Genetic control of the murine corneal response to Pseudomonas aeruginosa.

Inbred mouse strains differ in susceptibility to intracorneal challenge with Pseudomonas aeruginosa. Genetic studies indicate that resistance to corneal infection is dominant over susceptibility and is controlled by autosomal genes, at least one of which is located outside of the H-2 locus. On the basis of genetic complementation studies, the susceptible strains BALB/c and C57BL/6 each bear one resistance gene, since the F1 hybrid (BALB/c X C57BL/6) was uniformly resistant to infection.     

Genetics of murine resistance to Trypanosoma cruzi.

Resistance to the protozoan parasite Trypanosoma cruzi is governed by multiple genetic factors, including at least one coded for by a locus in or near the major histocompatibility complex of the mouse. The influence of the H-2 locus on resistance was evident when H-2 congenic mice on a strain background of intermediate resistance were challenged or when the survival of H-2 typed F2 mice was followed. The H-2k haplotype of the susceptible C3H/An strain was associated with higher mortality when compared with the H-2b haplotype of the resistant C57BL/10 strain. Genetic studies showed that resistance was a dominant trait and increased with genetic heterozygosity. F1 mice derived from crosses between resistant and susceptible strains, or even between two susceptible strains, were much more resistant than either parent. Crosses between two resistant strains, C57BL/6J and DBA/2J, led to resistant progeny in the F1 and F2 generations; but when recombinant inbred strains derived from these parental strains were challenged, susceptible strains were identified, indicating that different genes were responsible for resistance in the two strains.     

Role of the H-2s haplotype in survival of mice after infection with Trypanosoma cruzi.

In studies of the resistance of inbred mice to infection with Trypanosoma cruzi Peru, mouse strain B10.S was the only strain which survived the infection resulting from the inoculation of 10(3) trypomastigotes. This is the only inbred mouse strain studied to survive infection. To investigate the effect of the H-2 haplotype on survival, C57BL/10 congenic mouse strains bearing H-2S recombinant haplotypes and mouse strains A.SWSn/J and SJL/J were tested for their ability to overcome the T. cruzi infection. None of the recombinant strains tested, including B10.S(7R), B10.S(8R), B10.S(9R), and B10.HTT, survived the infection, indicating that at least two or more regions of the H-2 locus must be H-2S to ensure survival. Strains A.SWSn/J and SJL/J with the H-2S haplotype did not survive, indicating that the genetic background outside the H-2 complex also influences survival. The congenic F1 hybrid (C57BL/10 X B10.S) F1 exhibited intermediate survival levels when compared with the parental strains, indicating that H-2S survival is affected by gene dosage. The F1 hybrid strain [B10.S(7R) X B10.S(8R)]F1, which possesses the complete H-2S haplotype in the trans configuration, did not survive T. cruzi infection, suggesting that H-2S-mediated survival does not operate by trans complementation.     

Polyoma tumorigenesis in mice: evidence for dominant resistance and dominant susceptibility genes of the host.

We have determined the tumor responses of nine inbred mouse strains and of two F1 hybrids following inoculation with polyoma virus. The results showed wide variations in the frequencies of mice developing tumors. Correlation with H-2 haplotype were evident. C3H/BiDa mice of H-2k type were fully susceptible, while C57BL/6 mice of H-2b type were completely resistant. DBA/2 and BALB/c mice, both H-2d, were of low susceptibility. Contributions of the major histocompatibility complex were demonstrated using pairs of H-2 congenic mice. Substitution of H-2k on either a BALB/c or a C57BL/10 background resulted in an increase in the frequencies and kinds of tumors induced. Susceptibilities of BALB and C57BL mice bearing the H-2k haplotype were still well below those of C3H/BiDa mice, however. Crosses of C3H/BiDa with BALB/c or BALB.K (H-2k) produced F1s that were of moderate and full susceptibility, respectively. These results indicate two distinct classes of host genes, one at the H-2 locus where different alleles confer varying degrees of resistance and the other a dominant susceptibility gene(s) carried in C3H/BiDa mice.     

Resistance and susceptibility of mice to bacterial infection: genetics of listeriosis.

