Definitive identification ofa genethatconfers resistance against Toxoplasma cystburdenandencephalitis

SUMMARY Control ofresistance tocystburden following per-oral infection withToxoplasma gondii hasbeen mappedpreviously toa region ofmouse chromosome 17ofapproximately 140kb.Thisregion is contiguous withandcontains theclass Igene,Ld.Resistance todevelopment oftoxoplasmic encephalitis hasalsobeenreported tobecontrolled bygenesinthis region ofH-2.TNF-a, D andL genes,aswell asunidentified genes,arealsointhis region. Theworkdescribed here was performed toidentify definitively thegene(s) inthis140kbregion thatconfers resistance tocystsand encephalitis. Thestudydemonstrates thatrelative resistance toT.gondii organisms andcyst burdeninbrain, andtoxoplasmic encephalitis, 30daysfollowing per-oral T.gondii infection is correlated absolutely withthepresenceoftheLdgeneininbred, recombinant, mutantandC3H.Ld transgenic mice. MicewiththeLdgenehadlowercystburdens andless encephalitis thanthose without theLdgene.Specifically, 30daysafter infection micewiththeLdgene hadminimal perivascular inflammation andmeningeal inflammation andvery fewToxoplasma cystsor organisms inimmunoperoxidase-stained preparations oftheir brains. Micewithout theLdgene hadasimilar pattern ofinflammation, butinaddition theyhadcollections ofinflammatory cells in thebrainparenchyma. Freetachyzoites were foundwithin these foci ofinflammation andcysts werepresent inthese areasaswell asincontiguous areaswithout inflammatory cells. There were CD4+ andCD8+ T lymphocytes intheareasofinflammation andthroughout thebrain parenchyma. Micethat wereresistant tocystsandencephalitis hadlittle detectable brain cytokine mRNA expression, while micethat weresusceptible hadelevated levels ofmRNA for awide rangeof cytokines, consistent withtheir greater amountsofinflammation. Thepresent workdefinitively demonstrates that aL4-restricted responsedecreases thenumberoforganisms andcystswithin the brain andthereby limits toxoplasmic encephalitis andlevels ofinterferon-y (IFN-y), tumournecrosis factor-a (TNF-a), interleukin-2 (IL-2), IL-6, IL-10, transforming growth factor-f (TGF-fl), IL-la, ILllandmacrophage inhibiting protein (MIP)mRNA inthebrain 30daysafter per-oral infection.