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Module 3 > Module 2 references > Flashcards

Module 2 references Flashcards

1
Q

Neisseria

A

meningitis- Vieusseux Geneva 1805; Goldschneider- bactericidal antibodies; Virgi et al- addition of sialic acid to LPS- less complement; ab mediated killing; phagocytosis; CEACAM dysregulated by infalm cytokines- higher affinity between Opa; reverse vaccinology-Rappuoli; Bexsero- 75% against 85 strains->90% with adjuvants; menC- 81% carriage 199-2001; MenAfriVac- mass 2010; by end of 2011- no menA cases in several countries; MeNZB- 90% menB strain; decreased by >10% cases ; 10-30% serious sequelae; 10% mortality; 50% carriage isolates have capsule; Schnider et al- moelcular mimicry of FHbp; LPS >700ng/l almost always fatal; nsapharynx 20-40%; menB- incidence rate ratio by 50% in vaccine eligible cohort, irrespecitve of vaccination status or predicted mneB strain coverage- 2016 report; gonococcus- T4SS; GGI- singel stranded DNA into extracellular lieu; similar freq of GGI in asx and sympatomc ifection; allows survivial without Ton complex- iron acquisition and survival- in meningitides not known as genes are mutated or missing

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2
Q

Salmonella

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deletion of eitehr NLRP3 or NLRC4 increases susceptibility to infection KO SPI-2- reduce rplication index 0.5- Figueria; NOD2 KO- decreased inflam cytokines- Salucci; flagellin KO- imparied activation of casp1 and reduced death- Amer; autophagy- siRNA for gal8- 30/40 inc NDP52 80 inc with slamonella infection; Setpins recruited to curvature of dividn cells- Bridges et al. McGhie- persistent in gallbaldder and BM reseeding mucosal surfaces periodically; Hardt-SPI-1 stimualtes proinflam; non-replicating bacteria >50%- 15% relapase; Reddy- most common cause of bloodstream in Africa - 22-45% mortality; vireunce genes 3.5%; low pH-fur atr; small intestin- flg; lpf; penetrate epithelim- inv and spa; blood stream; rfb adn rfc; sopB-RhoGTPasesl Sip a and c- bacterial uptake spatal locatisation; Stapels et al.- SPI-2 modeulstes macrophage to promote longter mbacterial survival through STeE; Listeria- TLR2 reocgnisiton f lipoproteins or NOD1/2 peptiodyglcan; IL-1 or IL1R KO exacerbates and increases suscepibiltiy

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3
Q

S.aureus

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golden pigment inc antixoidant acitivty and prevents neutrophil killing- Liu; Pader et al- daptomycin (phosphatidylglycerol) inactivation by memrbane phospholipids; Tranum-Jensen- alpha haemolysin- pore-forming toxin works diff at low and high, low- bind to specfiic unidentified recetpor and pores- apoptosis; high- non-specificially uncontrolled Ca influc- necrosis;Peterson- apoB prevents AIP to argC sensor- mice deficiency more susceptible to invasive agr but not agr-; ETA cleaves dsg1 bewteen cadherin repeats Nishifuji; clumping factor- fibrinogen bidning (phago) and factor I; complement inhibitor- C3 convertase; staphylokinase- cleave Ig; protein A- bind Fc; FnBPs- allow adherence and invasion (FAK and Src, when FAK delet-no invasion) PVL- C5aR and C5L2; Dancer- ETs glutamate specific serine proteases; arD pro-autoinducing peptides; arB- transpore; agrC histidine kinase; agrA- P2 and P3; 30% colonisation; dsg folding needs calcium; bacteraemia mortality 20-40%; vanc resistant- conjugal transfer and transposition of vanA operon from enterococcus faecalis vs vac insensitive spont mutations (cell wall inhibitor, changed substrate); co-amox- C.diff 25% mortality in frail; dalfoprisint and linezolid- protein syntehsis inhibitors