A survey of various strains of mice showed distinct differences in resistance or susceptibility to Listeria monocytogenes. C57B1, related sublines, NZB, and SJL were resistant to Listeria, whereas BALB/c, CBA, A, DBA/1, C3H, LP.RIII, 129, and WB were susceptible. The gene(s) responsible for resistance and susceptibility to Listeria were studied in detail. C57BL6/6, B10.D2, and B10.A mice were 100 times more resistant than were BALB/c, CBA, and A. Resistance of the (C57B1/6 X BALB/C)F1 was intermediate between the two parents, suggesting partial penetration of a dominant gene. Backcross studies in which the (C57B1/6 X BALB/c)F1 were crossed with the susceptible BALB/c parent suggested that a single gene or group of linked genes were the major determinant of resistance, although the possibility that other genes exerted a modifying influence was not excluded. By using the backcross and various congenic and recombinant mice, linkage of the genes involved to the H-1, H-2, H-3, H-4, H-7, or H-8 loci, to the immunoglobulin allotype, to the Thy-1 gene, to the Hc gene specifying C5, or to coat color genes (B, c) was excluded. There was no difference in the response of males and females. In all studies, the powerful overriding influence of the C57B1 genome was evident.     

Genetic control of murine resistance to Toxoplasma gondii.

The genetics of murine susceptibility to Toxoplasma gondii was investigated in inbred mice and their F1 and F2 offspring. Among four strains of congenic mice of the B10 background, those with H-2a/a and H-2b/b genotypes were more susceptible than were those with H-2d/d and H-2k/k genotypes. Breeding studies utilizing three of these strains demonstrated linkage between the H-2a allele and greater susceptibility. These data suggest the existence of an H-2-linked gene affecting susceptibility to T. gondii. In challenge of recombinant inbred mice derived from C57Bl/6J (high susceptibility) and BALB/c (low susceptibility) strains, lines BE, BJ, and BK were more susceptible than lines BD, BG, BH, and BI. These data are consistent with the existence of a second disease susceptibility gene linked to the H-13 locus. F1 offspring of the C57B1/6J X B10.D2 mice were significantly less susceptible than either parent. This phenotypic complementary suggests the presence of more than one genetic mechanism of resistance to T. gondii. From these combined data, we conclude that (i) susceptibility to T. gondii in mice is affected by at least two genes, (ii) one of the genes is linked to the H-2 and one to the H-13 locus, and (iii) more than a single mechanism of resistance must be considered to explain the observed genetic controls of susceptibility.     

Asymmetry in the serological response and mixed lymphocyte reactions between C57Bl/6 and the congenic mutant C57Bl/6.CH-2ba [H(Zl)]

Asymmetry in the relationship between the H-2K mutant strain C57Bl/6.CH-2ba (H-2ba) and the wild-type congenic C57Bl/6 has been demonstrated both in MLR and serologically by haemagglutination. MLR between these strains, when B6 was the responder, was as strong as that toward allogeneic stimulator cells: H-2ba was regularly less responsive toward B6. Responses in both directions were increased, in terms of augmented proliferative responses, by prior immunization. In this context the MLR resembles that towards minor H-locus antigens rather than those controlled by the H-2 locus. Immunization of (H-2ba X BALB/c)F1 hybridgs with B6 lymphoid cells induced the production of a haemagglutinating antibody not directed toward any known H-2 specificity. The B6 haemagglutinogen, termed He, was present on B6 lymphoid as well as red blood cells. Segregation studies of F2 and back-cross progeny of (H-2ba X BALB/c)F1 hybrids suggest that the response to He is controlled by two Ir genes, one of which is linked to H-2.     

Yersinia enterocolitica infection in resistant and susceptible strains of mice.

