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MICROBES - Coggle Diagram

- - - - brings myeloid and lymphoid cells to infection site /brings antigens to immune cells site such as lymph nodes / brings immune cells from developmentnsites to function sites
    - - Thymus - grows fast and is biggest in first years of life - shrinks from puberty - divided into two lobes - smaller subdivisions =lobules - divided into outer zone (cortex) and inner zone (medulla) - cortex has a high lymphocyte level and is site of proliferation - t cells that are produced in cortex migrate to medulla where they enter blood through medullary veins adding to lymphocytes seen in peripheral blood and lymphoid organs
      - lymph nodes - at locations that immune cells can easily reach - allows communication between immune cells - divided into compartments w/ each compartment performing an important function - outer layer (cortex) contains b-cell areas or follicles, middle layer (paracortex) - populated by T cells and dendritic cells
      - spleen - removes RBCs from circulation and therefore can remove blood-borne microrganisms - white pulp is high organised lymphoid region where adaptive immune response can be initiated - composed of seperate areas for B and T cells surrounded by marginal zone - contains subsets of macrophages and B cells - entry of leukocytes to white pulp requires activation of specific recptors - process similar to mulitistep extravasation like leukocytes leaving blood and entering tissues
    - - immune cells origin : leukocytes originate in bon =e marrow - develop from haemotopoietic stem cells / red bone marrow contains haematopoietiic stem cells that can become RBCs, leucocytes and platelets / yellow bone marrow made of mesenchymal stem cells that become cartilage, fat or bone
      - myeloid and lymphoid lineages: myeloid progenitors become erythrocytes, paltelets, monocytes, dendritic cell, neutrophil, eosinophil, basophil ,phagocytes / lymphoid progenitor becomes T cell, B cell (both lymphocytes), NK cell, plasma cell
        
        myeloid lineage : phagocytic cells : 1. memebrane evaginations = pseudopodia - surround pathogens - pathogen is engulfed by andocytosis - vacuole conatining pathogen fuses w/lysosome to form phagolysosome - lysosome releases its enzymes, thus detsroying pathogen- debris from pathogen is released from cell by exocytosis
        
        Body wide mononuclear phagocytic system - reticuloendothelial system - how macrophages respond: cytokines have role in amplification and proliferation --> actiavted macropahge produces cytokines (TNF alpha, IL-6, IL-8, IFN gamma) --> activate immune mechnaims and drive acute phase response - encourages bone marrow to produce more immune cells to fight infection - cytokines recruit and activate other myeloid cells eg granulocytes
        
        lymphoid lineage: NK cells identify and kill altered self - secret cytokines / T lymphocytes: respond to specific antigens; kill specific targets; secret cytokines / B lymphocytes: express specific receptors, differentiate into plasma cells secreting antibodies of same specificty
        
        natural killer cells : identify and kill altered self (virally infceted cells) - recognises them as a result of altered expression of surface markers on virally infected cells - recognises surface marker chnage and kills them (by releasing lytic granules) --> molecules on surface of healthy cells stop NK cells from killing
      - growth factors and cytokines determine which cell type will develop form haematopoietic stem cells
      - how immune cells enter target tissues:
        
        passive movement
        
        presence of inflammatory cues - increase expression of receptors on endothelial cell - increases chances of leucocytes to bind
        
        binding interactions allows rapidly moving leukocytes to bind to epithelium - brings immune cells into contact w/endothelial cell so that immune cell can be futher activated
        
        contact of chemokines w/chemokine receptors on immune cells - production of integrins - once activated, leukocyte integrins bind tightly to their ligands on endothelial cells - allows leukocytes to fully arrest on endothelial surface
        
        adherent immune cells crawl to nearby endothelial borders in prep for extravasation into tissues - immune cells squeeze into tissues via endothelial bordered = diapedesis
- - - - B lymphocyte: B cell receptor (BCR) - consists of antigen binding subunit that binds epitope, two heavy and two light chain subunits - both have a variable region created through gene rearrangement, a transmembrane region, a signalling subunit - each B cell expresses one BCR of a single specificity
        
        by lymphocytes and plasma cells - plasma cells differentiate from B lymphocytes - b lymphoctes express antigen specific B cell receptors (BCR) - these then become plasma cells or memory B cells - antibodies are secreted from BCR
        
