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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.

Killing of Mycobacterium smegmatis by macrophages from genetically susceptible and resistant mice.

The bactericidal function of macrophages was investigated in congenic mice expressing the phenotype of susceptibility (B10.A, Bcgs) or resistance (B10.A.Bcgr) to mycobacterial infection. When splenic and peritoneal macrophages from these two mouse strains were infected in vitro with Mycobacterium smegmatis, the Bcgr macrophages were shown to inactivate M. smegmatis more efficiently than their Bcgs congenic counterparts. The mechanisms of this superior antimycobacterial activity was studied further. Addition of catalase did not abolish killing to a significant degree in either allelic type of macrophage, suggesting that hydrogen peroxide production was not involved in the killing activity controlled by the Bcg gene. Activation of Beg macrophages by exposure to crude lymphokines rendered them equally as efficient as their Bcgr counterparts in their capacity to destroy M. smegmatis. This finding suggests that both the genetically resistant and susceptible macrophages have the potential to kill M. smegmatis in vitro. This potential is expressed constitutively by the Bcgr but not Bcga macrophages and can be induced, by lymphokine treatment, in the Bcga macrophages. In a final set of experiments, the macrophage killing of M. smegmatis was evaluated as a test system to type for the Bcg gene allelic type in vitro, using a set of AXB and BXA recombinant inbred strains of mice. Results obtained show that typing of AXB/BXA recombinant inbred strains for the trait of bactericidal activity vs. M. smegmatis in vitro revealed a perfect match with the strain distribution pattern of resistance/susceptibility to Mycobacterium bovis BCG in vivo.

Genetic basis of host resistance and susceptibility to intracellular pathogens.

History provides numerous examples of variable susceptibility of human populations to viral, bacterial and parasitic infections, both during epidemics and in the endemic areas of the world. Although the influence of environmental factors must be considered in any explanation of such variability, it has recently become clear, mainly on the basis of studying experimental infections in inbred animals, that genetic factors play decisive role in individual susceptibility.

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.