Exam 5 - Final New Content PDF

_______________________Ch.21: Mechanisms of Pathogenesis ______________________ Effective pathogen properties - - High transmissibility Receptor that bind to host cells Infectivity Resistance to phagocytosis - Opsonization - Intracellular killing Avoid immune sys Use host’s resources - Toxin → host...

_______________________Ch.21: Mechanisms of Pathogenesis ______________________ Effective pathogen properties - - High transmissibility Receptor that bind to host cells Infectivity Resistance to phagocytosis - Opsonization - Intracellular killing Avoid immune sys Use host’s resources - Toxin → host cells die, use resources instead of them Progression of disease - Not too fast/slow Pathogenesis - Entry of pathogenic microorganism Entry → colonize →harm us (=pathogen) Portals of entry - Skin - Parental entry (=wound) - Mucous mem (GI, respiratory, genitourinary) (tradeoff b/w protection ⇔ nutrient) Portals of entry - Skin Parental entry (=wound) Mucous mem (GI, respiratory, genitourinary) (tradeoff b/w protection ⇔ nutrient) Preference and potency - - Staphylococcus aureus entry/# 따라 disease 달라짐 - Skin = boils (fruncles, carbuncles) - Eye = stye - GI = food poisoning - Bone = osteomyelitis - Bloodstream = get into heart valves - Lung = pneumonia - Genital = toxic shock syndrome - *Scalded skin syndrom = new bor skin comes off b/c of staphylococcus toxin ID 50 = describe infectious dose = make 50% sick LD 50 = describe toxicity = make 50% die - Bacteria adhere to cell surface in body adhesins/ligands bind to cell surface protein (protein-protein interaction) Attachment necessary for colonization Adherence and colonization - Intestinal epithelium=microvilli cells (nutrient and water movement) - E. coli=attach to intestinal surface - - Biofilm - Rearrangement of actin → create pedestal (less microvilli) → diarrhea (cannot move nutrients/water) - Virulence factor (knocked out E. coli) - Orange juice with knocked out gene → no diarrhea - Orange juice with wild type → diarrhea - Testing for virulence factor in human population (ethical, surprisingly) virulence=microbe causes disease through mechanisms Attaching to body surface=microbes specific interactions of protein/surfaces - Direct contact - body=lipid bilayer - Some proteins/oligosaccharides have sugars attached to them (decorated) - Microbes attach to surface with oligosaccharide and sometimes proteins - Sugars on surface = determine where bacteria can attach + makes harder to not present - Don’t put sugar on cell → can’t function (still need the sugar) - selectin=derivative of lectin - P-selectin bind to sugars on proteins (iCAMs/LFAs) - Bacteria target proteins that cells need via evolution - Target things that are frequently present + difficult to change - E. coli and N. gonorrhoeae=adhesins on fimbriae - Shigella=induce endocytosis (make cell take it up) - *E.coli and Shingella under one groupx; very similar subgroup Non specific Most microbes x attach to tooth, attach to biofilm + other microbes already attached on there Use secreted glycocalyx to form film on surface Oral biofilm - Streptococci - = early colonizing bacteria - Evasion of host defenses - Capsule - - - Form specific attachment to tooth using proteins it make, other microbes then attach to streptococci Contribute to dental cavity streptococci/actinomyces = oral biofilm Streptococcus mutans = higher chance of cavity (turn dietary sugar intoa acid) After entry, need to avoid being destroyed Innate immunity - Neutrophil, macrophage, complement Adaptive immunity - T/B cell (lymphocytes), antibody, specificity Ways to avoid immune sys - 1. Go into host cell (hide) - 2. Cover w/ sugar - Especially using sugar in our own body (ex.collagen) w/ repeating structure - X recognize sugar that well compared to protein - 3. Antigen similar to our body - T/B x self-reactive so avoid them - 4. Change antigen - Quick generation time (E.coli 20 min) - Bacteria - Specific part that is Hyper Changeable - 5. Capsule S. pneumoniae - capsule = essential virulence factor K. pneumoniae - Urinary tract infection; climb urethra → kidney infection - High antibiotic resistance Haemophilus influenzae - Cause meningitis and pneumonia in infants - First