        B cell response to immunisation: first infection (antigen exposure) - naive B cells, activated B cells - short lived plasma cells in lymphoid organs - long lived plasma cells in bone marrow - low level antibody production // second infection: memory b cells - plasma cells - long lived plasma cells in bone marrow <-- primary and secondary antibody response
        
        B cell activation by antigen and helper T cells -> antibody secretion by plasma cells
        
        Neutralization: antibody prevents bacterial adherence
        
        opsonization: antibody promotes phagocytosis
        
        complement activation: antibody activates complement - enhances opsonization and lyses some bacteria
      - Adaptive immunity is mediated by T cell subtypes - dendritic cell activates the naive T cell (CD4) by presenting antigens - t cell becomes:
        Th1 cell which release IFN-gamma -> immunity to intracellular pathogens/tumours - autoimmunity
        Th2 cell which releases IL-4 (cytokine) -> immunity to extracellular pathogens - allergy
        Treg cell which releases IL-10/TGF-beta -> immunity to infection /inflammation -> autoimmunity
  - - - IgM: role in initial immune system defence
      - IgD: Prevention of respiratory tract infection
      - IgE: immunity to parasites
      - IgG: main antibody in blood - can bind to bacteria and toxins - only isotype that can pass through placenta
      - IgA: mainly a monomer but can form dimer in secretions like nasal discharge and saliva - prevent bacterial invasion from a mucous membrane
    - - neutralisation: toxin binds to sell-surface receptor - endocytosis of toxin-recpetor complex - dissociation of toxin to release active chain which poisons cell - neutralizing antibody blocks binding of toxin to cell-surface receptor
      - opsonization: digestion in lysosome
      - complement: cascade of proteins - found in serum; tightly regulated, normally inactive - synthesis increased during inflammation - critical to getting rid of infection
  - - - humoral immunity : B cells and antibodies - prevention of infection and re-infection / extracellular bacteria
      - cell-mediated immunity: t cells - help for Ab production - control of infection / intracellular bacteria
      - bacteria trigger macrophages to release cytokines and chemokines -> vasodilation and increased vascular permeability cause redness, heat and swelling -> inflammatory cells migrate into tissue, releasing inflammatory mediators that cause pain
      - cell mediated immunity to bacteria : many obligate intracellular bacteria resistant to Ab+ C -> CD4, Th1 cel,l IFN-gamma production -> activates macrophages -> enhances MHC expression, activates killing mechanisms, stimulates release of bacteria from macrophages // CD8+ T cells has a role in certain infections eg salmonella // NK cells involved in early IFN-gamma production
  - - - antigenic drift = neutralising antibodies against hemagglutinin block binding to cells -> mutations alter epitopes in haemagglutinin so that neutralising antibody no longer binds
        
        influenza virus haemagglutinin evades immune responses by antigenic variation
- - - - exotoxin : eg S.aureus or Shiga Toxin
        
        Shiga Toxin - produces e.coli - key virulence factor to cause hemolytic uremic syndrome (affects blood clotting) - 2 types:Stx1, Stx2 - located and transmitted by prophages on chromosomes - Stx released from cells when phage goes into lytic cycle (virus introduces its genome into a host cell and initiates replication by hijacking the host's cellular machinery to make new copies of the virus) - antibiotics can be detrimental ... stress on bacterial cells can induce lytic cycle of phage
        
        mechanism of shiga toxin: enzymatically inactivate the eukaryotic ribosome by removal of a single adenine base from 28S rRNA within the large (60S) ribosomal subunit - results in cell apoptosis, disruption of endothelium and inflammation
      - staphylococcus enterotoxin(s) (SE) - gram pos. e.g. staphylococcus aureus / 2 protein domains / heat stable amd resistant to digestion, therefore can make food posisonous - symptoms: vomiting, diarrhoea / superantigen - unspecific stimulation of antigen-presenting cell and T-cells / function as superantigens i.e. activate large proportion of t-cells --> excessive and uncontrolled secretion of pro-inflammatory cytokines + chemokines/ can occur in milk, cheese
      - endotoxins: part of cell envelope of gram neg. bacteria - released upon cell division/cell death - e.g. Lipopolysaccharide (LPS) : toxicity mediated by Lipid A - thermostabile (can be in hot temps) - low immunogenicity (ability to provoke immune response) : induction of neutralising antibodies - low toxicity - binds to CD14 and LPS-binding protein - chromosomally encoded
        
