Lecture 15 - Chapter 18 - Microbial Pathogenesis PDF

CHAPTER 18 Microbial Pathogenesis Copyright © 2021 W. W. Norton & Company, Inc. Microbial Pathogenesis Chapter Objectives ▪ Describe the major molecular “tools” microbes use to cause disease. ▪ Discuss the strategies different pathogens use to survive in a host. ▪ Compare the pathogenic m...

CHAPTER 18 Microbial Pathogenesis Copyright © 2021 W. W. Norton & Company, Inc. Microbial Pathogenesis Chapter Objectives ▪ Describe the major molecular “tools” microbes use to cause disease. ▪ Discuss the strategies different pathogens use to survive in a host. ▪ Compare the pathogenic mechanisms of viral, bacterial, fungal, and protozoan pathogens. 2 18.2 Pathogen Entry and Colonization Section Objectives ▪ Explain why pathogens need to attach to host cells. ▪ Describe various microbial attachment techniques. ▪ Differentiate the structure and function of type I and type IV pili. ▪ Discuss the role of biofilms in pathogenicity. 3 Ex. Body mechanisms to prevent colonization ▪ The lungs: Mucociliary escalator → moves pathogens out. ▪ The intestine: Peristaltic action → constant flow ▪ The bladder: Detrusor contraction → propels urine with tremendous force.  Entry and Colonization ▪ The first step toward infection is attachment (adhesion). ▪ Types of adhesins. Pili adhesins: Hairlike appendages - tips with receptors for host cells surface. Non-pili adhesins Colonization and biofilming formation Pilus Assembly – 1 ▪ Pili are made up of identical pilin protein subunits. The tip of the pilus contains an adhesion protein that binds host cell receptors. 6 Pilus Assembly – 2 ▪ Assembly of the pili starts with the tip protein. It will bind to carbohydrates on the host cell surface. Pyelonephritis-associated pilus (Pap) assembly in E. coli: The Sec system secretes proteins to the periplasm → PapD chaperones them to the site of assembly → Assembly starts with the tip protein (PapG) → subunits fit together → growing pilus → binds to carbohydrates on host membranes. 7 Types of Pili ▪ Type I pili: static, hairlike ▪ Type IV pili: dynamic, thin, appendages used only for and flexible for “twitching attachment motility” Uropathogenic E. coli binding to epithelial Ex. Vibrio cholerae, Pseudomonas aeruginosa, certain cells by pili. pathogenic strains of E. coli, Neisseria meningitidis, and N. gonorrhoeae. 8  Step 1: Colonization Escherichia coli (UPEC) colonize the vaginal and periurethral areas. Step 2: Migration to Bladder Uropathogens migrate from the periurethral area to the bladder. Step 3: UPEC Adherence & Internalization UPEC type 1 pili (FimH protein at the tip) binds to uroplakins/mannosylated glycoproteins on superficial bladder umbrella cells → internalization. Step 4: Formation of Intracellular Bacterial Communities (IBCs) Inside the cells, UPEC multiply to form IBCs. Step 5: Efflux & Reinvasion UPEC efflux from IBCs to reinvade neighboring cells. Sihra, N., Goodman, A., Zakri, R. et al. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat Rev Urol 15, 750–776 (2018). https://doi.org/10.1038/s41585-018-0106-x Nonpilus Adhesions ▪ Cell wall associated proteins that bind to host proteins like integrin or fibronectin causing a more intimate attachment: Bordetella pertactin: host integrin Streptococcus protein F: host fibronectin Streptococcus protein M: host fibronectin and the complement regulatory factor H ▪ Neisseria meningitidis type IV pili → Neisserial Opa nonpilis membrane proteins → more intimate attachment. 11  Discretion is advised From: https://www.nhs.uk/conditions/pressure-sores/ From: https://www.accessmedicinenetwork.com/posts/53226-pressure-ulcer-staging-and-treatment 18.3 Surviving within a Host Section Objectives ▪ Explain why and how pathogens distinguish between intracellular and extracellular existence. ▪ Describe various strategies pathogens use to avoid the immune system. ▪ Distinguish extracellular pathogens from facultative and obligate intracellular pathogens. ▪ Discuss the three main ways intracellular pathogens avoid intracellular destruction. 