vaccine for baby - Superinfection - Lung damage → haemophilus influenzae bac. come in, cause superinfection B. anthracis - B. = all soil bac, closely related, AT rich, 16s very similar - B. thuringiensis x capsule - Insect pathogenesis - B. cereus x capsule - 1 plasmid that produce entoxin enzyme → food poisoning - B. anthracis - Pxo1 plasmid → Anthrax toxin - - Cell surface proteins and structures Zoonoses Biological weapon Spore into body → into tissue in body → germinate → cause toxin (3 types of toxin) - 1) lethal toxin - 2) edema toxin - 3) protective antigen - Protect against antibody Strain makes toxin but x capsule - Dangerous but X KILL YOU b/c x capsule - Y. pestis - Streptococcus 1) Group A strep - Streptococcus pyogenius - Have landfill antigen - Strep throat, toxic shock syndrome - M protein o 2) Group B strep - Cause purple fever - Pneumonia 3) Group D/G strep - X pathogenic strep - Found in mouth - - - M protein - Long filament - Block ability of antibody to bind to surface of streptococci and trigger phagocytic response - Biological mimic of myocardial cell protein - Rheumatic fever - Inflammation around heart → fluid buildup + fever - Staphylococci - G+ - Protein A bind to Fc part of any antibody - - - Enzymes that interfere w/ immune sys function - - - - - Co-immunoprecipitation (CoIP) - Protein of interest (x) binds to antibody - Add bead w/ protein A - Protein x isolated N.gonorrhoeae - Opa protein - = opacity factor - Protect bacteria against infection - Cause colony to become opaque - Inhibit phagocytic cell IgA protease - Neisseria meningitidis - IgA usually highly resistant to protease b/c of secretory component (IgA = mucosal surface antibody) - Break down Fc region/secreted IgA Collagenase - Clostridium - All tissues fall out (break matrix) - collagen = triple helix protein at extracellular matrix Hyaluronidase - Streptococcus - collagenase와 비슷, break matrix → allow to spread into tissue - Hyaluronic acid = part of ECM Coagulases - Staphylococcus - Cause blood clot - Blood contains neutrophil, antibody, B/T, monocytes; blood clot, they x move too Kinases - Staphylococcus and Streptococcus - Dissolve blood clot - Staph → protein A, coagulase (early virulence factor) → kinase, superantigenic toxin (late virulence factor) - While staph grow, protected from immune sys by protein A and blood clot → quorum sensing, certain amount reached → spread to body → kinases, downregulate protein A, upregulate toxin, float around in blood Antigen variation - - Invasion - - - Bacterial pathogen that steal iron - - Trypanosome (euk) - Change surface protein → long term disease - Chagas disease Opa factor in Neisseria gonorrhoeae - Phase variation = switch identity as cycle change Influenza - Change very rapidly - Flu - Segmented genome (two flu infect same cell at same time, genome combine → new) - X proofreading → many mistakes → 5~10 mistake every replication - b/c make many copies in one reproduction, x care if some are mutated and x work; but bacteria, b/c replication produce 1 copy, offspring viable or not very important Invade host cell, live in cell cytoplasm Good way to avoid immune sys, get deeper into body - Endocytosis => E.coli, salmonella - Inject directly Shigella - G- Similar to E.coli - ARPs (= actin related proteins) - Move b/w cells - Propel using actin filaments Listeria - G+ - Similar process to shigella (propel using actin filament) but x related to shigella (distant, x family) Bordetella pertussis - Cause whooping cough - Need siderophores - Siderophore = organic heme based compound that scavenge iron - X produce siderophore, no matter of what toxin they have, can’t grow and can’t spread - Hemolytic enzyme → break RBC → iron released → siderophore bind to iron - A cellular pertussis = vaccine for pertussis In our body, free iron scarce - Hemoglobin - Ferritin Transferrin Lactoferrin _____________________________Ch.22: Bacterial Toxins_____________________________ Bacterial toxins - - - Membrane disruption toxin - Exotoxins ‘venomous snake’ - produced/secreted by bacterium - Specific target o - made to disrupt bodily function - Can act distant from bacterium - Our body makes Antitoxin (=block toxin) Endotoxins ‘poisonous mushroom’ - All