Lecture 18: Trickery of Bacterial Pathogens

• Colonization of human host a. either as part of gut flora or harmony with the host b. or subverting host defences, causing disease • Few microbes can invade tissues & prod toxic substances/inflict damage

• Organism needs to attach to hose tissue • Need to replicate and evade immunity • Damage host tissues to escape

• Microbes cause disease whilst stealing: a. space b. nutrients c. and/or living tissue from host (e.g., us) • How do they do this? a. Gain access to host (‘contamination’) b. Adhere to host (‘adherence’) c. Replicate on host (‘colonization’) d. Invade tissues (‘invasion’) e. Production of toxins, proteins, or other agents that cause host harm (‘damage’)

• Toxin ingestion following production a. Bacillus cereus b. not ingesting the pathogen, just its toxin c. sometimes associated with food poisoning • Toxin production following colonization a. Clostridium botulinum • Invasion of host tissues without toxin production a. Mycobacterium tuberculosis • Tissue invasion followed by toxin production a. Vibrio cholerae

• Robert Koch a. founder of public health b. developed koch’s postulates • In 1800’s, discovered: a. Tuberculosis = Mycobacterium tuberculosis b. Cholera = Vibrio cholerae c. Anthrax = Bacillus anthracis

• Sense environment a. sense they’re inside the human host e.g., sensing the temperature (37) • Need to know where they are… • must express proteins to survive stress • must express proteins required for adhesion or invasion • May make toxins • May enter host cell and replicate • May spread through host cells

• Incubation period: interval between exposure and illness onset • Illness phase: may still be infectious during incubation or convalescence phases • Covalence phase: time of recuperation and recovery from illness

• Primary pathogen: microbe or virus that causes disease in healthy individual. a. E.g., plague, malaria, measles • Opportunistic pathogen: causes disease only when body’s innate or adaptive defences are compromised or when introduced into unusual location a. Can be members of normal microbiota or common in environment (Pseudomonas)

• Refers to degree of pathogenicity 2. Allow microorganism to cause disease

• Endotoxin • Capsule • Antigenic phase variation • Sequestration of growth factors • Resistance to serum killing • Antimicrobial resistance

• Exotoxin production • Expression of adhesion factors • Intracellular survival and manipulation

show that a gene found in a pathogenic microorganism encodes a product that contributes to the disease caused by the pathogen - virulence factor 1. specific inactivation of gene(s) lead to measurable loss in pathogenicity 2. reintroducing gene should restore pathogenicity 3. gene causing virulence must be expressed during infection 4. immunity must be protective 5. phenotype or property under investigation should be associated with pathogenic members of genus

• Key adherence factors • How do cells avoid physical & immunological removal? a. adhere to cell surfaces and ECM b. Solid surfaces (e.g., teeth, heart valves) c. Other bacteria • How do cells adhere? a. Often located at ends of fimbria or curli b. & other outer membrane proteins • Adherence often combined with manipulation of host cell signalling and cytoskeleton (salmonella a. Adherence b. invasion

• free iron is low in bodily fluids (it is bound to other things) • Many different systems for scavenging: a. Siderophores chelate available iron & transport into bacteria b. scavenged direct from iron-binding proteins (e.g., lactoferrin-binding proteins) c. Often co-ordinately regulated d. Some pathogens avoid problem by cutting off need for iron (e.g., Treponema pallidum - syphilis) • Low level iron switches on aggressive virulence factors a. Diphtheria toxin (controlled by DtxR repressor) b. Shiga-like toxin c. Pseudomonas aeruginosa exotoxin A

• Capsule around them - avoids recognition by phagocyte

• Exotoxins: proteins with specific damaging effects a. secreted or leak into tissue following bacterial lysis - foodborne intoxication = consumption - destroyed by heating b. act locally or systernically c. Proteins, immune system can generate Ab’s

• Toxoids: inactivated toxins • Antitoxin: suspension of neutralising Ab’s • Neurotoxins: damage NS • Enterotoxins: cause intestinal disturbance • Cytotoxins: damage variety of cell types

• A = active subunit, toxic, usually an enzyme • B = binds to cell, determines affected cell type a. Structure of B subunit allows novel approaches for vaccines and therapies, can be used to deliver medically useful compounds to specific cell type

• other bacteria cell wall components • Endotoxin: lipid A of LPS • Lipid A triggers inflammatory response a. when localized helps clear infection b. When systemic, widespread response - septic shock or endotoxic shock • lipid A released following cell lysis • activates innate and adaptive defences a. toll-like receptors induce cytokine production; T-independent antigen response of B-cells at high concentrations

• fever • Hypotension a. life-threatening complication of septicaemia b. endotoxic shock seen with intraveous equipment • MOST EFFECTS OF ENDOTOXIN MEDIATED BY TUMOUR NECROSIS FACTOR

• one of many categories of diarrheagenic E. coli • well established cause of human diarrhoea - particularly young children • Hallmark of EPEC is A/E histopathology, often observed in small bowel biopsy specimens from infected patients

• Formation of actin pedestals • localized actin accumulation is so distinct it is the basis of vitro diagnostic test for EPEC

• Essentially a needle • Five components: a. Regulators b. Chaperons c. Secretion apparatus d. Translocators e. Effectors • Five functions a. Export proteins across bacterial envelope b. Bring bacterial & host cells close together c. Translocate proteins between d. Translocated proteins across cell membranes e. Translocated proteins subvert host cell functions