        Endotoxins released when gram neg. bacteria die : Endotoxins exert their toxic effects by activating the immune system, particularly through interaction with Toll-like receptor 4 (TLR4) on immune cells such as macrophages and dendritic cells. This interaction triggers a cascade of inflammatory responses, leading to the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6).
  - - - Attack phase -> attachment -> invasion -> resealing ->early predator growth -> late predator growth -> exhaustion of prey resources -> septation -> division -> predator exit
  - - - lytic cycle of Phage T4 (virulent phage): 1. attachment, 2. entry of phage dna and degradation of host dna, 3. synthesis of viral genomes and proteins, 4. self assembly, 5. release
      - lysogenic cycle: = the cycle replicates phage genome w/out destroying host - viral dna molecule incorporated into host cells' chromosome = phage dna integrates into bacterial chromosome - prophage is copied w/bacterial chromosome - many cell divisions create many infected bacteria - daughter cell w/prophage - a prophage occasionally exits bacterial chromosome, initiating lytic cycle
      - Phages that use both lytic and lysogenic cycle = temperate phages
        
        Lytic and Lysogenic Cycles of Phage λ (temperate phage)
        
        part 1: Lytic cycle: phage injects its dna - phage dna circularizes - lytic cycle induced - phage dna and proteins synthesised and assembled - cell lyses, releasing phages
        
        part 2: lysogenic cycle: daughter cell w/prophage - lysogenic cycle entered - prophage (= integrated viral DNA) copied w/bacterial chromosome - many cell divisions create many infected bacteria - every time the host divides, it copies the phage dna and passes copies to daughter cells - environmental signal can trigger virus genome to exit bacterial chromosome and switch to lytic mode
      - bacterial defenses against phages - natural selection favors bacterial mutants w/surface proteins that cant be recognized as receptors by a particular phage type / foreign DNA can be identified and cut up by cellular enzymes (restriction enzymes) / bacteriums own dna is protected from restriction enzymes by being methylated
        
        restriction modification (RM) systems
        
        dna methylation - eliminates foreign dna molecules - endonucleolytic cleavage - protects genome by modification of the cognate endonuclease target // 2 RM systems per bacterium - tandam systems (dna methyltransferase and restriction endonuclease are adjacent genes) or orphan (solitary dna methyltransferase)
        
        restriction enzymes (or restriction endonuclease) - enzymes that cut dsDNA
        
        using a restriction enzyme and DNA ligase to make a recombinant dna : restriction enzyme cuts the sugar-phosphate backbones at each arrow - base pairing of sticky ends produces various combos - dna ligase seals strands
        
        distinction of self and non-self dna
        
        methylation at GATC sites - A or C is methylated / transfer of methyl group from S-adenosyl-methionine (SAM) to dna
        
        Dam - dna methyltransferase/ catalyses addition of methyl group to A base / trails DNA replication fork
        
        two RM Systems - productive replication still likely
        
        Multiple RM systems - productuve replication likly to reach dead end
      - CRISPR-Cas9 = Cluster of Regular Interspaced Short Palindromic Repeats (found in e.coli)
        
        Cas = CRISPR-associated protein(s) - > nucleases
        
        adaptive immune system in bacteria and archaea - defence from incoming DNA eg phage dna
        
        present in bacteria and archaea
        
        when a phage infects a bacterial cell w. CRISPR-Cas - phage DNA is integrated between two repeat sequences - if cell survives infection - can block any attempt of same type of phage to reinfect it - attempt of phage to infect cell triggers transcription of CRISPR region - resulting RNAs cut into pieces and bound to Cas proteins.
        
        Cas proteins use phage-related rna to target invading phage dna - phage dna is cut and detroyed - relationship between phage and bacteria in in constant evolutionary flux
        
        Type 2 system repurposed for easy and precise genome editing for pro-/euk-karyotes - precise introduction of dna double strand breaks by Cas9protein guided by RNA molecule - during dna repair mediated by endogenous dna repair machinery, dna mods can be performed ie deletions, insertions, exchanges
        
        CRISPR system composed of : operon of CRISPR associated genes and a CRISPR array including: a leader sequence followed by short identical repeats and interspersed by short unique spacers sequences
        spacer sequences originate from mobile genetic elements memorized upon first 'infection'
        
