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InfectionsTopics The immune system - innate, adaptive, complement Pathogens and infection - natural history, virulence Fighting infection - antibiotics, vaccines, infection control System specific infections - GI, STIs, sepsis, hepatitis, respImmunityThe Immune System • Innate system: Immediate response to infection that is non-specific and transient • Adaptive system: Humoral response with b cells and cell mediated response with t cells. Adaptive Innate Slower Faster Learning No learning Memory No memory Specific antigen receptors Pattern recognition receptors T cells and B cells NK cells, macrophages, neutrophils, dendritic cellsInnate immunity 1. Cellular response 2. Humoral response • Complement system – serum proteins and cytokines Detection of the pathogens : • Pattern Recognition Receptors (PRRs) can identify Pathogen Associated Molecular Pattern (PAMPs) or Damage Associated Molecular Pattern (DAMPs) • Types of PRRs: Toll Like Receptor PAMP PAMP Group TLR 2 Peptioglycan Gram + Bacteria TLR 3 dsRNA Viruses TLR 4 LPS Gram - Bacteria TLR 5 Flagellin Bacteria TLR 7 ssDNA VirusesComplement System Your complement system activates proteins that work with your immune system to keep you healthy. • Large group of serum proteins which produce effector molecules involved in immunity • Helps link adaptive and innate immunity. • • Mainly involved in destruction of bacteria, coating of virus particles and recruitment of phagocytes • responseswith one another both to opsonise pathogens and to induce inflammatory • killing via Membrane Attack Complex (MAC). • Always present at low levels in the blood but only become activated after cleavage. • Cleavage cascade, results in an amplification effect that produces a large number of the effector molecules.Adaptive Immunity T cells: • Cell-mediated response • Activated by dendritic cells • Two types: • Cytotoxic (CD8+) – recognize viral antigenic on MHC Iand release perforin or granzymes to induce apoptosis. • CD4+ (T-helper) cells – activate b cells, antibodies, macrophages and CD8+ • These cells are attacked in HIV. B cells: - Act as an antigen presenting cells to activate T cells - T-helper cells mature B cells to either a memory b cell or plasma cells. - Plasma cells: make antibodies against antigens - Memory B cells: initiate rapid response when exposed to the same antigen again.Definitions • Pathogen: an organism that causes damage to the host. • Virulence: the degree of pathogenicity • Toxigenesis: the ability to produce toxinsBacteria • Gram stain to differentiate organisms of bacteria: • Gram + cells = thick peptidoglycan layer • Stain blue and purple • Gram – cells = thin peptidoglycan layer • Stain red and pink • DNA or RNA bound by a protective capsid forming a Virus nucleocapsid. • Capsids are derived from protomersExotoxin A toxin released by a living bacteria into the environment. • Secreted by Gram + and Gram bacteria • Type I: Super antigens - bind surface molecules of immune cells, resulting in toxic cytokine production • Toxic shock syndrome toxin (TSST) - S. Aureus staph - enchances inflammatory activation by cytokines • Type II: Membrane disrupting. Lyse host cells. • Type III: A-B toxins disrupt cell functionEndotoxin A toxin present inside a bacterial cell that is released when it disintegrates. • Released by Gram – bacteria • It is apart of the cell wall – lipopolysaccharides • It is recognized by PRRs – TLR 4 • Induces immune system and inflammationSepsisSepsis Life threatening organ dysfunction due to an infectious pathogen or dysregulation of systems. • Septic shock: Circulatory, cellular and metabolic abnormalities due to compensatory mechanisms being overwhelmed • Decompensated = low bp • Compensated – normal bp • Ultimate goal = MAINTAIN PERFUSION! • Increased HR • Increased Stroke volume • Increased SVR • BP = (HR X SV) x SVRPathophysiology 1. Vasodilation • Increased vessel diameter • Reduced SVR • Tachycardia 2. Vasoconstriction • Increased SVR • Try to maintain organ perfusion 3. Capillary leakage • Hypovolaemia 4. Reduced venous return • Reduced BP 5. Reduced vital organ perfusion • Organ ischaemia • Tissue hypoxia • Organ dysfunction • AcidosisManagement: SEPSIS 6 • Give 3, take 