We investigated natural resistance in mice to Yersinia enterocolitica, an enteric bacterial pathogen of humans, with a view to determine host genetic factors that are important in resistance. Most mouse strains studied (C3H/HeN, BALB/c, BALB.B, DBA/2, A, Swiss, and SWR) were highly susceptible to infection (50% lethal dose [LD50], 2 X 10(2) to 6 X 10(2) Y. enterocolitica administered intravenously [i.v.]). In contrast, C57BL/6 mice were highly resistant (LD50, 2 X 10(5) Y. enterocolitica administered i.v.). Resistance to i.v. Yersinia infection did not appear to be related to the Ity locus (which codes for resistance to Salmonella typhimurium and other pathogens) because Ityr mice (C3H/HeN, DBA/2, A, and SWR) were more susceptible to Y. enterocolitica than were Itys (C57BL/6) mice. In addition, because BALB.B mice (congenic to C57BL/6 mice at the H-2 locus) were susceptible, resistance was probably not H-2 linked. BALB/c X C57BL/6 F1 mice were intermediate in their resistance to Y. enterocolitica infection (LD50, 3 X 10(4) organisms administered i.v.), suggesting that resistance to Y. enterocolitica depends on a gene dosage affect or a resistance gene(s) interaction between susceptible and resistant parents. Further studies with C57BL/6 and BALB/c mice as prototype resistant and susceptible strains were undertaken. A time course study of Y. enterocolitica growth in various organs following i.v. infection revealed no strain difference in bacterial growth during the first 48 h of infection. Thereafter, however, C57BL/6 mice were capable of restricting Y. enterocolitica growth in all tissues (liver, lung, spleen, kidneys), whereas extensive bacterial proliferation occurred in BALB/c mice tissues. BALB/c mice were also more susceptible to oral Y. enterocolitica infection than were C57BL/6 mice, demonstrating increased mortality and greater numbers of bacteria in the Peyer's patches. Finally, whereas thymus-bearing C57BL/6 X BALB/c F1 mice were resistant to infection, athymic (nude) C57BL/6 X BALB/c F1 mice were susceptible. These studies provide a model to investigate natural immunity to enteric pathogens at mucosal surfaces, as well as provide the basis for clarifying the role of host genotype in Y. enterocolitica resistance.     

Genetics of carbon tetrachloride-induced liver injury in mice. II. Multigenic regulation.

Mice from many different congenic inbred strains were given an intramuscular injection of carbon tetrachloride (CCl4) in olive oil to determine the genetic influences on induction of, and recovery from, liver damage. Liver and blood samples were taken at days 1, 4 and 7. The degree of necrosis and lymphoid infiltration appeared to be controlled, qualitatively and quantitatively, by both H-2-linked and Ah-linked genes. Strain differences were noted in the patterns of hepatocellular necrosis and the proportions of lymphoid, monocytic and other inflammatory cells which characterized the infiltrating population. Kinetic studies of F1 hybrids from matings between the susceptible BALB/cJ male parent and the resistant SJL/J female parent suggested that two dominant genetic influences play a major role in CCl4-induced liver damage. The gene contributed from the BALB/cJ parent affects the extent of liver necrosis and a second gene from SJL/J augments recovery. These results suggest, therefore, that the CCl4-induced liver damage and subsequent recovery are under multigenic control by H-2, Ah and possibly other genes.     

Host Defenses in Experimental Scrub Typhus: Genetics of Natural Resistance to Infection

Genetic resistance to lethal infection with Rickettsia tsutsugamushi was studied in over 30 inbred strains, inbred hybrids, and outbred stocks of mice. Inbred mice infected intraperitoneally with the Gilliam strain of R. tsutsugamushi showed three patterns of response: susceptible (A/HeJ, C3H/HeDub, C3H/HeJ, C3H/HeN, C3H/St, CBA/J, DBA/1J, DBA/2J, and SJL/J), resistant (AKR/J, BALB/cDub, BALB/cJ, C57BL/6J, C57L/J, and SWR/J), and selectively resistant (A/J). The selectively resistant pattern was characterized by random deaths occurring throughout the titration range and was also observed in three of the six outbred mouse stocks surveyed. No correlation was evident between the H-2 haplotype of inbred mice and their response to Gilliam infection. The progeny from five different Gilliam-resistant by Gilliam-susceptible inbred parental crosses were all resistant. Study of F(1), F(2), and parental backcross generations of BALB/cDub (resistant) and C3H/HeDub (susceptible) hybrids indicated resistance was dominant and was controlled by a single gene or a closely linked cluster of genes that were autosomal and not linked to coat color. The resistance of BALB/cDub mice was not due to an inability of host cells to support rickettsial growth, since C3H/HeDub and BALB/cDub embryo cell cultures supported similar growth of Gilliam organisms. C3H/HeDub mice, although susceptible to intraperitoneal Gilliam infection, were capable of mounting an immune response to Gilliam antigens, since subcutaneous infection was not lethal and did protect animals against subsequent intraperitoneal challenge with either the Gilliam or Karp strains of R. tsutsugamushi.     

Role of the major histocompatibility complex in resistance and granuloma formation in response to Mycobacterium lepraemurium infection.