        CRISPR spacer acquisition: fragmentation of invading DNA ie phage dna - selection of protospacer by recognition of the protospacer adjacent motif (PAM) - Nicking of leader end repeat in CRISPR locus - integration of new spacer and duplication of flanking repeat
        
        Gene editing using CRISPR-Cas9 system:
        
        Cas9 protein has active sites that can cut DNA, the Guide RNA can guide Cas9 to a target gene- a complementary sequence can be bound to target gene
        
        The target gene is bound and cut within Cas9
        
        scientist can disable the target gene to study its normal function, if the target gene has a mutation it can be repaired
- - - - sinusitis = caused by allergy or infection - follows a bout w/common cold - symptoms: nasal congestion, pressure in nose/forehead, headache, facial swelling, green/yellow discharge, discharge casused by allergy accompanied by itchy, watery eyes
      - acute otitis media (ear infection) - viral infection -> inflammation of Eustachian tube - fluid buildup in middle ear - bacteria; multiplication in fluids - bacteria can migrate along Eustachian tube from upper respiratory - multiply - pus production - continued fluid secretion // chronic form = fluid remains in middle ear for indefinite period (caused by biofilm bacteria), symptoms: fullness sensation in ear, hearing loss - eardrum rupture in severe cases
      - pharyngitis = inflammation of throat - swelling, pain, reddened mucosa, swollen tonsils, swollen mucous membranes 0swallowing affected), bad breath smell - transmitted via droplet or direct contact
      - Diphtheria (toxin) - Sore throat, lack of appetite, low-grade fever, pseudomembrane forms on tonsils or pharnyx // droplet contact or direct contact
  - - - found in nature ie soil, water, in human microbiota, in nose, skin , intestinal tact - spread easily and quickly (not through air)
      - In a hospital setting - a frequent cause of human nosomial infections - significant amount of hospital-acquired soft tissue and urinary tract infections and pneumonia - ability to spread rapidly - exposure to: bacteria via respiratory tract (pneumonia), blood - infection in blood, person-to-person contact - principal pathogenic reservoirs for transmission: GI tract, contaminated employee hands, patients - higher risk of infection for patients that need catheters/ventilators or that are administered broad-spectrum antibiotic treatment (disruption of normal microbiota - higher pathogen susceptibility)
      - virulence factors: Klebsiella members express two types of antigens on cell surface: lipopolysaccharide (O antigen) and Capsular polysaccharide (K antigen) - both contribute to pathogenicity - structural variability of the K and O antigen are a basis for classification into serotypes - virulence of all serotypes is similiar
      - Capsule: encases entire cell surface - accounts for its large appearance on a Gram stain - increases its virulence - physical barrier to evade host's immune response - protects cell from dessication
    - - opportunistic pathogen (associated w/cystic fibrosis patients) - has impact in a nosocomial setting - higher prevelance
      - vast array of virulence factors exacerbate the problem : efflux pumps (antibiotic resistance), extracellular polysaccharide (biofilm formation) and outer membrane proteins, multiple secretion systems (delivery of toxins), flagellum, T6SS and T3SS, quorum sensing
      - Cystic fibrosis Lung environment: hyperinflammatory, anoxia, low Ph, poor mucociliary clearance
      - acute vs chronic infection (of respiratory epithelium) : in CHRONIC : has a biofilm, loss of toxicity, haemoglobin use, non piliated, non-flagellated, LPS modifcation, reduced SQ communication
  - - - two symptom stages: Catarrhal Stage - incubation 3-21 - bacteria in respiratory tract - appears as a cold - last 1-2 weeks // paroxysmal stage - sever and uncontrollable coughing that can result in burst eye blood vessels/vomiting - long recovery phase - complete recovery can take months - toher microorganisms can more easily cause a secondary infection
  - - - Latent TB: perioid of hidden infection-asymptomatic - accompanied by mild fever - after 3 weeks, immune system mounts a cell-mediated assualt - large influx of mononuclear cells into lungs - tubercles form - centres of tubercles b/down into necrotic caseous lesions thta gradually heal by calcification (Ca build up)
        
        occurs when a person breaths in bacteria and it reaches alveoli of lung - immune system keeps bacilli contained and under control - person isnt infectious and has no symptoms
      - reactivation of tuberculosis: live bacteria can remain dormant and reacted months later
      - chronic TB: tubercles filled w/bacteria expand and drain into bronchial tubes and upper respiratory tract - sever symptoms: chest pain, fever, chillls, night sweats etc
      - Extrapulomnary TB: outisde of lungs - more common in immunosupressed patients and children - regional lymph nodes, kidneys, bones, brain
      - active disaese : occurs when immune system cant keep bacilli contained - bacilli multiply rapidly - development of TB symptoms
    - - 4 first line drugs: Isoniazid (NH), rIFAMPICIN (rif), Pyrazinamide (PZA), Ethambutol (EMB) - Adjust regimen when drug susceptibility results become available
        