13 Environment or Host? ▪ The microbe monitors the conditions and detect changes when in a host such as: Temperature Iron levels Yes? Expression of Magnesium levels Host? virulence genes pH levels Hormones ▪ The virulence factors expressed depends on: Extracellular pathogen Intracellular pathogen Facultative intracellular pathogen Extracellular Pathogens ▪ Extracellular immune avoidance Capsules: coat bacterial cell walls and can prevent phagocytes from binding. – Opsonizing antibodies can bind to the capsule. 16 Extracellular Pathogens ▪ Extracellular immune avoidance Cell surface proteins like protein A (S. aureus) can sequester antibodies. – Bind Fc region of antibodies 17 Kobayashi SD, DeLeo FR.2013.Staphylococcus aureus Protein A Promotes Immune Suppression. mBio4:10.1128/mbio.00764-13.https://doi.org/10.1128/mbio.00764-13 Extracellular Pathogens ▪ Extracellular immune avoidance Some pathogens vary surface antigens to avoid immune detection. ▪ Salmonella expressing Flagellin A can change to Flagellin B. 18 Extracellular Pathogens ▪ Extracellular immune avoidance Cell-cell communication via quorum sensing can also help pathogens evade the immune system. – Autoinducer molecule will rise as the number of bacteria increases. 19 Intracellular Pathogens ▪ Intracellular pathogens avoid innate and humoral immune mechanisms by living inside host cells → not detected. ▪ Facultative intracellular pathogens can invade host cells but can also survive outside the host cell. Example: Salmonella, Shigella, Listeria ▪ Obligate intracellular pathogens invade and reproduce inside a host cell only. Example: Rickettsia, Coxiella, Bartonella 20 Intracellular Pathogens ▪ Fates of intracellular pathogens 21 18.4 Host Damage and Manipulation – 1 Section Objectives ▪ Describe the nine basic cellular targets for bacterial toxins. ▪ Explain the modes of action for staphylococcal alpha toxin, cholera toxin, diphtheria toxin, Shiga toxin, and anthrax toxin. ▪ Differentiate endotoxin from exotoxin. ▪ Describe secretion systems pathogens use to export exotoxins/effector proteins. 22  Exotoxin Modes of Action – 1 Microbial exotoxins are categorized on the basis of their cellular targets and mechanisms of action. Pores formation Actin polymerization and depolymerization 23 Exotoxin Modes of Action – 2 ▪ Two-subunit AB toxins A subunit is toxic. B subunit binds host cell receptors. ‘A’ subunit possess an ADP-ribosyltransferase → inactivates or alters ADP- ribosylates target The G protein controls the cAMP- proteins (G-protein). producing enzyme adenylyl cyclase. 24 Exotoxin Modes of Action – 3 ▪ Toxins that disrupt the membrane: ▪ Alpha toxin forms a seven-membered transmembrane pore in target cell membranes. Causes cell contents to leak Cell lysis 27 Exotoxin Modes of Action – 4 ▪ Toxins that disrupt signal transduction: E. coli binds to the villus and secretes toxins that disrupt normal function. ▪ How does diarrhea benefit the pathogen? 28 Cholera and labile toxins Exotoxin Modes of Action – 5 ▪ Toxins that disrupt protein synthesis: C. diphtheriae remains in the pharynx. Low levels of iron? → Diphtheria toxin released (also an ADP- ribosyltransferase and AB toxin). ▪ How does this bacteria can cause nervous system or cardiovascular affections? ▪ Can you name another toxin? 30 Endotoxin (LPS) ▪ Endotoxin Part of the outer membrane of the Gram-negative cell wall that includes lipopolysaccharide – Fever – Activation/Depletion of clotting factors (petechiae) – Activation of complement, – Vasodilation – Shock → death 31 Secretion of Virulence Proteins 32 Secretion of Virulence Proteins ‒ 3 ▪ Type II secretion system “Piston” delivery 33 Secretion of Virulence Proteins ‒ 4 ▪ Type III secretion system “Syringe” delivery ▪ Type IV secretion system “Tube” delivery → to the host plasma membrane 34 Salmonella: A Model of Bacterial Pathogenesis 35