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4
Q

TB immunity

A

Rees and Hart- chronically infected latent mice suscepbility to isonaizid so heterogenous latency; Ernst- mice defienctin both TLR2 and 9 fail to develop normal CD4 responses; Russell- phagosomes in macoaphges conatin live Mtb don’t fully acidify; Walberger- PknG promotes survival by blocking phagolysosomal fusion; NETs trap rather than kill mycobacteria (unlike gram -ve)- Braian; Neutrophilia increases mortality- Dallenga (protective- deliver bacilli in good form DC) or failure of Th1 as IFNy inhibitsIL-17 and neutrophil survival; B defiecnet mice increased immunopathology and neutrophilia- Kazkiewicz(opson inc phagolysosomal fusion); Siddiqui- latent express Acr1- increase tolerance moelcules; weak DC- less able to engulf–neutralisation of ACr1 is crucial; ESAT6 mutation linked to virulence- vaccine-Wards; Ernst- Mtb manipulate cell niche- avoid lysosomal mechanisms; virulence mechanism for cell-cell: ESX1 (typ 7SS) promotes necoris and inc uptake by neighboring cells; inhibits apoptosis; 50% clear; of 50%- 95% latent; epithelial cells TLR2 and TLR4; macaque model varying presentation; TLR2- LAM; TRL9- MTb DNA; MyD88 inc susceptibility; TLR4 stim with LPS inc autophagy; NLRP3- ESX1; IL10 KO have dec bacterial load in spleen and lungs; M.tb favours DCSIGN- IL-10 ; TNF KO- Mtb fatal- inc bacillary load; KO CD4/MHc-II inc suscetpiblity; CD1 KO in mice- no effect but dont have important isotype; KO yd T cells- enhanced susceptibiltiy; miRNAs- resulate innate response to M.tb; infection specific- Rothschild et al.- can distinguish active/LTBI; modulate atipahgy and apoptosis- host directed therapy; apoptosis- inactivate secA2 encodes superoxide dismutase inc apoptosis; necorosis- inc LXA4 and dec PDE2; Blomgram- TB inhibits apoptosis inhibiting apoptotic bodies by DCs; arg1 deficiency mic have better protection; PIM- H-subunit; PIMs- recruit Rab14 earlt endocomsm; aprABC locus- lipid synthesis; acid phosphatase- block fusion; Young- no biomarkers for latency; blood transcriptional signature- IFN genes- correlates with CXR disease; HIV- 10% risk/year vs 10% lifetime; small no. in LTBI- low yield and no resistane with IZD- below pson mutation freq; development of mutations in macaues with latent; PknG KO in lysosomes; MBL deficiency protect

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5
Q

TB drugs

A

first 1943 streptomcyin- Waksman; >95% efficacy; 80% sensitivity; Bedaquilline (first in 40 years)- EBA trial- inhibits ATP synthase; spuputm neg 83 vs 125 days but too small for stat signif reduced lung CFU; Gillespie- reMOX (moxifloxacin)- rapid decline in load that showed culture neg at 8 weeks when substituted for RIPE; shorterning of tx by 2mo nths rif- rpob gene (beta RNA pol); EMB 70% embB- arabinosyl transferase; fluoroquinolones- gyrA and gyrB; IZD- KatG catalase peroxidase; PYZ- pncA pyrazinamidase; introduced w/o targeting resistance mechanisms; RIF and PYZ- latent 2 months but hepatotoxic- inhibition of trans-translation- freeing up ribsosomes; drug tolerance to IZD and EMB reduced by pump inhibitor reserpine; verampamil inhibits RF pump and accelerates clearance; PnkG- AX20017- kill Mtb and requried for metabolic adaption in hypoxia; isocitrate lyases- needed for anti-oxidative defence; reducing tx- reduce tranmsission- 2 month regime math model in s.e asia- reduce deaths by 25% and 20% cases over 18 years; PA-824- signif bactericidal activity NO release- electron flow nad ATP homosstia and mycolci acid- with mox and PyZ superior bactercidal during 8 weeks vs standard in sus and MDR- phase III; rifapentine- reduced MIC and 5x half-life; induce durable cure afetr 3 months with once weekly in mice; but in huamsn inc relapse- increased dose?; rifaquin- moxi and rif- non-inferior at 6 months not 4 but only twice weekly; 30% treatment failure in MDR; delaminid- MDR mycobacterial cell wall- faster conversion and red mortality