        Directly Observed Therapy (DOT) - health care workers watch patient swallow medication - ensure adherence - reduces TB relapse and acquired drug resistance
    - - Primary Drug Resistance = infection w/strain of M.tuberculosis thats already resistant to 2 or more drugs - ie in area of high prevelancy of drug resistant TB
        Acquired resistance = infection w/ strain of M. tuberculosis that becomes drug resistant due to inadequate treatment / malabsorption / drug-drug interactions causing low serum levels
      - TDR-TB = Totaly drug resistant = resistant to a wider range of drugs than strains classified XDR-TB -> no treatment options
      - MDR-TB = multi-drug resistant TB - i.e. are rifampicin resistant - need second line treatment regimens
      - XDR-TB - treatment options restricted
      - Mycobacterium tuberculosis (Mtb) : gram stains as pos but isn't / acid fast bacilli - causative agent of TB - faculative intracellular - abundant in nature - mainly a human pathogen
        
        Mtb Cell Wall is v. complex: contains Lipoarabinomannan (LAM), phosphatidylinositol mannosides (PIMs), Cord factor, Antugen 85 protein complex
        
        Efflux pumps - proteins that pump antibiotics out for drug resistance
        
        mycobacteria share many antigens
        
        specific antigens - coded by genes in Region of Difference - not present in the majority of atypical mycobacteria - induce production of IFN-gamma : ESTAT-6 (early secretory antigenic target), CFP-10 (culture filtrate protein) <-- are v. specififc - only present in m.tuberculosis and two other diseases
        
        virulence factors expressed during latency/latency antigens - m.tuberculosis able to switch to a dormant state/latency during stress conditions (drug-tolerant persistor cells)- tolerance of pathogens to antibiotics - 'persistors'
        
        specialized survivors - not mutants - phenotypic variants of actively dividing cells - non growing dormant cells - arise stochastically
        
        tolerant to bactericidal antibiotics - depend on presence of active targets to kill cell
        
        Evasion Strategies: pH changes - inhibition of oxidatuve burst - inhibition of phagosome/lysosome fusion - inhibition of antigen processing - rupture of pahgolysosome membrane
    - - humans easily infected w/ mycobacterium tuberculossis but normally resistant to diseas - untreated TB progresses slowly into primary TB, secondary TB and then Miliary TB
      - probability of transmission depends on infectiousness, environment type, exposure length // transmission of mycobacterium tuberculosis between people via airborne particles (droplet nuclei) - prolonged contact needed for transmission
      - sites of TB disease
        
        Pulmonary TB (most cases)
        
        extrapulmonary - other than the lungs -> larynx, lymph nodes, brain and spine, kidneys, bones and joints
        
        miliary TB - tubercle bacilli enters blood and carried around body
      - symptoms: productive cough, chest pain, night sweats, fever, weight loss, poor appetite
      - TB Pathogenesis: exposure - aerosols - bacteria inhalation - infcetion or infection of alveolar macrophages - bacterial replication - granuloma formation (caseous necrosis) - halt of bacterial growth (calcofcation of lesion) and immunosupression and then reactivation / liquefaction of lesions and then dissemination and death / bacilli in cough sputum
        
        granuloma = an attempt to contain infection - can be caseous, non-necrotizing, fibrotic
      - Persons at high risk: Those recently infected, HIV infected persons, injection drug users, malnourished people, cartain medical conditions
- - - - Detection occurs when pattern recognition receptors (PAMPs) detect conserved microbial patterns that are unique to microbes = microbe associated molecular patterns (MAMPs) - MAMPs are unqiue to many micro-organisms, not found on vertebrate cilia and are excellent recognition targets as they dont chnage over time
        
