Philippe Gros

Regulation of resistance to leprosy by chromosome 1 locus in the mouse.

Mice of different inbred strains vary in their resistance to intravenous infection with Mycobacterium lepraemurium (MLM). The mean survival time of MLM-infected A/J and DBA/2 mice is significantly longer than that of similarly infected C57BL/6 and BALB/c mice. The typing of AXB/BXA recombinant inbred strains (A = A/J, B = C57BL/6) for the trait of relative resistance/susceptibility to MLM revealed a perfect match with the strain distribution pattern of resistance/susceptibility to Mycobacterium bovis (BCG), the trait which is controlled by the Bcg (Ity, Lsh) locus on chromosome 1. The control, by this gene, of response to MLM was further confirmed by the demonstration that BALB/c-Bcgr congenic mice,which carry the DBA/2-derived Bcgr (resistant) allele on chromosome 1, are significantly more resistant to MLM infection than their BALB/c (Bcgs, susceptible) counterparts.

Genetic control of innate resistance to mycobacterial infections

The Mendelian segregation of resistance to infection in different strains of mice infected with mycobacteria, Salmonella and Leishmania spp, all of which live in macrophages, is currently under close scrutiny. Here, Erwin Schurr and colleagues review the nature and function of the Bcg gene in controlling innate resistance to mycobacterial infection in mice and speculate on the occurrence of a possible human equivalent.

The Lps locus: Genetic regulation of host responses to bacterial lipopolysaccharide

Abstract. Lipopolysaccharide (LPS), an abundant glycolipid of the outer membrane of Gram-negative bacteria, is able to provoke a generalized proinflammatory response in the infected host. Genetic regulation of this trait has been localized to the Lps locus on mouse chromosome 4. Several inbred mouse strains, including C3H/HeJ, C57BL/10ScNCr and C57BL/10ScCr, bear mutations at the Lps locus (Lpsd) that confer hyporesponsiveness to the immunostimulatory properties of LPS and susceptibility to overwhelming Gram-negative bacterial infection. The phenotypic expression of Lpsd is pleiotropic, affecting several cell types crucial to host defense, including the macrophage. By positional cloning, Toll-like receptor 4 (Tlr4), a transmembrane protein with a cytoplasmic domain that bears homology to the Interleukin-1 receptor, has been identified as the gene encoded by Lps. Tlr4 is a member of a novel gene family that participates in host defense against microbial infection in plants, invertebrates and mammals. Discovery of the molecular basis of the Lps mutation represents a significant advance in defining the fundamental mechanisms of cellular activation by LPS.

Identification of a highly polymorphic length variant in the 3'UTR of NRAMP1

Natural resistance to infection by intracellular parasites such as Mycobacteriae, Leishmaniae, and Salmonellae in the mouse has been shown to be controlled by a single gene named Bcg/Lsh/Ity located on mouse proximal chromosome 1 (Blackwell 1989). A candidate gene for Bcg, Nrampl, or natural resistance-associated macrophage protein-1 was identified and predicted to encode a macrophage-specific polytopic membrane protein (Malo et al. 1994; Vidal et al. 1993). The human homologue NRAMP1 was recently cloned and its genomic organization was established (Cellier et al. 1994). Located on chromosome 2 region q35, NRAMP1 contains at least 15 exons and spans a genomic length of approximately 14 kilobases (kb). Predicted amino acid sequence analyses indicate that the NRAMP1 gene encodes a 550-amino acid membrane protein with ten to twelve putative transmembrane domains, two N-linked glycosylation sites, and an evolutionarily-conserved consensus transport motif (Cellier et al. 1994). Single-strand conformation analysis and direct sequencing have thus far revealed nine polymorphisms and sequence variants which are useful markers in genetic analyses of NRAMP1 in susceptibility to infectious diseases (Liu et al. 1995). In the present study, the 3 untranslated region (UTR) of NRAMP1 was isolated in the search for additional alleles. Sequence analyses of this region identified a highly polymorphic 4 base pair (bp) insertion/deletion at the poly A tail of an Alu element.

Host response to infection with mycobacterium bovis (BCG) in mice: genetic study of natural resistance.

Resistance of mice to several infectious agents has recently been shown to be under simple genetic control (reviewed in 1). Genetic differences in the response of outbred and inbred mice to infection with mycobacteria such as Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium lepraemurium have been noted for many years (2,3). We have recently reported that clear segregation of resistance and susceptibility to Mycobacterium bovis (BCG), exists among mice of inbred strains infected with a single intravenous dose of this bacillus (4). The present study deals with detailed genetic analysis of the trait of BCG resistance.

CHROMOSOME 1 LOCUS : A MAJOR REGULATOR OF NATURAL RESISTANCE TO INTRACELLULAR PATHOGENS

Publisher Summary Natural resistance to infection with several intracellular pathogens— both bacterial and protozoal—has recently been demonstrated to be under genetic control. The ability of genetically-resistant mouse strains to prevent growth, in the reticuloendothelial tissues, of Mycobacterium bovis (BCG) is controlled by a single, dominant, autosomal gene designated Bcg. In a study described in the chapter, mice of 17 inbred strains were infected intravenously with 10 4 CFU of M. bovis (BCG) and Bcg typed 3 weeks later as either resistant (r) or susceptible (s) according to the level of bacterial burden in their spleens. Because the strain survey and the analysis of recombinant inbred strains suggested a close linkage (or identity) of Bcg, Lsh, and Ity genes, a formal proof was sought by the examination of individual animals obtained from a segregating population for the distribution of the three phenotypes in question. Twenty-six backcross animals and the appropriate parental and F 1 hybrid controls were infected with BCG and they were splenectomized three weeks later for Bcg typing. The recent availability of mouse strains that are congenie except for the Bcg (Lsh, Ity) gene should greatly enhance the functional studies on the phenotypic expression of this gene.