Abstract:
|
Agenetic basis for resistance to infection by intracellular pathogens was
proposed several years ago.1-6 This concept was confirmed upon the
positional cloning of the dominant autosomal gene Ity/Lsh/Bcg based on
its ability to confer on inbred mice an innate resistance to infection by
diverse intracellular pathogens.7 These include Salmonella typhimurium,
2 Leishmania donovani,3 and some species of Mycobacterium
such as M bovis5 and M intracellulare.8 Targeted ablation of Ity/Lsh/
Bcg9 or allelic exchange in susceptible mice10 confirmed its requirement
for resistance to infection. Ity/Lsh/Bcg encodes the phagocyte-specific
solute carrier 11a1 protein Slc11a1 (formerly Nramp1),11-13 which
restricts pathogen replication by inducing the expression of major
histocompatibility complex (MHC) class II molecules, cytokines (eg,
TNF ), and chemokines.14 SLC11A1/Slc11a1 belongs to a family of
polytopic membrane proteins whose functions include divalent cation
acquisition in mammals (DCT1/DMT1/NRAMP2),15 taste perception
in the fruit fly (malvolio),16 and stress signal transduction in plants
(EIN2).17 In mice, a single nonsynonymous mutation in Slc11a1 codon
169 determines resistance (Gly169) or susceptibility (Asp169) to
intracellular bacterial and leishmanial infections.7 Compared with
susceptible mice, macrophages from mice that are resistant to infection
also show increased oxidative burst and expression of the MHC class II
transactivator CIITA, and I-A antigen.18-21
Human genetic variation and disease association studies have
undergone a paradigm shift from mutation detection in susceptibility
genes to whole-genome scans for single nucleotide polymorphisms
(SNPs)22 and transcriptional analyses of the cognate genes to better
understand the evolution of complex traits such as disease risk. Cis
and/or trans-acting regulatory variation accounts greatly for quantitative
differences in such traits.23-31 Evidence suggests that structural variation
in candidate susceptibility genes (eg, due to mutations) cannot wholly
account for such differences. In most cases, there are no identifiable
mutations within such genes, including SLC11A1,32,33 yet there are
demonstrable phenotypic differences (eg, in resistance to infection). No
mutations occur in (human) SLC11A1 analogous to the functional
coding region mutation in the murine ortholog, despite the apparent
association of the gene with a variety of infectious and inflammatory
diseases, including tuberculosis and rheumatoid arthritis (reviewed by
Blackwell et al14,34). Disease association was found between specific
(noncoding) polymorphic loci that included introns and microsatellites
in both the 5 and 3 regions of the gene.32,35 Population-based
Submitted December 20, 2006; accepted June 13, 2007. Prepublished online
as Blood First Edition paper, July 2, 2007; DOI 10.1182/blood-2006-12-063289.
The online version of this article contains a data supplement.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734. |