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6
Q

TB vaccine

A

BCG- Calmette and Guerin 1921 first; Hesseling- risk of vaccinating HIV infected children may outweight benefits as protective effect unknown; Fine- BCG 0-80%; Brandt et al- decreased sensitisation in mice of BCG with environemntal TB; MVA-85A- Tameris- no efficacy despite Th1 and IFNy powerful viral vector of vaccinia antiara expressing Ag85a-lots of evidence in animals, currently trialled in HIV+ adults- correlatiosn with outcome to improve vaccine trials; M72- PPE and inactive protease in lipsoomal adjuvant- effective in 4 animals phase II- Penn Nicolson- immunogenicity and safety in HIV-ve adolescents; Kumarasamy- immunogenciity and tolerated in HIV+ adults; Gillard- phase II- immunogenic but high local hypsensitivity- stopped prematurely; VPM1002 (rBCG-urease C-listeriolysin) release of dsDNA sensed by AIM2 adn STING improved ag presentation- Saiga; phase IIa- inc CD8+ and IL-17+ T cells; IIa- HIV+ newborns; MTBVAC- PhoP ->2% genome and RadD26- enzymes in cell wall; immunogenic but not powered for outcomes- Sperlini; BCG booster- decreased TB 45.4% vs placebo;

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7
Q

TB general

A

Robert Koch- late 19th centry; Paul Erlich acid-fast (resist decolurisation with acidifed alcohol when stained with arylmethane); adapted by Ziehl and Neilsen; WHO end TB- 95% reuction by 2035; 1/3rd popultaion; lungs 80%; HIV don’t have positive sputum- improved with LED microscope; Xpert/RF- NAAT; HIV <100 or ill- LAM POCT; improve TST with RD1 antigens; IFny- stim with RD1 - poor predictive values (latent–active) END TB- 2035 incidence <10/100,000; 6000 years

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8
Q

HTLV1

A

Bangham- ectopic CTCG inserted into human genome- increased risk ofi nsertional mutagenesis; spread via virological synapse- Igakura; Laydon- median 30,000 clones per patient; Katsuya- survival for ATLL hasn’t improved from 80s-20s; Takasaki- chemo for chronic leukaemi is worse; HLA-A02; HLA-cW08- prevents 48% potential cases; KIR2DL2, Macnamara-50% reduction in developing HAM 3x dec in VL; CD4 inc CCL22-CCR4 on Tregs; HTLV1- STAT1 or p53; mitotic route 99.9%; evolution 1000x slower than HIV1; 2-6% ATLL; 1-4% HAM; McMichael- inverse between PVL and CTLs; predict cases of HAM based on strong binding in 55%; induces cytokine inhibitor SOCS1; 10^5-10^6 clonal populations; ATLL 5% 4 year survival; 95% CD4; Japanese- protective HLA alleles prevented 58% casesl 50% asx carrier have PVL>1%; SNPs in IL-6; IL-10 and TNF inc in HAM; 4:1 ratio HAM; walking aid 6 years; Martin et al- 4s increse/year in 10m timed walk; Tax can immortalise rat fiboroblasts in culture; 20% ATLL have GOF in CCR4- HBZ;

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9
Q

Leishmania

A

new technique- scraping for cut Leishmania- non-invaseive then DNA PCR for species- Taslimi; healing through Th1 IFN- OH-arg; L.arginine- reduces CD4/CD8 prolfieration and CD3 zeta; arginase T cell suppression; ornithine- polyamines-survival; arginase affinity higher in chornic patients than acute; higher in acute than healthy- Rafati; HIV inc arginase; reduced tx efficacy and increased relapses 30% visceral cases have HIV.. 350 million people infected;

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10
Q

Malaria

A

clinical immunity acquired fast in areas of higher transmission- Anderson and May; first pre-erthryocytic vaccine- RTS/ASO1- circumsporozoite- 40% efficacy from phase II; SSM-VMIT are trnamission blocking- altrutic; blods gametocyte phase I/II; 88% p. falciparum; 70 species of anopheles; half world population; 3x more deaths than armed conflicr 50% parasites don’t leave skin; passive transsfer studies of abs sucessfully treats severe malraia; Kurura- ab against MSP-1 wekaly but if both T cells with IFNy and abs- protection; sporozoites- circumsporozoites; merozoite-MSP2 and 3; infected RBC-PfEMP1; 2000-2015- 60% dec in mormtality; P.knowlesi; IRS and bed nets- 2/3rds of cases averted between 2000-2015; chemoprevention has been effective in reducing 80% and 50% mortality;

