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Pathogenesis of Bacterial Pathogens

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Pathogenesis of Bacterial Pathogens FMM/RAS/298: Strengthening capacities, policies and national action plans on prudent and responsible use of antimicrobials in fisheries Bacterial Pathogenesis Larry A. Hanson [email protected] Aquatic AMR Workshop 1: 10-11 April 2017, Mangalore, India Host-Parasite Relationships: Pathogenesis of Infections In any host-pathogen encounter, there are two determinants of the outcome: 1. Virulence of the parasite 2. Resistance of the host In some cases, the host-pathogen relationship is very complex: -Commensal but opportunistic will take advantage of weakened host and invade tissues setting up a potentially life- threatening infection Examples include motile Aeromonads- natural inhabitants of intestine but cause septicemia when fish is immune suppressed o Bacteria cause disease by 2 basic mechanisms: 1-Direct damage of host cells 2-Indirectly by stimulating exaggerated host inflammatory/immune response Virulence factors are molecular components expressed by a pathogen that increases its ability to cause disease Virulence factors can be divided into two categories: • 1. Those that cause damage to the host (toxins) • 2. Those that do not directly damage the host but promote colonization and survival of infecting bacteria A. Bacterial toxins 1. Exotoxin: protein molecule liberated from intact living bacterium. a. They are antigenic and can elicit protective antitoxic antibodies. Many of these toxins can be converted to nontoxic immunizing agents termed toxoids. b. Three roles of exotoxins in disease: i. Ingestion of preformed toxin (botulism) ii. Colonization of wound or surface followed by toxin production (cholera and diphtheria toxins) iii. Exotoxin produced by bacteria in tissues to aid growth and spread (Clostridium perfringens alpha-toxin) d. Types of exotoxins: i. A-B toxins (intracellular acting) 1) Composed of two parts: A and B portions 2) The B portion mediates binding to a specific host cell receptor. 3) After binding to the host cell, the A portion is translocated into host cells and has biological activity against an intracellular target or 4) Examples: a) Diphtheria toxin: ADP-ribosylation of host EF-2; host cells are killed by blocking translation. b) Cholera toxin: ADP-ribosylation of a cAMP regulatory protein, which causes loss of ion regulation, water loss, diarrhea. c) Shiga toxin cleaves host rRNA, which blocks translation and kills the host cell. d) Clostridium botulinum- large subunit targets neurons, small subunit cleave snare proteins inhibiting neurotransmitter release from neurons- causes paralysis BoNT- E in fish (most toxic substance known) ii. Membrane disrupting (surface damaging) 1) Cause damage or disruption of plasma membranes, which leads to osmotic lysis and cell death. Many were originally termed “hemolysins” because they lyse RBCs. 2) Three types of membrane disrupting toxins: a) Enzymes that hydrolyze phospholipids: phospholipase, sphingomyelinase b) Toxins with detergent-like surfactant activity that disrupt by membrane solubilization c) Pore forming toxins (the most common): proteins that insert in the host membrane and form a hydrophilic pore Aeromonas produces up to 4 hemolysins- aerolysin A (AeroA) and Heat labile hemolysin AHH1- work synergistically, also some aeromonads produce the pore forming toxin RtxA Staphylococcus aureus alpha hemolysin, looking down the central pore iii. Superantigens 1) Toxins that bind directly to MHC II on macrophages (without being processed) and form a crosslink with T cell receptors. 2) Crosslinking causes stimulation of up to 1 in 5 T cells in the body (normal antigens cause stimulation of 1 in 10,000). 3) Excessive IL-2 production results from the massive stimulation of T helper cells, 4) Stimulation of other cytokines by IL-2 lead to shock. Example: staphylococcal toxic-shock syndrome iv. Extracellular enzymes: break down host macromolecules. play an important role in disease development by providing a nutrients or aiding in dissemination. Can cause extensive tissue damage Examples: a) Coagulase – clots fibrin, thus protecting the bacteria. b) Hyaluronidases and proteases – aid in the spread of bacteria by degrading extracellular matrix. c) Collagenase – aids in dissemination d) DNase – reduces viscosity of debris from dead cells (may help escape DNA net by neutrophil). A. hydrophila - Express diverse extracellular enzymes can contribute to virulence including collagenase, elastase, enolase, lipases (heat stable lipase, pla and Plc), metallo protease, and serine protease, Rnase R. 2. Endotoxin- released when cells die: lipopolysaccharide (LPS) produced by gram- negative bacteria. In gram-positive bacteria peptidoglycan and teichoic acids. a. LPS is bound by LPS binding proteins