G- LPS lipiad A in G3 types of toxins - 1) Membrane disrupting toxin hemolysis and bicidins - 2) AB subunit toxins - active/binding subunit - 3) Superantigen - Cause our immune sys to go crazy - Subunits that insert themselves into membrane Hemolysin = target RBC Leukocidin = target WBC Cytolysin = attack any cell Staphylococcus aureus and Streptococcus pyogenes make a lot of these toxins Create channel in the membrane → unregulated pore - Need high conc. of toxin to actually work, so usually x very effective A-B subunit toxin - MOST IMPORTANT A subunit = active subunit = contain toxicity B subunit = bind to cell surface → endocytosis Diphtheria Toxin - transcribed/translated as single gene/aa chain unit (A-B subunit toxin ex) - - Post translational cleavage, reduction to active form by host cell B subunit bind to receptor protein on surface → receptor-mediated endocytosis → lysosome+endosome cause pH drops → change in shape of protein (T domain) → T domain inserted into mem., make hole→ active subunit cleave and leave out of endosome to cytoplasm (functional toxin) Target: ADP ribosylation of EF-2 - Toxin add ADP ribose to EF-2, protein synthesis (translation) in cell x happen b/c EF-2 not functional anymore Superantigen toxin - *T cell overstimulation - - Antigen = foreign thing that our immune sys recognizes Target T cell activation (T cell ONLY) Bypass specificity of T cell receptor peptide MHC complex by interacting w/ t cell receptor that is less variable (v beta region) than part that binds to peptide (hypervariable region) Superantigen binds to v beta region - in VDJ recombination, part that is ‘less’ variable Cause T cell overctivation → too much cytokines made → cytokine signal other cells, so other cells think something bad happening to body → immune sys overstimulated → overwhelming immune response triggered = toxic shock Semi-specific activation Toxins which bind to TCR and MHC activate immune sys Important Exotoxins - - Endotoxins - A-B subunit toxins - Botulinum - Tetanus - Cholera - Diphtheria toxin - Shiga toxin - E.coli enterotoxins Superantigen toxin - Streptococcal erythrogenic toxin - = pyrogenic = causing fever (scarlet fever) - *erythrogenic = causing redness - *pyogenic = causing pus - Staphylococcal enterotoxins - Toxic shock syndrome toxin 1 Anthrax - rare, so not in the list LPS - - - Just part of bacterial cell, making outer mem = lipiad A (endotoxin) + oligosaccharise Released during G- cell death - Bacterimia (lots of bacteria in blood stream) → G-, bac. killed by immune sys → LPS released (septicemia) → LPS react w/ inflammatory response, cause septic shock - *Bacterimia = significant amount of bac. in blood - *Septicemia = G- negative toxin (LPS) in bloodstream - *Septic shock = enough LPS to generate shock - Low blood pressure + disseminated vascular clotting = death Treatment w/ antibiotics can make this worse - Lyse bacteria w/ antibody → more LPS released → trigger septic shock Detailed Process: - G- bac. cell lysed → LPS released→ LPS binding protein + LPS protein complex forms → interact w/ macrophage → pro-inflammatory cytokine signaling (IL-1 = endogenous pyrogen, TNF = tumor necrosis factor, other cytokines)→ up-regulation of prostaglandins and leukotrienes → pro-inflammatory cascade EVERYWHERE in body at the same time - Pathogenicity - - Plasmids and - Limulus amoebocyte lysate assay (LAL assay) - Detect presence of LPS - Human likely to have endotoxin over body (everything we touch has G-); hard to get rid of LPS (LPS-free is hard) - Liminulus = Horseshoe crab - Amoebocyte - macrophage for horseshoe crab - sensitive to endotoxin - X adaptive immunity b/c arthropod Toxin genes not present in stable genome - present in mobile genome of bacteria Most plasmids, few transposons Mobile gene elements w/ toxin genes - Bacteriophage-lysogenic conversion (phages usually carry toxins; antibiotic resistance rare) - Plasmids (more common) (carry toxin/antibiotic resistance) - Transposons (less common) (usually carry antibiotic resistance than virulence factor) - Pathogenicity islands E.coli - Presence of plasmid w/ toxin gene that make diff kinds of E.coli Virulence plasmid passed through conjugation/transduction/transformation in pathogens