3!GI infections Enterobacteriaceae – secretory Disease Organism Symptom Pathophysiology Cholera Vibrio cholerae Rice water diarrhoea Bacteria digest mucous lining of intestinal cells and then attache proximal to small intestine. Secretes toxin (ab toxin) - ribosylates Gs with adenylate cyclase active and increase cAMP. Disrupts ion movement into lumen: increases Cl-and decreases absorbtion of Na2+ —> watery diarrhoea Food poisoning Clostridium perfringens Intense abdominal cramps and watery a large range of invasins and toxins, diarrhea including Clostridium perfringens enterotoxin (CPE) – Distrupts ion transport in enterocytes Travellers diarrhoea Escherichia coli Marked by a rapid onset of non-bloody, First ETEC must colonize the small watery diarrhea, accompanied by little intestine to cause disease. Then, the pilli or no fever - can have abdominal liaise attaches to specific receptors on cramping, bloating, fever, and malaise villous enterocytes. ETEC produces two types of enterotoxins which are heat-labile toxin (LT) and heat stable toxin (ST) Enterobacteriaceae – inflammatory Disease Organism Symptom Pathophysiology Dysentry Shigella dysenteriae Bloody Diarrhoea Bacteria overcome gastric acid, Fever invade cells of distal ileum and colon Abdominal cramps epithelium. It then escapes vesicle and replicates intracellularly and spreads cell to cell. Causes local inflammation, ulcers and bleeding Some strains release Shiga Toxin Salmonellosis Salmonella Can be asymptomatic; •Nausea Bacteria multiply in the small •Vomiting intestine. Produces toxin to inhibit •Abdominal cramps •Diarrhoea immune system causing •Fever inflammation leading diarrhoea •Chills •Headache •Blood in the stool Diarrhorea Clostridium difficile Watery diarrhoea, which can be Antibiotic treatment disrupts normal bloody. painful tummy cramps. gut flora but C.Difficile survive as it feeling sick. signs of dehydration, forms spores. Spores germinate such as a dry mouth, headaches and after antibiotics. Rapid growth. peeing less often than normal, fever, Produces two toxins A (alters fluid loss of appetite and weight loss. leading to watery diarrhea and toxin B kills epithelia leading to pseudomebranes Gastrointestinal infections Disease Organism Symptom Pathphysiology Gastroenteritis - viral Rotaviruses Aymptomatic Infects intestinal epithelial Norovirus cells, replicates and lyses ,Impairs absorption of Poliovirus Sore throat nutrients causing vomiting Fever and diarrhoea Tiredness Nausea Headeache Stomach pain Enteric adenoviruses Vomiting Mild fever Watery diarrhoea Gastrointestinal infections Disease Organism Symptom Pathophysiology Gastroenteritis - bacterial Clostridium difficile watery diarrhoea, which can be bloody. Antibiotic treatment disrupts normal gut painful tummy cramps. feeling sick. signs flora but C.Difficile survive as it forms of dehydration, such as a dry mouth, spores. Spores germinate after headaches and peeing less often than antibiotics. Rapid growth. Produces two normal, fever, loss of appetite and weight toxins A (alters fluid leading to watery loss. diarrhea and toxin B kills epithelia leading to pesudomebranes. Listeria monocytogenes Campylobcter jejuni Diarhoea Fever Stomach cramps Nausea Vomitting Bacillus cereus Vomitting Nausea Diarrhoea Abdominal pain Cholera - Vibrio cholerae Rice water diarrhoea Bacteria digest mucous lining of intestinal cells and then attache proximal to small intestine. Secretes toxin (ab toxin) - ribosylates Gs with adenylate cyclase active and increase cAMP. Disrupts ion movement into lumen: increases Cl-and decreases absorbtion of Na2+ —> watery diarrhoeaRespiratory infectionsRespiratory tract infections Disease Organism Symptoms Pathophysiology Common cold Rhinovirus, coronaviruses The usual.. Binds to upper respiratory tract epithelium, High fever, pharyngitis, congestion, cough, local inflammation causes exudate. myalgia, chills, muscular aches, runny nose and cough. Influenza Influenzvirus a,b,c Infects upper respiratory tract haemagglutinin (HA) binds sialic acid. Virus replicates and lyses cells leading to necrosis of epithelium, stimulating inflammatory response. Macrophages produce IL causing vasodilation and oedema. Pneumonia Community-acquired pneumonia: Chest