02795nas a2200421   4500000000100000008004100001260001300042653002400055653001200079653002100091653003000112653003800142653001100180653002600191653001800217653001200235653002600247653002200273653000900295653002800304653002900332653001700361100001800378700001500396700001400411700001400425700001300439700001800452700001300470700001300483700001500496700001400511245010600525300001100631490000700642520171000649022001402359       1994                            d  c1994 Dec10aAmino Acid Sequence10aAnimals10aCarrier Proteins10aCation Transport Proteins10aGenetic Predisposition to Disease10aHumans10aIron-Binding Proteins10aLeishmaniasis10aleprosy10aMacrophage Activation10aMembrane Proteins10aMice10aMolecular Sequence Data10aMycobacterium Infections10aTuberculosis1 aBlackwell J M1 aBarton C H1 aWhite J K1 aRoach T I1 aShaw M A1 aWhitehead S H1 aMock B A1 aSearle S1 aWilliams H1 aBaker A M00aGenetic regulation of leishmanial and mycobacterial infections: the Lsh/Ity/Bcg gene story continues.  a99-1070 v433 a<p>A common basis to genetic regulation of leishmanial and mycobacterial infections is provided by the action of the murine Lsh/Ity/Bcg gene in controlling the priming/activation of macrophages for antimicrobial activity. This relies on the TNF-alpha-dependent sustained expression of the inducible nitric oxide synthase (iNOS) gene responsible for the generation of large amounts of toxic nitric oxide (NO). The Lsh/Ity/Bcg gene has many pleiotropic effects, including differential expression of the early response gene KC following stimulation of macrophages with bacterial lipopolysaccharide (LPS) and mycobacterial lipoarabinomannan (LAM). The major signal transduction pathway involved in KC induction requires the generation of low levels of NO via constitutive nitric oxide synthase (cNOS) activity, leading to activation of guanylate cyclase and the cGMP-dependent kinase pathway. NO therefore appears to provide a common link between the early influence of Lsh in regulating the expression of genes which mediate many pleiotropic effects, and the later production of NO as the final effector mechanism for kill. The recently cloned candidate for Lsh/Ity/Bcg, designated Nramp for Natural resistance associated macrophage protein, encodes a polytopic integral membrane protein that has structural features common to prokaryotic and eukaryotic transporters and includes a conserved binding-protein-dependent transport motif which may be involved in interaction with peripheral ATP-binding subunits. The N-terminal sequence also carries a proline/serine rich putative SH3 binding domain, consistent with a role for tyrosine kinases in regulating Nramp function. (ABSTRACT TRUNCATED AT 250 WORDS)</p>  a0165-2478