Resistance to a subcutaneous infection with a moderate dose of Mycobacterium lepraemurium was investigated in C57BL/6 mice and in three congenic strains with the BALB background (BALB/c, BALB/B, and BALB/K). Resistance after 10 weeks of infection was found not to be linked to the major histocompatibility complex. The ability to develop a delayed hypersensitivity response to an ultrasonicate of M. lepraemurium was associated with the background genes, and this ability had no influence on resistance to M. lepraemurium. Granuloma formation at the infection site in the early stages appeared to be linked to the H-2b haplotype. The types of cells involved in the granulomas were also investigated.     

Perturbation of differentiated functions during viral infection in vivo. In vivo relationship of host genes and lymphocytic choriomeningitis virus to growth hormone deficiency.

Retarded growth and disordered glucose metabolism secondary to growth hormone (GH) deficiency are associated with persistent lymphocytic choriomeningitis virus (LCMV) infection of GH-producing cells in the anterior lobe of the pituitary gland. Infected C3H/ST mice, which are H-2k haplotype, become GH deficient, and LCMV replicates in most (more than 90%) of their GH-producing cells. In contrast, BALB/WEHI and SWR/J mice, which are H-2d and H-2q, respectively, do not develop this GH deficiency, and less than 20% of their GH-producing cells are infected by virus. Yet all three strains infected at birth with LCMV strain Armstrong (ARM) carry equivalent amounts of virus in their blood, brain, heart, kidney, liver, spleen, and thymus throughout life. Of five additional H-2k murine strains tested, C3H/HEJ and CBA/N mice develop this GH-like disorder, whereas neither AKR/J, B10/BR, nor BALB/KAE mice do, indicating that the H-2K haplotype does not control the GH susceptibility. Furthermore C3H/SW mice, which have the H-2b haplotype on the C3H background, develop the disease, again negating any correlation with H-2k but inferring that the C3H background is responsible. One half of the hybrid offspring produced by crossing the C3H/ST GH-deficient strain with BALB/WEHI-resistant mice develop the disease, but the trait is not sex linked. F1 hybrid backcrosses with the susceptible C3H/ST parental strain or resistant BALB/WEHI strain indicate the involvement of more than two genes. Hence the development of a GH deficiency by LCMV-infected C3H/ST mice is not linked to the MHC haplotype, is not sex linked, and is not due to a dominant gene. Multiple genes are involved and these are related to C3H background.     

Dominant suppressive effect of the silent Eb alpha allele on an in vivo T helper cell response under Ed beta Ed alpha region-linked immune response gene control

Previous adoptive spleen cell transfer experiments have demonstrated that an immune response (Ir) gene linked to the Ed beta Ed alpha region allows BALB/c T helper lymphocytes (Th) to respond to an idiotope on the V lambda 2(315) fragment of isologous myeloma protein M315. BALB.K (H-2k) and BALB.B (H-2b) do not respond to V lambda 2(315). While (H-2d X H-2k)F1 hybrids have been shown to be responders, it is now demonstrated that (H-2d X H-2b)F1 hybrids are low responders. By crossing BALB/c with various H-2 recombinants on B10 background and probing Th responsiveness to V lambda 2(315) in these F1 hybrids, the dominant suppressive gene of the H-2b haplotype is mapped to Eb alpha Sb. It is argued that the suppressive gene is Eb alpha, which is a silent allele. A likely explanation for the suppressive effect of the Eb alpha allele is that reduced amounts of Ed beta: Ed alpha restriction elements are present on antigen-presenting cells of (H-2d X H-2b)F1 hybrids because only one E alpha gene is functional in such mice. The present report extends previous in vitro findings from other laboratories to the in vivo situation and suggests that silent alleles for class II molecule chains may profoundly affect certain immune responses of individuals heterozygous for the silent allele.     

Genetic control of mouse cytomegalovirus-induced myocarditis.

Mouse cytomegalovirus (MCMV) infection of mice induced myocarditis, characterized by a mononuclear cell infiltrate with associated necrosis of myofibres. Myocarditis was observed in parallel with viral inclusion-bearing cells in the heart during the acute phase of the infection. Myocarditis also persisted after the acute phase when viral antigens were no longer detectable by immunoperoxidase histochemistry and infectious virus could not be cultivated from various organs. The influence of host genetic factors on the development of cytomegalovirus-induced myocarditis was investigated using H-2 congenic and recombinant inbred mouse strains. Analysis of congenic variants with C57BL/10 and BALB/c backgrounds and the A/J strain revealed that genes linked to the H-2 complex influenced susceptibility to peak levels of MCMV-induced myocarditis seen 7 and 10 days post-infection. In addition, non-H-2 genes of the BALB/c background were important in determining the severity of myocarditis. Analysis of the strain distribution pattern of the CXB recombinant inbred series did not disclose the identity of the BALB/c non-H-2-linked allele conferring susceptibility to MCMV-induced myocarditis. The level of myocarditis seen in the F1 hybrid between the high-responder BALB/c and low-responder C57BL/6 strains suggested dominant inheritance. The amount of viral replication in the major target organs did not correlate with the severity of myocarditis. In conclusion, at least two genes, one mapping to the H-2 complex and another non-H-2-linked gene, influenced the development of myocarditis in MCMV-infected mice.     

