Mechanisms of pathogenecity-Bacteria I (11-14-2023).pdf

14/11/23 Mechanisms of pathogenecity: Bacteria I 1 Principles of Pathogenesis • A microorganism is a pathogen if it is capable of causing disease; however, some organisms are highly pathogenic (i.e., they often cause disease), whereas others cause disease rarely • “True” pathogens: capable of...

14/11/23 Mechanisms of pathogenecity: Bacteria I 1 Principles of Pathogenesis • A microorganism is a pathogen if it is capable of causing disease; however, some organisms are highly pathogenic (i.e., they often cause disease), whereas others cause disease rarely • “True” pathogens: capable of causing disease in healthy persons with normal immune defenses. (e.g. influenza virus, SARS-Cov2, malarial protozoan) • Opportunistic pathogens § Microorganisms that rarely, if ever, cause disease in immunocompetent people but can cause serious infection in immunocompromised patients. Frequent are members of the body’s normal flora (e.g. Pseudomonas sp, Candida albicans) § Microorganisms that gain access (injury) to sterile regions • Exogenous agents originate from source outside the body • Endogenous agents already exist on or in the body (normal flora) • Virulence is a quantitative measure of pathogenicity and is measured by the number of organisms required to cause disease • The 50% lethal dose (LD50) is the number of organisms needed to kill half the hosts. Organisms with a lower LD50 are said to be more virulent than those with a higher LD50 because fewer organisms are needed to cause death or disease 2 1 14/11/23 Virulence Factors=Virulence Determinants • A pathogen’s ability to infect or damage its host tissues is determined by the virulence factors. These are often molecules synthesized by the bacteria or virus and encoded in their genome, but may also be acquired from the environment via transmissible genetic elements Staphylococcus aureus main virulence factors PLoS Pathogens, 10-2016; 12(10) • Virulence factors are molecules that cause damage to the host • They mainly involve the following functions: (1) colonization in the host; (2) immune escape; (3) immunosuppression; (4) cellular entry and exit; (5) and extraction of nutrients from the host 3 Why do People Get Infectious Diseases? • Infectious diseases: microorganisms overpower our host defenses (balance between the organism and the host shifts in favor of the organism) • The organism or its products are then present in sufficient amount to induce various symptoms, such as fever and inflammation, which we interpret as those of an infectious disease • Two critical determinants in overpowering the host: Ø Number of organisms to which the host, or person, is exposed Ø Virulence of these organisms • The greater the number of organisms, the greater is the likelihood of infection • An small number of highly virulent organisms can cause disease just as a large number of less virulent organisms can 4 2 14/11/23 (Preferred) Portals of Entry Mucous membranes • • • • Respiratory tract Gastro-intestinal tract Genitourinary tract Conjunctiva Portals of entry where pathogens can gain access into the body Skin • Impenetrable for most microorganisms • Possible to enter through hair follicles and sweat ducts Parenteral Route • Trauma • Arthropods • Injections 5 Transmission of Infectious Diseases 6 3 14/11/23 Bacterial Virulence Mechanisms • • • • • • • • • • • Capsule and Biofilm Adherence Invasion By-products of growth (gas, acid) Toxins Degradative enzymes Endotoxin Resistance to antibiotics Intracellular growth Superantigen Induction of excess inflammation 7 How do Pathogens Cause an Infectious Disease? IM M U N O PATH O G EN ESIS 1. Toxicity: specific toxin(s) produced by bacteria in the host (local or systemic effect) 2. Invasiveness: microorganism proliferation/dissemintation. Invasion. Enzymes. Tissue destruction 3. Immunopathology: excessive/Ineffective immune response to the microorganisms • Tissue destruction: by-products of bacterial growth, especially fermentation, include acids, gas, and other substances that are toxic to tissue • Infectious disease: result of a complex set of interactions including damage induced by pathogen and the consequences of human immune response against the pathogen 8 4 14/11/23 How do Pathogens Cause an Infectious Disease ? IM M U N O PATH O G EN ESIS EXPOSURE • Fecal-Oral • Wounds, burns • Contact (human, animals) • Vectors • Mother-Son • Splashes • Fomites • Polluted air 9 How do Pathogens Cause an Infectious Disease? IMMUNOPATHOGENESIS ADHERENCE 1. Capsule 1. Capsule 2. Fimbriae 2. Fimbriae 3. Flagella 4. Biofilm 5. Specific Proteins 10 5 14/11/23 How do Pathogens Cause