Lysogenic conversion Pathogenicity islands population Tetanus toxin, Staph. Enterotoxins (D, E, G, I), E.coli virulence factors - Cholera toxin - Carried on CTX phage - Staph enterotoxin A (SEA) - Diphtheria toxin - Vaccine against diphtheria is not against bacteria, it’s against toxin - Change ecosystem of respiratory system so that Corynebacterium w/o diphtheria toxin is favored - Immune sys blocks toxin, so making toxin is disavantageous => unfavored in selection - Botulinum toxin - Gene from phage increase fitness to survive, but once lysogeny → lytic, bac. cell would lyse and get killed (having time-limit bomb) - - Pathogenicity island = contain virulence genes GC content - GC content diff by each bac, so if gene came from diff bac (bac B), GC content of that gene will be diff from rest of gene in bac A (horizontal gene transfer 증거) Pathogenicity island move from cell to cell present in pathogenic strains, absent from avirulent __________________________________Ch.23_____________________________________ Antimicrobial chemotherapy - - Target structure essential to pathogens but diff from our essential parts Easiet ←—-bacterial —------fungi/protozoa/worms (euk)—------virus—-> hard Bac easiest b/c x really related to us = most different Euk (fungi, protozoa, worm) - Sexual reproduction - Diploidity - High diversity Virus hardest - *except vaccine (vaccine works really well - X alive so reproduce only through host - Grow inside host → need to target yourself Sources of antibiotics - - - - Bacteria produce antibody to kill neighbors - Dense bacteria population (competition for resources) - Limited diffusion Antibiotic producing bacteria found in soil - Bacillus (G+ rod) - Streptomyces - Actidomyces (type of strep) - Fungi Almost all antibiotic are derivatives from natural antibiotic Hard to find antibiotic that can be given to human - Hard to make in lab - X work in human (or target something in human) - Injection vs pill Dose makes the poison = dosage is important; anything can be toxic if taken too much (even water) - Therapeutic window - dosage range between minimum effective concentration and maximum toxic concentration Antibiotic targets - Cell wall (most antibiotics) = beta lactam Protein synthesis = tetracyclines DNA replication = tetracyclines Ribosome Antibiotic spectrum - Chlamydias, Rickettsias - G- Obligate intracellular - *둘이 not related Mycobacteria - Mycolic acid - waxy acid fa layer that x allow antibiotic to come in - Isoniazid = antibiotic for mycobacteria; specifically targets mycolic acid synthesis - G+ - Obligate intracellular (live inside macrophage) - Modes of action - - Tetracycline: x work on mycobacteria, o work on every other pork Streptomycin: x work on G+, chlamydias+rickettsias / o work on mycobacteria, G- Weird b/c x work on G+ but o work on mycobacteria (G+) Isoniazid: target mycobacteria specifically - 2 billion ppl w/ tuberculosis Penicillin: o work on G+, x effective in G-(but still o try using) (b/c of cell wall) Virus = target nucleic acid replication bacteriostatic antibiotic = x kill bac, but stop protein synthesis (inhibit growth) - Advantageous than cidal when killing G- can release LPS and lead to septic shock bacteriocidal antibiotic = kill bac directly (lyse cel) Antibiotic resistance 1. Destroy antibiotic - Ex. Beta lactamase = destroy beta lactam antibiotics (like penicillin) 2. Mutation in target site - Antibiotics can’t bind anymore (ex. Alternation to ribosome) - Ex. MRSA 3. Efflux pump - Pump antibiotic out of cell Beta-lactamases - Chemically alter antibiotics in irreversible way Break B-lactam ring, antibiotic can’t interact w/ penicillin binding protein Prevent B-lactam doing D ala D ala transpeptidase reaction Target alteration - MRSA = make pbp 2-a (alternative pbp) → penicillin x work Bac growth rate gets slower = less fit w/ absence of antibody Point mutation → target alteration → becomes 1000 times more antibiotic resistant 남은 slide ashley note 보기 ________________________________Ch.24 Fungus_________________________________ Disease Organism/species names Drug Fungi - Fungi = euk - Filamentous = branching hyphae, multinucleate, forming mycelium - Yeast = ovoid, spherical single cells, budding/division reproduction