pain Pneumonia starts as an upper respiratory Streptococcus pneumoniae • Confusion tract infection that moves into the lower Hospital acquired: • Cough, which may produce phlegm respiratory tract to cause inflammation of Staphylococcus aureus, P • Fatigue the lung. • Fever, sweating and shaking chills Viral infection can predispose to secondary • Lower than normal body temperature • bacterial infection. Nausea, vomiting or diarrhea • Shortness of breath Tuberculosis Mycobacterium Tuberculosis • A persistent cough that lasts more than Following the M. tb transmission to the new three weeks and usually brings up host, the bacilli enter the lung and get phlegm, which may be bloody. ingested by macrophages. Further immune • Weight loss. cells are recruited to wall off the infected • Night sweats. macrophages, leading to the formation of • High temperature (fever) the granuloma, the hallmark of TB. • Tiredness and fatigue. • Loss of appetite. • New swellings that haven't gone away after a few weeks.STIs Reproductive system Disease Organism Symptom Pathobiology Bacterial Vaginosis Gardnerellavaginalis overgrowth Thin, gray, whiteorgreenvaginal discharge Changeinnormal microfloraafterchangeinph(>4.5) Foul-smelling"fishy" vaginal odorVaginal itching results inremoval of protectivelactobacilli. Seecluecells Burningduringurination (vaginal epithelial cells coatedwithbacteria) Thrush CandidaAlbicans Pruritus, vaginal soreness, dyspareunia, external dysuriaCandidal loadincreasesandcausesanintenselyirritant andabnormal vaginal discharges vaginitiswithacheesyvaginal discharge. Bartholin’sCyst E.Coli Large, painful, unilateral cyst Barthlins glandsreleaselubricantthatcangetblocked duetotheE.coli andformacyst. Chlamydia Chlamydiatrachomatis commonlyasymptomatic, urethritis, PID Elementarybodynfectscolumnaepitheliumwhich generates. ReticulateDamages GUtractcanspread infemales Gonhorrhea NeiseriaGonorrhoeae commonlyasymptomatic Bacteriaattachesviapili tomucosal cells - adherence preventswashing. UsesIgAproteasetoevadeIgA defenses. Endocytosedbycells, destroysciliatedcellsand creates inflammatoryresponse. Canattachtospermin ordertospreadthroughfemaleGUtract. Syphilis Treponomapallidum PrimarySyphilis:painlessopensoreappearonthebody, Invadesmucousmembraneorbreaksinskin, enters disappearsin~14days. SecondStage:Flu-likesymptoms bloodstreamandspreads tobodysites. Progressive andhrash. Thirdstage- transmissiontosexual partners tissuedestruction andnewborns, nerveandbraindamage, blindness, physical damage, death. Degenerativelesionscalled gummas FincDissease Organism Symptom Pathobiolody HPV – Herpes Simplex Virus Human papilloma virus Painless warts I Irritation/discomfort Can be asymptomatic HSV Genital herpes small blisters that burst to Invade mucosal membranes leave red, open sores around and then replicate in genitals epithelium, then taken up by vaginal discharge in women nerve fibres – retrograde pain pass urine transport to the neuronal cell bodies near the spinal cord. Acute infection is followed by lifelong latent infection - virus remains in a dormant state within collection of nerve cells. Periodically, reactivated - anterograde transport back to skin or mucosa, where replication occurs and the virus is shed HIV Primary infection • HIV virions breach mucosal tissues and travels to lymph node. Here, they replicate and enter general circulation – causing viraemia Host immune system is activated: • HIV-specific cytotoxic CD8+ T cells partially contain infection • Continuous HIV replication outpaces production of new • Anti-HIV antibodies are produced and can be detected in the blood • This marks seroconversion, occurs approximately two weeks after infection • Clinically, individuals experience flu-like symptoms such as fever, muscle and joint pains and enlarged lymph nodes = acute retroviral syndrome Chronic infection (several years) • Continuous viral replication in the lymph nodes and spleen • Clinical latency - largely asymptomatic • Continuous HIV replication leading to significant T cell loss • Progression to AIDS characterised by immunosuppression, susceptibility to opportunistic infections and neoplasia that can lead to deathHIV Life Cycle 1. Binds to CD4 receptor 2. The envelope fuses with the membrane of the