        PRRs : Toll Like Receptors (TLRs) = trans membrane recptors consisting of an extracellular domain that recognises microbial product (or MAMP) and a intracellular cytoplasmic tail responsible for inducing cell signalling and activating gene transcription - activation of the PRR signalling pathways drives anti-microbial defences within the cell
        
        each TLR recognises one more more molecular patterns or MAMPs on microorganisms - most widely studied TKR = TLR4 - recognises lipopolysaccharide (LPS) on gram neg bacteria / TLR5 binds flagellin in tail of bacteria / TLR2 can hetrodimerise w/TLR1 to recognise bacterial lipopeptides or heterodimerise w/TLR6 to recognise lipoteichoic acid (component of gram pos bacteria _ - can also recognise Zymosan produced by fungi / TLR3 can recognises double stranded viral RNA/ tlr 7,8,9 recognise microbial nucleic acids
        
        TLR expression : expressed on innate cell types incl. macrophages, Kupffer cells in liver, Langerhans cells in skin or alveolar macrophages in lung / are also expressed by dendritic cells - can be expressed by stromal and epithelial cells / broad expression pattern of TLRs --> initation of antimicrobial response in all tissues v quickly
        
        TLR location: placed in cell to best recognise specific MAMPs they are targeted towards - TLRs can be cell surface receptors and recognise bacterial molecules - others are located intracellularly in endosome where they can detect microbial nucleic acids or parts of microbes that have been taken into cell by pahgocytosis - four of the mammalian TLRs recognise nucleic acids (TLR 3,7,8,9) - loacted in endosoem which contain proteases capable of degrading internalised mcirobes, releasing their nucleic acids for recognition by TLRs
        
        TLR Signalling: upon engagemnt of TLR w/its ligand/MAMP/, a intercellular siganlling pathway is induced - TLR activation results in actiavtion of transcription factor NFxB - more specifically actiavted by movement of NFxB from cytoplasm to nucleus where it binds DNA and initiates gene transcription - mammalian TLR activation can also induce Interferon regulatory Factor (IRF) via activation of a second pathway.
        
        induction of these pathways and activation of these TFs -> expression of genes ie interferons, chemokines, cytokines, antimicrobial peptides // many immune relevant genes have NFxK and /or IRF binding sites in their promoter regions
        
        TLR Signalling Pathway and regulators (EXTENSIVE): in STUDY NOTEBOOK
  - - - IL1: activates vascular endothelium / activates lymphocytes / local destruction / increases access of effector cells --> results in fever and IL-6 production
      - TNF-alpha: ACTIAVTES VASCULAR ENDOTHELIUM AND INCREASES VASCULAR PERMEABILITY -> increased entry of IgG, complement and cells to tissues and increased fluiddrainage to lymph nodes -> results in fever
      - IL-6 : lymphocyte activation / increased antibody production
      - IL-8 : chemotactic factor recruits neutrophils, basophils and T cells to infection site
      - IL-12 : activates NK cells / induces differentiation of CD4 T CELLS INTO TH1 cells
      - control of inflammatory cytokines e.g. TNFalpha:
        
        endogenous: solutble receptors= RI and RII, shed from cell surfaces, upregulated during inflammation, bind and neutralise TNF
        
        exogenous: steroids, soluble receptor, neutralising antibody
    - - bacteria induce macrophages to produce IL-6 - acts on hepatocytes to acute phase proteins which actiavte, amplify, opsonise, kill
      - mannose binding lectin binds mannose residues on bacterial surfaces, acting as opsonin and also activating complement
      - Regulators of inflammation: intracellular signalling inhibitors (SOCS = suppressor of cytokine signalling), endogenous steroids, soluble cytokine receptors, regulatory cells - cytokines, apoptosis of inflammatory cells
        
        SOCS block Jak-STAT pathway and block IL-6, IFNs and many cytokines
        
        we make our own steroids = endogenous glucocorticoids -> suppress inflammatory activity and regulate adhesion molecule expression and dampen cytokine expression
        
        anti-inflammatory cytokines eg TGFbeta -> expressed by myeloid suppressor cells, endothelial cells and mesenchymal cells - blocks iNOS induction in macrophages, inhibits TNF/IL-1, down regulates TNF receptor expression
        
        IL-10: produced by regulatory macropahges - feedback loop to suppress pro-inflammatory cytokine production - reduces Th1cytokine profile - destabilises mRNA
- - - - 1. Kinetoplastids (african and american trypanosomes)
        
