at the neuromuscular junction to prevent the transmission of nerve impulses leading to flaccid paralysis and death from respiratory failure.

58 Tetnus toxin Tetanus toxin produced by Clostridium tetani. This toxin causes excitation of the CNS leading to spasmodic contractions and death from respiratory failure. The disease it produces is also called lockjaw.

59 Diphtheria toxin Diphtheria toxin produced by Corynebacterium diphtheriae. This toxin inhibits protein synthesis in eukaryotic cells and can cause death.

60 Vibrio enterotoxin Vibrio enterotoxin produced by Vibrio cholera. This toxin alters the water and electrolyte balance in the intestine leading to a very severe, life threatening, watery diarrhea.

61 Endotoxins Endotoxins are part of the outer membrane of most gram negative bacteria. Endotoxins are the lipid A part of the LPS. Exert their effects when gram negative bacteria die and the LPS is released. All produce the same signs and symptoms, i.e., they are not disease specific. These symptoms include fever (pyrogenic response), weakness, generalized aches and pains and sometimes shock. Antibodies produced against them do not protect the host from their effects. Only large doses are lethal.

62 Pyrogenic response against endotoxins

63 Endotoxin versus exotoxin

64 Next lecture Antibacterial Agents & Conditions