cell using co- receptor (gp41) and enters cells 3. Reverse transcription – CD4 cell uses reverse transcriptase to convert HIV RNA to HIV DNA. 4. Integrate DNA genome into the DNA of the CD4 cell – integrase enzyme 5. Host cell machinery replicates viral DNA 6. New HIV particles assemble 7. Budding of the particles to be released and spread.Hepatitis Hepatitis Organisms Spread Symptoms Chronic? Complication HAV fecal-oral Common clinical manifestations are fever, anorexia, nausea Incubation period: 2-Not chronic. Most cases resolve Liver failure rare, not associated with chronic liver disease and vomiting, jaundice is more common in adults. spontaneously in 2-6 weeks or hepatocarcinoma HEV fecal-oral e HBV PParenteral (sexual contact, blood and blood products, Jaundice Abdominal pain •Dark urine •Fever Yes! HEP D infection ; liver cirrhosis; liver failure and cancer vertical) fecal-oral •Joint pain (vaccine) •Loss of appetite •Nausea and vomiting •Weakness and fatigue virus replicates in the hepatocytes of the liver. The host immune response causes both hepatocellular damage and viral clearance. HCV Yes! nfection ; liver cirrhosis; liver failure and cancer (no vaccine) HDV Sexual contact Only able to replicate in a cell infected with HBV. Yes - 5% coinfection; 80% superinfection Coinfection: Severe acute disease, More severe than HBV Blood alone, Low risk of chronic infection seesagueedisease Superinfection: Accelerated course of chronic hepatitis-B related liver disease, High risk of severe chronic liver disease, May present as an acute hepatitis.PrionsPrions Neurodegenerative diseases due to the formation of prions – misfolded proteins. • Proliferation astrocytes & microglia • Amyloid plaque build up Symptoms: • Asymptomatic for a long period of time • Anxiety • Ataxia • Memory loss • Dystonia PrP^c -> PrP^scTreatmentAntibiotics • Cell wall - Inhibit cell wall synthesis – disrupt peptidoglycan crosslinks • 70S Ribosome - Inhibit protein synthesis • • Enzymes • Inhibit DNA or RNA synthesis • Inhibit essential metabolic pathways • • Cell Membrane - Disrupt membrane integrity to render them leakyExamples Family/class of antibacterial Examples Main cellular target B-lactams Penicillins Bacterial cell wall prevents peptidoglycan cell wall cross- Cephalosporins Cefalexin Glycopeptides Vancomycin linking/synthesis Tetracyclines Tetracycline, doxycycline, Bacterial protein synthesis – locks lymecycline tRNA to septal site of mRNIA Aminoglycosidases Gentamicin, neomycin Bacterial protein synthesis – on 30S prevents mRNA translation into protein Macrolides Erythromycin, clarithromycin, Bacterial protein synthesis – binds azithromycin to 50s Quinolones Ciprofloxacin, levofloxacin, Bacterial DNA – inhibiting bacterial norfloxacin DNA gyrase which inhibits coiling – DNA damageAntibiotic stewardship The optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance. • Basic principles of good stewardship: • (1) reduce inappropriate use of • (2) encourage targeted treatment with narrow spectrum drugs • (3) limit adverse effects Vaccines train your immune system to create antibodies, just as it does when it's exposed to a disease.Vaccinations Type of Vaccination Role Advantage Disadvantage Attenuated Vaccines Lived but weakened form of Single dose effectiveness // It can become an active resistant pathogen Longevity and Strong Immunity form // Not suitable for immunocompromised patients Toxoid Vaccines Targets bacteria exotoxins rather Advantage: Compatible with other Large doses required than the bacteria itself vaccines —> Combination vaccines Only successful against bacteria that produces toxins Subunit Vaccines Inactivated vaccine that contains If denatured, immune response is the antigens of the pathogen inadequate. T-cell independent // Poor immune response // Short term immunity Recombinant Vaccines A pathogens genes are inserted into • They can be produced in large bacteria or yeast where antigenic quantities proteins are produced. These are • The risk of them being harmful what is used in the vaccine to is low as it doesn’t contain the trigger an immune response in live pathogen humans. • Don’t handle with the pathogen first hand Adjuvents A substance that enhances the immune response to vaccinesThank you!