        Examples: Chagas Disease (south america), African trypanosomiasis (sleeping sickness), leishmaniasis
        
        Kinetoplast = dense DNA (kDNA) containing granule w/in the cell's single mitochondrion -> is found near basal body which is at base of flagellum
        
        African trypanosomiasis = sleeping sickness - exhibiits patchy distribution in afruca
        
        T.brucei rhodesiense (TBR) = East African sleeping sickness (infects animals/livestock)
        
        T.brucei gambiense (TBG) = west and central african sleeping sickness
        
        transmission:
        
        Life Cycle - Tsetse fly = fly ingests trypomastigotes as part of blood meal - transform in procyclic trypomastigotes in fly gut and then into epimastigotes - epimastigotes migrate to slaivary glands and transform into metacyclic trypomastigotes- can be passed on during feeding
        
        Life Cycle-Human = all stages are extracellular - trypanosome transmitted through insect bite - insect vector tsetse fly - metacyclic trypomastigotes injected into skin tissue - enter lymphatic system - into blood - disseminate in host body fluid (lymph, blood, spinal fluid) - replication by binary fission
        
        Other transmission routes: mother to child - tryanosome can cross placenta and infect fetus / mechanical transmission via other blood sucking insects // contaminated needles in labs / sexual conatct
        
        TBR: antelope-fly-human transmission // TBG: human-fly-human transmission
        
        Disease course and symptoms
        
        TBR - rapidly progressing but TBG is slow progressing // disease progression characterised by invasion of lymphatics in TBG infections
        
        assymtomatic period of two weeks - local inflammatory nodule = trypanosomal chancre
        
        acute blood stage infection - characterised by irregular fevers and headaches
        
        TBG - parasite blood conc is low // TBR has high parasite blood count
        
        blood -> lymphatics -> CNS
        
        Symptoms in lymphatic stage: enlarged lymph nodes,, weight loss, itching (in earlier blood stage - symptoms are fever, headache, weakness)
        
        invasion of CNS and NS impairment -> apathy, fatigue, confusion, motor changes --> 6-12 months before neurological symptoms are apparent for TBG // neurological manifestations within weeks after TBR infections --> if untreated , CNS stage progresses to include convulsions or coma followed by death (both infections)
        
        Diagnosis:
        
        parasite detection in blood - microscopy or giemsa stained blood smears
        
        mini-anion exchange centrifugation technique - blood cells more neg charged than trypansomes and retained on column
        
        trypanosomes more likely to be detected during symptomatic periods
        
        treatment differes whether the is CNS involved -> involved if detection of parasites in cerebral spinal fluid or elevated WBCs in cerebral spinal fluid
        
        treatment:
        
        Pentamidine: effective against early stage TBG - but adverse side effects and non-oral
        
        melarsoprol : first line drug for late stage TBG/R involving CNS - but parasite resistance and adverse siide effects
        
        no vaccines
        
        (T. cruzi) American Trypanosomiasis = Chagas Disease - endemic in south and central america - insect vector is triatomine bug
        
        Life Cycle: epimastigotes replicate in gut of triatomine bug - transform into infective stage (metacyclic trypomastigotes) -transmission by contamination of bug bite wound w/feces containing trypomastigotes - trypomastigotes enter blood and invade cells of liver, spleen, lymph nodes - inside cells, transformation into amastigotes (replicative form:binary fission) - transformation into trypomastigotes inside host cells - cells burst and surrounding cells infected or enter blood - can be ingested by blood-sucking triatomine bug
        
        The 3 -igotes
        
        Epimastigotes: Elongated, motile forms found in insect vectors.
        
        Trypomastigotes: Infective forms found in the bloodstream of mammalian hosts.
        
        Amastigotes: Intracellular, non-motile forms found within host cells.
        
        Diagnosis and Treatment
        
        diagnosis: blood screening - large amount of assymtomatic carriers (silent spreaders)
        
        chronic chagas disease manifests itself in cardiomyopathy - sudeen death due to damage of heart cells
        
        80% cure for acute disease, less effective for chronic / no vaccine
      - Anaerobic Protozoa (giardia spp.)
        