in plasma, which then binds CD14. This complex binds Toll-like receptor 4 (TLR4) on macrophages and monocytes. TLR2 binds teichoic acids. TLR1 binds peptidoglycan. b. Macrophages and monocytes release cytokines (IL-1, IL-6, IL-8, TNF alpha, Platelet Activating Factor), which subsequently trigger prostaglandin and leukotriene release c. The complement and coagulation cascades are activated. e. endotoxic shock occurs when bacterial products reach high enough levels in the blood to trigger complement activation, cytokine release, and coagulation cascade activation in many parts of the body. Circulatory system collapse followed by multiple organ system failure occurs. B. Bacterial invasion of host tissues 1. Host damage is caused during invasion by either: a. direct disruption of function b. an exaggerated immune response that compromises tissue function. 2. The invasive bacteria are classified as: a. Facultative Intracellular Parasites i. FIPs are not confined to cells ii. Some can multiply in professional phagocytic cells. iii. When a balance is established between the bacterium and phagocyte, the bacteria may survive in this intracellular state for months or years (example: Mycobacterium). b. Obligate Intracellular Parasites; can only propagate inside host cells. Examples include chlamydia and rickettsia c. Extracellular parasites, which cause tissue damage while they are outside phagocytes and other cells and do not have the ability to survive long periods in cells. 3. Steps in bacterial invasion: a. Motility i. Flagella are the best characterized; adapted for low viscosity fluids. ii. Other types of motility: corkscrew type (Spirochetes--best in viscous solutions), gliding motility (Flavobacterium columnare and cytophagas, myxobacteria--movement over solid surfaces). iii. Chemotaxis is directional swimming using a gradient (especially nutrients). A. hydrophila produce lateral flagella for surface movement and polar flagella for movement in suspension. Glycosylation of polar flagella involved in biofilm formation, binding to cells and mucosal adherence b. Adherence i. Two common strategies: fimbriae and monomeric protein adhesins. ii. Fimbriae (pili): receptors are usually carbohydrate residues of glycoproteins or glycolipids. Attachment is more fragile. Highly specific binding, often mediated by adhesins, can be blocked by antibodies, often specific for host tissue type/location. iii. Monomeric protein adhesins: mediated by cell surface proteins, tighter binding to host cell, may recognize proteins on host cell surface, may follow looser fimbrial attachment. Aeromonas-bundle-forming pilus (encoded by bfp) is a critical internal colonizing factor c. Invasion of host cells (intracellular pathogens) i. Some invasive bacteria have mechanisms for entering host cells that are not naturally phagocytic. ii. Two types of bacterial-mediated invasion: a. Zippering: bacteria present ligands on their surface allowing them to bind to host cells and initiate the entry process. It is similar to FcR- and CR3- mediated phagocytosis, which is characterized by the formation of inclusion shaped by the bacteria they ingest (Yersinia pestis Ail). b. Triggering: bacteria inject effectors into host cells via T3SS to regulate phagocytosis (Salmonella). iii. Following attachment to host cells, pathogens cause changes in host cell cytoskeleton (actin) that cause the pathogen to be internalized. iv. Some pathogens can utilize actin fibers intracellularly to move through host cells (transcytosis). v. Invasins may also mediate uptake of bacteria into professional phagocytic cells in a way that bypasses normal phagosome formation. d. Manipulation of host cell functions i. Bacterial pathogens are often very manipulative of host cell functions; both extracellular and intracellular pathogens will cause host cells to perform functions favorable to the pathogen. a. For example, leukotoxin produced by Mannheimia haemolytica (extracellular pathogen) induces cytokine secretion. b. Listeria monocytogenes (intracellular pathogen) produces a protein that mobilizes actin to propel bacteria through the cell and into neighboring cells. ii. Some bacterial pathogens have a specialized type III secretion system (TTSS) that forms a needle-like structure that injects effector proteins directly into the host cell cytoplasm. a. In some cases, these effector proteins serve as receptors in the host membrane for bacterial attachment. b. In some cases, these effector proteins can mobilize cytoskeleton to cause phagocytosis. c. In some cases, effector proteins can induce or prevent apoptosis. Aeromonas express type II, III and VI secretion systems III and VI can inject effector proteins into host cells (II is for extracellular release of proteins). 4. Obtaining nutrients a. Pathogenic bacteria have intricate methods to obtain
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