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11
Q

Viruses

A

Zharikova- SCID mice die 35 days post infection but WT restore normal fx; DeVincenao- symptoma high each day depsite VL dec; Lot100- vaccine unsuccessful in prevention with formalin-inactivated RSV, children higher hospitalation rate 78 v 5

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12
Q

Mouse models

A

Dorner et al- first immunocompetent mouse for HCV; huamnised mice susceptbilit to HIV, Bnabs durably suppress- Klein; Rongavaux- MISTRG mice- IL-3; GM-CSF, thrombopoeitin- functional NK cells; Evans- huaminsed mice cannot recapitulate as need high titres vs normal low doses in trnamission

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13
Q

Fungal infections

A

Romani et al- Pentraxin 3 handling of Aspergillus conidia, def inc susceptibility; A fumgates- mainly TLR4/MyD88; >180 species but 38 survive at body temp; 85-90% aspergillus is fumigatus; macrophage depleted mice aren’t more suscepibiltiy to infeciton; single cell-coiling phagocytosis- IL-12; hyphae- cipper type- IL10; TL4- pulmoanry aspergillus; ABPA- TLR9 polymorphisms; dectin 1- suscepibility to invase disesse instem cell tranplnts; CARD9-chornic mucocutanous candidasis; eosinhopsil- reudced clearance; IL-17A full eosinohpilic recruitment; 10% asthmatics positive on skin prick; New Orlenas- increased admission; Chicago- inc asthma; damp hosuing and inc admission; invasive -10-15% BMTs;

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14
Q

immune system

A

deletion of MyD88- profound bacterial, fungal infections and death;Franchi et al- use adaptor ASC; Schroder- 3 models for NLRP3 activation- NLRP3 leads to ROS and act; ATP to P2S7-K efflux- pennxin1 memrbane pore allows external agonist in; lysosomal damage Shigella- manipulates mitocnohdria- Friedman and Nunnari

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15
Q

Resistance

A

A.Fleming; MRSA-SCC element mecA; Lister- Pseudomonas- fluoroquinolone ressitance- overexpression of efflux pumps; Skold et al- inc production PABA ressitance to sulfonamides, outcompetes sulgonamides for binding to DHPS, e.g Ecoli

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16
Q

Bacteriophage

A

discovered-Hankin; antibacterial activity- Twort; first for dysentery-1919; Testz- increase intesntial permeability- chronic inflam- not pathogenic?; Dubos- phages can pass thorugh BBB- meningitis tx?; Hajitou- AAVP novel hybrid vector; Pet Dogs- bacteriopahge efficacy in spon soft tissue sarcomas- stopped grwoth;

17
Q

HIV general

A

HIV transmission- Hahn- one quasispecies will infect and thrive; Li - CRISPR/Casp9 with adnovirus vector to cause CCR5 KO; Cavazzana-Calvo- X-SCID with retroviruses with leukaemia; Fadel- LEDGF KO reduction in HIV integration, in cytoplasm; 90% red in infection efficacy ; WHO 90-90-90: know HIV status; on ARt; VL suppressed by 2020–21 mill deaths; 1959- case; 1983 discovery; 10^11 virions a day; env mutations 1% individual 25% average between; 99% is CCR5; gp41- pre-hairpin intermediate–fusion pore; 25 days- all over body; endogenous -8-12 % ; Vpr- nuclear import; Mitchell et al.- HIV targets transcription units 73% vs 31%; Decaon et al.- group of pts from same attenutaed virus all low viramie for years; females have lower av HIVrNA; HLA-B57 ; 95% positive at month with 4th generation test

