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S1- Antigen persistence in liverstages is not required for protection
Directly contradictory data ADDIN EN.CITE Mueller200732932917Mueller, A. K.Deckert, M.Heiss, K.Goetz, K.Matuschewski, K.Schluter, D.Genetically attenuated Plasmodium berghei liver stages persist and elicit sterile protection primarily via CD8 T cellsAm J PatholAm J Pathol107-151711GAP, liverstage antigen, window antigen2007dataLabaied20071240124017Labaied, M.Harupa, A.Dumpit, R. F.Coppens, I.Mikolajczak, S. A.Kappe, S. H.Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109-5219, USA.Plasmodium yoelii sporozoites with simultaneous deletion of P52 and P36 are completely attenuated and confer sterile immunity against infectionInfect ImmunInfect Immun3758-68758AnimalsCulicidae/parasitologyCytoplasm/parasitologyDisease Models, AnimalFemaleGene DeletionGene TargetingHepatocytes/parasitology/ultrastructureMalaria/immunology/*prevention & controlMiceMicroscopy, Electron, TransmissionMicroscopy, FluorescencePlasmodium yoelii/genetics/growth & development/*immunology/*pathogenicityProtozoan Proteins/*genetics/immunologyRatsRats, WistarSporozoites/*immunologyVacuoles/parasitology2007Aug17517871Tarun200746946917Tarun, A. S.Dumpit, R. F.Camargo, N.Labaied, M.Liu, P.Takagi, A.Wang, R.Kappe, S. H.Protracted sterile protection with Plasmodium yoelii pre-erythrocytic genetically attenuated parasite malaria vaccines is independent of significant liver-stage persistence and is mediated by CD8+ T cellsJ Infect DisJ Infect Dis608-161964CD8+ response, liverstage, independent, GAP, p36, p522007datashows persistant liverstage parasite not actually neccessary for immunization- supports my notion that it is actually antigen presentation that is required. ergo, PQ treatment eliminates parasites but also blocks membrane trafficking and antigen presentation, so people have seen parasite elimination and attributed cause of lack of immunity, whereas it is actually antigen presentation that is blocked that blocks immunity
NB also, people going on about CD8 cells and IFN-g, but IFN-g is not required (zavala 2008) so looks like the induction of CD8 Tregs is what is happening in liver. there is likely to be big mix-up in lit; I'd better take a close look at the data hereScheller1995565617Scheller, L.F.,Azad, A.F.Maintenance of protective immunity against malaria by persistent hepatic parasites derived from irradiated sporozoitesProc Natl Acad Sci U S AProc Natl Acad Sci U S A4066-8929window antigens, window proof, liverstage, liverstage antigens, vaccination, memory?, tolerance, persistence, hepatic, liver, sporozoite, hepatic stages, Tcell response,1995[165,166,171,267] is also easily reconciled. Like increasing irradiation ADDIN EN.CITE Vanderberg19681452145217Vanderberg, J. P.Nussenzweig, R. S.Most, H.Orton, C. G.Protective immunity produced by the injection of x-irradiated sporozoites of Plasmodium berghei. II. Effects of radiation on sporozoitesJ ParasitolJ Parasitol1175-80546AnimalsImmunity, ActiveLarva/radiation effectsMalaria/*immunologyMicePlasmodium/*immunology/radiation effects*Radiation EffectsRats1968Dec5757691Scheller1995565617Scheller, L.F.,Azad, A.F.Maintenance of protective immunity against malaria by persistent hepatic parasites derived from irradiated sporozoitesProc Natl Acad Sci U S AProc Natl Acad Sci U S A4066-8929window antigens, window proof, liverstage, liverstage antigens, vaccination, memory?, tolerance, persistence, hepatic, liver, sporozoite, hepatic stages, Tcell response,1995[149,165], the drug primaquine (PQ) eliminates liverstages ADDIN EN.CITE Belnoue200410510517Belnoue, E.Costa, F. T.Frankenberg, T.Vigario, A. M.Voza, T.Leroy, N.Rodrigues, M. M.Landau, I.Snounou, G.Renia, L.Protective T cell immunity against malaria liver stage after vaccination with live sporozoites under chloroquine treatmentJ ImmunolJ Immunol24872495172sporozoite, live, attenuated, CD4+, CD8+, protection, liver, chloroquine, CQ, PQ, vaccine,TLR9, liverstage, window antigen, dose response, threshold, 4-amino-quinolone, 8-amino-quinolone, skin, irradiated, mouse, i.v, challenge, vaccine, excellent, quot2004mauricio 2004, really great on irrad spz gene expression profile
link to Orjih 1985, which shows CQ MUST BE GIVEN PRIOR TO LIVER INFECTION TO HAVE EFFECT ON FUTURE IMMUNITY,but together with Mauricios paper shows that there is a dose effect to the immune response. Maauricio (this paper) uses higher dose of parasites to immunize, at lower dose he also does not get immunity after 2-4 months.