Evidence for a histocompatibility locus probably linked to but distinct from Mls and H-25

BALB/c (Mlsb) and BALB.D2-Mlsa strains of mice, both H-2d, are congenic and differ for the Mls locus (and linked genes) located on chromosome 1. The BALB.D2-Mlsa strain was obtained by introducing the Mlsa allele of DBA/2 mice into BALB/c mice. In previous studies we showed that BALB.D2-Mlsa recipients reject, relatively rapidly, all skin grafts from BALB/c donors. We and other groups have questioned whether the rejections observed were indeed due to the incompatibility for Mlsb products or for products of a histocompatibility (non-H-2) locus linked to, but distinct from, Mlsb. To answer this question, several hybrids carrying either Mlsa or Mlsb in various genetic contexts were grafted with skin from Mls-compatible BALB/c or BALB.D2-Mlsa donors; in the genetic combinations selected, any rejection which might occur would reflect the effects of a non-Mls incompatibility between BALB/c and BALB.D2-Mlsa strains. In certain of the donor-recipient combinations studied, the skin grafts were tolerated for greater than 200 days, but a relatively rapid rejection of BALB/c skin grafts was observed in (B10.D2 x BALB.D2-Mlsa)F1 and (B10.BR x BALB. D2-Mlsa)F1 hybrid recipients. These results indicated that in addition to Mls, the BALB/c and BALB.D2-Mlsa strains differ for at least one other non-H-2 histocompatibility locus. The possible involvement of H-25 was then investigated. Indeed, disparity for H-25, which maps on chromosome 1 close to Mls, can induce relatively rapid skin graft rejection. The H-25 allele of the DBA/2 strain has not been defined: we considered, therefore, that BALB/c and DBA/2 could be disparate at the H-25 locus, and that H-25 (transmitted by DBA/2 to the BALB.D2-Mlsa strain, together with the Mlsa allele) could be responsible for the skin graft rejection we observed. Our results showed, however, that DBA/2, BALB/c and BALB.D2-Mlsa strains of mice all share the H-25c allele; they therefore ruled out a role for H-25 incompatibility in the skin graft rejections we observed, and indicated that these rejections are due to the effects of a yet undefined histocompatibility locus (locus 'x'), probably linked to, but distinct from, the Mls locus. Further experiments showed that the histocompatibility effect of locus 'x' cumulates with that exhibited by Mlsb (or by a putative histocompatibility locus linked to Mlsb).     

Control by H-2 genes of murine antibody responses to protein antigens of Mycobacterium tuberculosis.

The genetic control of antibody responses after immunization with Mycobacterium tuberculosis soluble antigens was examined in inbred and H-2 congenic mouse strains. Antibody levels to five distinct epitopes were determined by a competitive inhibition test using radiolabelled murine monoclonal probes. High or low responder antibody levels were associated with either the H-2b (TB23, TB71 and TB72 specificities) or the H-2k (TB68) allele on both B10 and BALB backgrounds. The high response of TB78 specificity associated with the H-2k on the BALB but with H-2b haplotype on B10 background. The phenotype of (C57BL/6 X CBA)F1 hybrids reflected the high response for four and the low or intermediary response for one (TB68) of the tested paratopes. This is the first demonstration of immune response gene control in respect of defined mycobacterial protein epitopes. The implications towards the analysis of pathogenic or protective mechanisms during mycobacterial infection are briefly outlined.     