18
Q

Immune response

A

loss of MALT- gut permeability- inflam-Brenchley; bnabs- <1%; polyreactive; hypersomatic mutation; long CRDH3 grousp; rare structural motifs; Beck- infectiveity inc by complement opson-CR2; Holmgren- expression of mucosa IgA differ after routes of vaccination; orginial antigenic sin; CD55- C3b for factor B; CD59- MAC; gp120/41 bind factor H; Fletcher et al- drug levels lower in LNs than blood; inc reservoir- inc clinical progression of viral rebound; HIV inc IDO by DCs; incomplete reverse trnascripts- HIV DNA which cause intesne inflam and local death; directly harm stem cells nad thymus; non-neutrlaising- nonfunctional; 40-50% glycsylation of gp120; Vif- APOBEC- Sheehy (cytidine deaminase- induced by type I IFNs); Vpu- counteracts tetherin; Nef- redcues CTLA4 and MHC-I- T cell prolfieration and inhibit CTL; decreases Bad (proapoptosis); Vpr- SAMDH1- limits deoxynucelotides for cDNA; TRIM5a- mutates caspid; viraemia- inversely assoc with gag-sepcific CTL; ECs- CTLs better function; prolfeiration; perforin; multiple cytokines; macaques- CD8 cells rapid return of SIV; KIR-3DL1; polymorphisms in TLR9; 50% controllers have no HIV-specific CD4 T cell activity; Felley- GWAS 2 genetic polymorphisms 15% variability in viral set point; inhiibts Jak/Stat signalling; activates DNA-PK; protease- caspase mediated apoptosis; Kenyan HIV-1 resistant workers ahev HIV-1 specific IgA in genital tract;

19
Q

HIV vaccines

A

VRCO1- CD4bs but modest effect on viral rebound, trialling VRCO1LS- longer half life; RV144- IgA in sera- 31% protection, 6-12m 61% but controversy with trial stat analysis- no CD4 count or VL effect- non-neutralising effective; bnabs- macaques prevented infection; humans- delay to 19weeks va 2.6, act as anti-viral dec VL by 2.5 logs; HIV prevention- Coates ; HIV superinfection- immune response not protective; DC primed vaccines no success; Dosenovic- murine models giving succession of immunogens to mimic hypermutation; APPROACH- mosaic Ad26/Ad26 and booster; 1 year- env ab-100%; ADCP-90%; T cells 83%-protection? macaques 67%. in phase IIb in Africa

20
Q

HIV cure

A

Visconti cohort- started wtihin 10 weeks and off ART maintained low VL for upto 10 years; Thaailand within 2 weeks- no control CLEAR study- histone deacetylase inhibitor inc latent viral replication; RIVER- histone deactylase, ART and boost- no difference in reservoir ; Shan- reversal of latency not sufficient to induce cytopathic effect - reinvigoration of anergic HIV CTLs; SIV- TLR7 agnosit and bnab- substantial delay and controlled viral replciation; Gene therapy using CRISPR Casp to dirupt HIV genome Berlin patietn 3 days- latency establish; combination bnab- extend viral rebound to 30 weeks;

21
Q

Mother to child transmission

A

1.5 mil HIV women get pregnant; 45% trnamsision without tx; overall UK-1%, but 0.1% if HAARt and VL 50; at 100,000 VL, AZT reduces 63% to 40%- Garcia et al.; prelabour C/S reduce 80% without otehr interention; on HAARt no diff; Peters- MTCT over all durations is 0,13 if HAART. Townsend- 0% MTCT if on AZT nad prelabour C/S. breastfeeding MTCT <1% if HAART. Gray et al- pregnant women 2x susceptible for HIV; Peters- higher T if prolonged memrbane rupture; AZT- 51% reudction in T; WITS cooper- HAARt 1.2 vs no tx 20%; Read- start ART before 24 weeks; Rouzioux’s model 95+ infants; 95% by 2 months- 65% day of delivery; PROMISE- inc 50% in PTB esp PI esp; started pregnancy; Short et al.- dec in IL-10 and IL-4 on ART and worse with PI; Short- higher anaerobes on ART- assoc with PTB;

22
Q

ART

A

HLA-B57 abacavir hypersensitiy- Mallal 14/18; Concorde- AZT va placebo- reduction in VL and inc CD4 but effect stopped after a few weeks- ressitance; trple therapy in 1997, AIDS incidence in 1998 dec 75%; CASCADE- av rate of CD4 ddec off ART is 67 cells.year; START- enhanced CD4 recovery with early ART 60% red in AE or death; PARTNER- VL laod is most ciritcal determinant of onward tranmssion ofer PrEP until VL udetectable; SMART- CVD and RFs linked to poorer cognitive performance; Kirtane- week long ARt pill in pig; time-of addition: 1h-entry; 3h-RTI; 7-integrase; dextran sulphate; maraviroc; T20; AZT (thymidine analogue)- anamia; hetaptic steatosis; lactic acidosis; tenofovir- TAF reduces kidney and bone toxcity; general NRTIs- mitconohrdrial otxicity; lipoatrophy and lactic acidosis; NNRTIs ( efavirnenz)- rash; hepatotoxicity nad CNS; integrase- CNS-insomnia; raltegravir; protease- CYP 3A4