if given after, no immunity on challenge: so response must be in place. but also must be sufficient magnitude. Dose response to immunizing dose.
also slight unmasking of bloodstream response; ie response to late liver stages. So parasite really needs to knock that out to survive, so, it does the LN trick.Mueller200732932917Mueller, A. K.Deckert, M.Heiss, K.Goetz, K.Matuschewski, K.Schluter, D.Genetically attenuated Plasmodium berghei liver stages persist and elicit sterile protection primarily via CD8 T cellsAm J PatholAm J Pathol107-151711GAP, liverstage antigen, window antigen2007data[47,166]. PQ however, also disrupts membrane and vesicular trafficking ADDIN EN.CITE Reid198950450417Reid, Pamela A.,Watts, ColinCycling of cell-surface MHC glycoproteins through primaquine-sensitive intracellular compartmentsNatureNature655-657346PQ, antigen presentation, cross-presentation, exogenous antigen, pDC, CQ, MHC I, MHC II, liver, skin, Treg, endosome, membrane trafificking1989datavan Weert200080680617van Weert, A. W.Geuze, H. J.Groothuis, B.Stoorvogel, W.Primaquine interferes with membrane recycling from endosomes to the plasma membrane through a direct interaction with endosomes which does not involve neutralisation of endosomal pH nor osmotic swelling of endosomesEur J Cell BiolEur J Cell Biol394-9796PQ, membrane trafficking, DC, pDC, get2000[159,268], temporarily eliminating all antigen presentation. This prevents immunity if used during immunization ADDIN EN.CITE Mueller200732932917Mueller, A. K.Deckert, M.Heiss, K.Goetz, K.Matuschewski, K.Schluter, D.Genetically attenuated Plasmodium berghei liver stages persist and elicit sterile protection primarily via CD8 T cellsAm J PatholAm J Pathol107-151711GAP, liverstage antigen, window antigen2007data[166], creating an apparent correlation between protection and parasite persistence ADDIN EN.CITE Mueller200732932917Mueller, A. K.Deckert, M.Heiss, K.Goetz, K.Matuschewski, K.Schluter, D.Genetically attenuated Plasmodium berghei liver stages persist and elicit sterile protection primarily via CD8 T cellsAm J PatholAm J Pathol107-151711GAP, liverstage antigen, window antigen2007data[166]. Used after intravenous immunization ADDIN EN.CITE Putrianti200963763717Putrianti, E. D.Silvie, O.Kordes, M.Borrmann, S.Matuschewski, K.Dr. Kai Matuschewski,
Parasitology Unit, Max Planck Institute
for Infection Biology,
Charitщplatz 1, 10117 Berlin, Germany
matuschewski@mpiib-berlin.mpg.deVaccine-like immunity against malaria by repeated causal-prophylactic treatment of liver-stage Plasmodium parasitesJ Infect DisJ Infect Dis899-90319962009[129], allowing early liverstage antigen presentation, however, multiple PQ-cure cycles provide sufficient cumulative antigen presentation to build immunity, without antigen persistence.
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