an Infectious Disease? IMMUNOPATHOGENESIS ADHERENCE 1. Capsule 3. Flagella 4. Biofilm 2. Fimbriae 3. Flagella 4. Biofilm 5. Specific Proteins 11 How do Pathogens Cause an Infectious Disease? IMMUNOPATHOGENESIS ADHERENCE 1. Capsule 2. Fimbriae 5. Specific Proteins The Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMMs) 3. Flagella 4. Biofilm 5. Specific Proteins Schematic view of ECM organization 12 6 14/11/23 How do Pathogens Cause an Infectious Disease? Entry into host cells and tissues IM M U N O PATH O G EN ESIS • Invasiveness - ability to spread to adjacent tissues • Penetration can be active or passive – Active occurs through lytic substances which • attack the extracellular matrix of integuments and intestinal linings • degrade carbohydrate-protein complexes between cells • disrupt host cell surface – Passive (e.g. skin lesions, insect bites, wounds) • spread to deeper tissues involves production of specific products and/or enzymes that promote spreading 13 Examples of Some Enzymes used by Pathogens for Destruction/Penetration • Exoenzymes: Some pathogens produce extracellular enzymes, or exoenzymes, that enable them to invade host cells and deeper tissues • Exoenzymes have a wide variety of targets Hyaluronidase Collagenase Streptokinase • Once in circulatory system, bacteria have access to all organs and systems (systemic infection) • Invasiveness varies among pathogens 14 7 14/11/23 DIFFERENT CLASSES OF EXOENZYMES AND THEIR TARGETS CLASS EXAMPLE FUNCTION Glycohydrolases Hyaluronidase S in Staphylococcus aureus Degrades hyaluronic acid that cements cells together to promote spreading through tissues Nucleases DNAse produced by S. aureus Degrades DNA released by dying cells (bacteria and host cells) that can trap the bacteria, thus promoting spread Phospholipases Degrades phospholipid bilayer of host cells, Phospholipase C of Bacillus causing cellular lysis, and degrade membrane of anthracis phagosomes to enable escape into the cytoplasm Proteases Collagenase in Clostridium Degrades collagen in connective tissue to perfringens promote spread 15 Example of a Diseases Caused by Bacteria Able to Proliferate, DISSEMINATE and Destroy Tissues Staphylococcus aureus Systemic infections !!! Normal Microbiota Meningitis Boils Pimples Wound infections Abscesses Respiratory Diseases Pneumonia Dissemination Septicemia Osteomyelitis Endocarditis Soft tissue infections Nephritis Enteritis Enterotoxin poisoning Toxic Shock Syndrome • Food Poisoning / Food Intoxication (only ingestion of preformed toxin ) Enzymes • Coagulase: converts fibrinogen to fibrin. Staphylococcal abscess. • Catalase: destroy H2O2 produced in phagocyte • Hyaluronidase: hydrolyze hylauronic acid, connective tissue. Dissemination • Lipases: lipid hydrolysis • Nuclesases: nucleic acid hydrolisis 16 8 14/11/23 How do Pathogens Cause an Infectious Disease? TOXICITY I. Exotoxins: proteins that are released into the surroundings as the pathogen grows (very specific target) II. Endotoxin: structural component of bacterial cell wall (LPS) III. Injected toxins: toxin injected directly into a mammalian cell IM M U N O PATH O G EN ESIS • Toxins can even induce disease in the absence of the microorganism that produce them 17 I. Exotoxins • Soluble, heat-labile, proteins • Secreted into surroundings as pathogen grows • Most exotoxin producers are Gram-negative • Often travel from site of infection to other tissues or cells where they exert their effects • Usually synthesized by specific bacteria that have toxin genes in their plasmids or prophage DNA • Among the most lethal substances known • Are highly immunogenic • Stimulate production of neutralizing antibodies (antitoxins) • Chemically inactivated to form immunogenic toxoids Ø e.g. tetanus toxoid 18 9 14/11/23 I. Exotoxins-Cont TOXICITY I. II. III. Exotoxins: proteins that are released into the surroundings as the pathogen grows (very specific target) Endotoxin: structural component of bacterial cell wall (LPS) Injected toxins: toxin injected directly into a mammalian cell Types of Exotoxins 1. AB exotoxins – composed of two subunits • A subunit – responsible for toxic effect • B subunit – binds to specific target cell 2. Membrane-disrupting exotoxins 3. Superantigens 19 I. Exotoxins-Cont TOXICITY I. II. III. Exotoxins: proteins that are released into the surroundings as the pathogen grows (very specific target) Endotoxin: structural component of bacterial cell wall (LPS) Injected toxins: toxin injected directly into a mammalian cell Types of Exotoxins 1. AB exotoxins – composed of two subunits • A subunit – responsible for toxic effect • B subunit – binds to specific target cell 