Fungal disease - Superficial mycoses = localized wound infection (skin) Deep mycoses = systemic infection (deeper in body) *severity driven by host immune sys Local fungal infection - Ringworm = skin fungus growing from central point Athlete’s foot (=tinea pedis) = spread b/c of moisture Thrush = throat, vaginal yeast infection (candidas in throat = thrush) - Treatment : systemic drug - Candida albicans = localized and systemic infection - Candida aureus = gold color, highly drug resistant, systemic infection Tinea Systemic fungal infection - - Treatment for fungal infection - - Fewer drug b/c - Close to humans on phylogenetic tree - Drug stop fungus from growing → immune sys clean up rest - Patients immunocompromised = drug needs to be more effective Ergosterol = fungal membrane - Human mem = cholesterol - Target for medication Amphotericin B = bind to ergosterol Azole = interfere w/ ergosterol synthesis - Single celled Intracellular and extracellular Systemic infection Immune evasion Introduction by arthropod vector (mosquito → malaria) - Protozoa Cryptococcal meningitis = fungal meningitis - Pass BBB → meningitis fluid infection - Capsule = virulence factor Aspergillosis - Farm workers + black mold - Spores get deep in lungs Insect borne protozoa - Gastroenteric (drink contaminated water → amoeba infection) - Toxoplasmosis = through oral intake - Amoeba target brain, liver, bloodstream, intestinal tract - Treatment: Metronidazole - Leishmania Leishmaniasis → sand fly Trypanosoma - Chagas disease → reduviid bug - African sleeping sickness - tsetse fly - Antigenic variation o → episodic (=up and down disease state) - Treatment: Pentamidine Plasmodium Malaria → Anopheles mosquito - Treamtnet: Quinine - Ingestion of cyst - - Treatment - Helminths - Cyst = dormant protozoa, similar to endospore but less resistance Eat cyst → to stomach acid → trophozoite (active, moving form that attack tissue + enter bloodstream) Risk factors: - Enter CNS - Dysentery = bloody diarrhea caused by disrupted bowel structure Systemic disease - Toxoplasma gondii Toxoplasma GI disease - Amoebas - Giardia Giardiasis (diarrheal disease) - Cryptosporidium - In water supply X many drug option b/c closely related by phylogenetic tree Metronidazole = treat amoeba and anaerobic bac. - Lots of side effects Pentamidine = treat Trypanosoma Quinine = treat malaria - Tonic water o quinine - From natural product (bark of tree) NTD = neglected tropical disease Blood flukes = schistosomes Flatworm = tapeworm Roundworm = filarial worms Transmission - Eat food contaminated w/ feces → ingest egg/cyst - Eat tissue of intermediate host → ingest larvae - Active skin penetration → larvae invade skin Schistosomiasis - - - Tapeworm - - Roundworm Nematode - = blood fluke = burrow in skin Affect 300~600 millino ppl Intermediate host = snail - Egg in feces/urine → water supply → snail (intermediate host) → form cercariae (float in water/burrow in skin) 3 species (target diff body sites) - Schistosomiasis japonicum = small intestine - Schistosomiasis mansoni = colon - Schistosomiasis haematobium - urinary tract X severe disease state Other fluke infection = lung, liver Few drug treatment (*b/c it’s NTD) - Praziquantel food borne (undercooked pork/beef) Adult form = intestinal tract Larval form - Intermediate host - disseminated tissue - cyst in brain+organ - varies by species Tapeworm attach to intestinal wall → make hole in intestine → eat you slowly → reproduce by dropping little debris in poop - Very diverse Protective cuticle Plant parasitic - Nematode in broccoli = x harmful Free living bacteriovorus Pathogenic nematode - Person to person - Arthropod vector - Zoonotic Elephantitis = biting insects and brugia malayi Onchocerciasis = eye onchocerca nematodei - Burgia malayi = nematode Wolbachia = endosymbiont (beneficial symbiont) for nematode Tetracycline = target wolbachia - Widespread Many associations - Arthropods vector of Insect bites disease - Transmits many diseases Plants, animals, humans Control insects → control disease Arthropod vector borne disease in bacteria (plaque), protozoa (malaria), nematode BUT NO FUNGAL DISEASE ________________________________Ch.25 Viral Pathogen___________________________