23
Q

HIV prevention

A

Coates- biomedical; social justice/huamn rights; condoms -80% in heterosexual and 80% for MSM; 50% unaware of HIV status; HAART/STIs; behavriou change; Gray- circumcision 57% reduction; Burns- oral PrEP approved by FDA ; PROUD- 86% reduction; IPERGAY- on demand- 86% red; 2 tab befroe; 1 24h and 1 48h- increased GI and renal; ASPIRE- dapivirine ring- 27% protection but 56% if remove 18-31; CAPRISA- tenofovir gel- 39% at 30 monts; 74 countries criminalise homosexuality UN-AIDS by 2030 none; Swiss statement- no risk of tranmission with VL; genital ulceration-5x inc in tramission; rectal mucosa-only one layer of columnar-toxicity; UK has stated it wll prevent tranmsision in next 10 years;

24
Q

HIV comorbidites

A

POPPY- increased CVS; CNS; resp and reduced BMD; SMART- high inflam-CRP; IL-6 and inc MIs and stroke; USA trial- functioanl impairment linked to high inflam markers; REPRIEVE- statin; POPPY- incr depression and suicide; Fabbiani- CVS risk factors strongly linked to lower cognitive fx; tobacco 2/3x; 1.5-2x risk of CVD in HIV when controlling for other factors; multicentre AIDs cohort study- men4x prevalence of DM; HIV-PPARy and inc sensitivity to glucocorticoids; lipoatrophy- beta-cells; HIV-infected women less iprovment with soame weight loss; less improvementi n Hba1c with metformin; increased #s at all ages; BMd-esp child; HIV proteins and PI- increase oxidative stress in MSCs ; approx prevalnce of HAD in adv HIV 20%; NRTIs- best CSF penetration and reudced HAD; ARt toxicity- efavirenz-HAD; gp120 and gp41 glutamate pathway- add gp120 to cultures get same dendritic alteration; >50% get cognitive impirment; functional studies- has to activate more widespread regions for same performance; SIV- assoc with infiltration of CD8 cells; highest RF for suicide- not being on ART;

25
Q

OI

A

early ARt favoured in tx of all OIs- Zopola; Roths and Sidmann- CD4 transferred into SCID mice with PCP; Wright- CD4/8 deplted mice inc pathogen but normal lung; CD4 depleted mice severe lung injury- reconstituion- same disease but pathogen clearance; Selwyn- HIV increases risk of reactivation of latent TB; IL-1 and TNF KO- no clearance nad requried for CD8 injury; higher mortality in PCP in non-AIDs; CMV retinitis-70%; pre-ARt-40% got; CMV <100; 40% peripheral CD8 CMV specific; adoptive transffer of CD8- intiate clearance in 8/9 stem cell transplants; 30 days for diagnosis with cryp; 40% abnormal CSF cell count and protein wtih crypt; normal imaging; opening pressure raised; inc mortality if ARt started within 72 horus; Th1 repsonses needed for immunity against crypt; 5-10% before ARt;

26
Q

Viruses

A

hepatitis -7th; IVDU HIV+ with HCV- 83% vs MSM-7%. 100 new cases/year; 15% HIV due to liver, hepc- 2/3rds of that; HCV-5-20% spon clearance; after 30 years-30% no evidenec; 40% fibrosis; 30% cirrhosis; poynard- HIV/HCV coinfected had fastest progression to fibrosis and cirrhosis out of otehr cohorts, even on HAARt; SVR rate at 12 weeks is 94-99%; resp viral infections 21% of all deaths via commmunivable iease; 59% of gP consultations in 1999. Spanish flu- 50-100million deaths; colds- 17% GP consultations; SCID mice die of infection after 35 days- Zhonora; hospitalisation after vaccine 78% vs 5%.

Module 3 (33 decks)

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