2. Membrane-disrupting exotoxins 3. Superantigens 20 10 14/11/23 I.1 AB exotoxins AB exotoxins • Composed of two subunits • A subunit – responsible for toxic effect • B subunit – binds to specific target cell • pH-dependent mechanism stimulates the separation of A part and B parts insertion of the toxin into the membrane and internalization /translocation of the A portion in the cytoplasm • Once the A portion has entered the host cell cytoplasm it becomes enzymatically active and exerts its toxic effects 21 I.1 AB exotoxins Biological effects of some bacterial AB exotoxins • “Crush” critical cellular functions (protein synthesis, nerve signaling etc) • Inhibits protein synthesis in animal cells resulting in death of the cells (diphtheria toxin, Pseudomonas exotoxin A, shiga toxin, etc) • Inhibits neurotransmitter release from inhibitory neurons in the CNS resulting in spastic paralysis (tetanus toxin) • Inhibits neurotransmission at neuromuscular synapses resulting in flaccid paralysis (botulinum toxin, botox!!) • Increased level of intracellular adenosine 3',5'-cyclic monophosphate (cAMP) promote secretion of fluid and electrolytes in intestinal epithelium leading to diarrhea (Vibrio cholera cholera toxin) • Increases cAMP in phagocytes leading to inhibition of phagocytosis by neutrophils and macrophages; (Bordetella pertussis AC toxin) 22 11 14/11/23 Disease Caused by Bacterial (AB) Exotoxins-Tetanus • Caused by Clostridium tetani – anaerobic, Gram-positive spore-former • endospores found in soil, dust, hospital environments, and mammalian feces • Portal of entry – skin wounds • Clinical manifestations – early in disease – tension or cramping and twisting of skeletal muscles and tightness of jaw muscle – advanced disease – trismus (“lockjaw”), characteristic facial expressions, board-like rigidity of trunk, tonic convulsions, and backward bowing of back 23 Disease Caused by Bacterial (AB) Exotoxins-Tetanus Tetanus toxin is a neurotoxin that prevents release of the inhibitory neurotransmitter glycine Neuromuscular junction Blockage of release of the inhibitory transmitter leads to convulsive contractions of the voluntary muscles, best exemplified by spasm of the jaw and neck muscles (“lockjaw”) 24 12 14/11/23 Disease Caused by Bacterial (AB) Exotoxins-Cholera Cholera: Vibrio cholerae 25 Disease Caused by Bacterial (AB) Exotoxins-Cholera-Cont • V. cholerae releases a toxin (AB) that binds to ganglioside receptors on the surface of intestinal epithelium cells • This toxin is internalized and triggers the production of cAMP within the cell • cAMP activates specific ion channels within the cell membrane, causing an efflux of ions from the cell • The build up of ions in the intestinal lumen draws water from cells and tissues via osmosis – causing acute diarrhea • As water is being removed from body tissues, dehydration will result if left untreated. If left untreated, severe dehydration can lead to shock, coma, and death within hours 26 13 14/11/23 Disease Caused by Bacterial (AB) Exotoxins-Cholera-Cont Diarrhea • Cholera-related diarrhea comes on suddenly and can quickly cause dangerous fluid loss — as much as about 1 liter an hour Rice water stool • Diarrhea due to cholera often has a pale, milky appearance that resembles water in which rice has been rinsed commonly known as “rice water” stool • Although V. cholerae is the causal agent for cholera, it is noteworthy that only a small number of V. cholerae are capable of producing cholera toxin which causes acute diarrhea 27 I. Exotoxins-Cont TOXICITY I. II. III. Exotoxins: proteins that are released into the surroundings as the pathogen grows (very specific target) Endotoxin: structural component of bacterial cell wall (LPS) Injected toxins: toxin injected directly into a mammalian cell Types of Exotoxins 1. AB exotoxins – composed of two subunits • A subunit – responsible for toxic effect • B subunit – binds to specific target cell 2. Membrane-disrupting exotoxins 3. Superantigens 28 14 14/11/23 I.2 Membrane Disrupting Toxins Two main subtypes of membrane-disrupting toxins: Pore forming toxins (the most common): Lyse host´s cell by making protein channels in the plasma membrane • Leukocidins: kill leukocytes (neutrophils, T lymphocytes), dendritic cells etc.innate and adaptive immune responsese.g. Staphylococcal leukocidins • Hemolysins: lysis red blood cells Listeriolysin in Listeria Streptolysins in Streptococcus- etc Enzymes that hydrolyze phospholipids: (phospholipases), • Clostridium perfringens α-toxin (phospholipase C) destroys the local population of white blood cells (Gas gangrene), red blood cells etc 29 Exotoxins Produced By Human Pathogens 30 15