        General: adapted to low oxygen in gut lumen / no mitochondria, cytochrome mediated electron transport, oxidative phosphorylation / energy from glucose by fermentation in cytosol
        
        Giardiasis
        
        parasitic disease caused by flagellate protozoan' Giardia Lamblia' - Giardia Lamblia inhabits digestive tract of animals
        
        symptoms: loss of appetite, diarrhoea, stomach cramps, bloating, watery stool <-- symptoms caused by giardia organisms infecting cells of duodenum and jejjunum / flattening of microvilli / reducing nutrient absorption
        
        Transmission: fecal-oral route w/ingestion of cycts , contaminated food or water / many are unknowingly carriers
        
        diagnosis: detection of antigens on surface of organisms in stool specimens - examiantion for motile trophozoites or distinctive oval G.lamblia cycsts
        
        treatment: not always necessary -> medication: metronidazole - inhibits nucleic acid synthesis and disrupts DNA
      - Apicomplexan Protozoa (plasmodium spp.) i.e. Malaraia
        
        Plasmodium Life Cycle : malaria is mosquito-borne infectious disease of humansand other animals caused by plasmodium genus - disease transmitted by bite of an infected Anopheles mosquito - bite introduces the parasites from mosquito's saliva into a person's blood - parasites travel to liver where they mature and reproduce
        
        five diff species of plasmodium that can infect humans - most deaths caused by P.falciparum (africa) -> milder for malaria: P.vivax (Asia)
        
        Symptoms of malaria caused by cycles of parasite multiplication inside erythrocytes -> one cycle is initiated as a result of erythrocyte invasion by a merozoite form -cycle lasts 24-72 hrs depending on species
        
        intra-erythrocytic parasites transform into male or female gametocytes - are taken up by a mosquito - gametocytes fuse in mosquito midget lumen - motile zygote (ookinete) crosses gut epithelium to transform into oocyst in which 1000s of sporozoites develop - sporozoites pass through salivary gland cells to enter salivary ducts - after bite, motile sporozoites reach liver they invade hepatocytes - intra-hepatocytic sporozoite generates many hepatic merozites which re-enter blood and invade erthyrocytes
        
        treatment: artemisinin: first line treatment - combo therapy - no full resistance so far
        
        IMMUNE RESPONSE TO MALARIA (L16)
        
        Plasmodium falciparum is a protozoan parasite -> species of plasmodium that cause malaria in humans : P. knowlesi, P.viva, P ovale, P malariae - transmitted by female mosquito
        
        complicated life cycle -> daily cycles of chills, fever, sweating, RBC loss
        
        malaria transmission cycle: infcetion from mosquito bite - sporozoited enetr liver > merozoites in liver cells -> merozoited released -> RBCs infected -> ring form -> trophozoites -> schizont > gametocytes -> pass to another mosquito
        
        RBCs infected leads to RCB lysis and then anaemia
        
        immune system activated leads to control of malaria and adaptive immunity or inflammation, tissue damage and death
        
        pathology: diagnosis from characteristic rings in blood smear / mass destruction of RBC / kidney damage and engalrged spleen and liver - inflammation in spleen (as macropahes try to clear infected RBCs) / inflammattion in blood (infected RBC bind to epithelium - monocytes try to clear infected RBC - inflammatory cytokines -clots)n-> inflammation of vasculature is what causes death
        
        how it causes inflammation?: PAMPS, DAMPS -> INNATE CELL ACTIAVTION
        
        T CELLS CONTRIBUTE TO INFLAMMATION: Activation or lyssi of T and B cells -> immune cell and endothelial cell actiavtion -> t cell further actiavtion and feedback loop
        
        placental malaria -> abnormal placenta stucture / impairment of gases and nutrients transport / increased cytokines and complement activation
        
        adaptive immunity in malaria -> immunity can occur in some people -> killing of infected RBC by CD8+ T cells
        
        RTS, S/AS01 : Malaria vaccine -> targets sporozoites and liver stage - CSP protein immobilises parasite and prevents hepatocyte infection // contains hepatitis B surface antigen 'S'
        
        LIVER HAS A CENTRAL ROLE IN SYSTEMIC INNATE IMMUNITY
        
        Site of synthesis of : acute phase proteins, pentraxins (CRP), amyloid etc / serum mannose binding lectin / complement components / inflammatory cytokines w/systemic effects eg IL6,IL1 / cytokines w/regulatory effects eg IL10
        
        immune cells in liver: Kupffer cells, DCs, NK cells, CD8 T cells
        
        is a site of immunological tolerance to malaria