The resistance of BALB/cJ mice to Yersinia pestis maps to the major histocompatibility complex of chromosome 17

Yersinia pestis, the causative agent of plague, has been well studied at the molecular and genetic levels, but little is known about the role that host genes play in combating this highly lethal pathogen. We challenged several inbred strains of mice with Y. pestis and found that BALB/cJ mice are highly resistant compared to susceptible strains such as C57BL/6J. This resistance was observed only in BALB/cJ mice and not in other BALB/c substrains. Compared to C57BL/6J mice, the BALB/cJ strain exhibited reduced bacterial burden in the spleen and liver early after infection as well as lower levels of serum interleukin-6. These differences were evident 24 h postinfection and became more pronounced with time. Although a significant influx of neutrophils in the spleen and liver was exhibited in both strains, occlusive fibrinous thrombi resulting in necrosis of the surrounding tissue was observed only in C57BL/6J mice. In an effort to identify the gene(s) responsible for resistance, we measured total splenic bacteria in 95 F(2) mice 48 h postinfection and performed quantitative trait locus mapping using 58 microsatellite markers spaced throughout the genome. This analysis revealed a single nonrecessive plague resistance locus, designated prl1 (plague resistance locus 1), which coincides with the major histocompatibility complex of chromosome 17. A second screen of 95 backcrossed mice verified that this locus confers resistance to Y. pestis early in infection. Finally, eighth generation backcrossed mice harboring prl1 were found to maintain resistance in the susceptible C57BL/6J background. These results identify a novel genetic locus in BALB/cJ mice that confers resistance to Y. pestis.     

Susceptibility of inbred strains of mice to Trypanosoma congolense: correlation with changes in spleen lymphocyte populations.

A comparison was made of the susceptibility of eight inbred strains of mice to infection with Trypanosoma congolense. Marked differences in susceptibility as judged by survival were found between the different strains. The capacity of certain strains to survive longer than others appeared to be related to their ability to limit the numbers of trypanosomes in the circulation. There was no difference in the infectivity of T. congolense for mice of high and low susceptibility. Furthermore, the findings of similar prepatent periods suggested that the initial replication rate was similar in the different strains. These findings suggested that the level of parasitaemia in different strains of may reflect differences in the nature of quality of the immune response to the trypanosome. In all of the strains of mice a marked increase in splenic B and null lymphocytes was found. This, allied to the finding of an increase in the background plaque-forming cells to sheep erythrocytes, indicated, as suggested by other workers, that trypanosome infection results in a non-specific polyclonal activation of lymphocytes, and that this affects primarily B lymphocytes. In strains of mice which survived longest, i.e. C57B1/6J and AKR/A, the increase in splenic B and null cells was less marked. Whether this is associated with a decreased susceptibility of these strains to polyclonal activation induced by trypanosome infection, or whether it is merely the result of lower levels of parasitaemia, remains to be determined. By comparing T. congolense infection in three strains of mice congenic at the H-2 locus, representing H-2a, H-2b and H-2k haplotypes, it was found that the susceptibility was not associated with the H-2 haplotype. The finding that (A/J X C57B1/6J)F1 hybrids were of similar susceptibility as the C57B1/6J parents indicated that the relative resistance of this strain is inherited as a dominant trait, although in the early stages of infection the F1 hybrids consistently showed somewhat higher levels of parasitaemia than the C57B1/6J mice. Athymic nude mice and surgically splenectomized mice were found to be more susceptible to T. congolense infection than intact mice of the same strain. However, the effect of splenectomy was much less pronounced in C57B1/6J mice than in the relatively more susceptible BALB/c/A mice.     

Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and relationship to major histocompatibility complex haplotype and Nramp1 genotype.

Six common inbred strains of mice and their F1 hybrids were examined for resistance to infection with the H37Rv strain of Mycobacterium tuberculosis. According to survival times after inoculation of 10(5) CFU intravenously (i.v.), the mice could be classified as being either highly susceptible (CBA, DBA/2, C3H, 129/SvJ) or highly resistant (BALB/c and C57BL/6). F1 hybrids of susceptible and resistant strains were resistant. Although an examination of a limited number of H-2 congenic strains showed that the H-2k haplotype could confer susceptibility on a resistant strain, it was evident that non-major histocompatibility complex (MHC) genes were much more important. Resistant strains all possessed the susceptibility allele of the anti-microbial resistance gene, Nramp1. Results obtained with selected strains infected with 10(2) CFU of M. tuberculosis by aerosol agreed with the results obtained with mice infected i.v. The size of the bacterial inoculum was important in distinguishing between resistant and susceptible strains, in that a 10(7) inoculum overcame the resistance advantage of one strain over another.     

H-2 linkage control of resistance to subcutaneous infection with Mycobacterium lepraemurium.

The H-2 linkage of the gene or genes controlling resistance to subcutaneous infection with 10(7) Mycobacterium lepraemurium organisms was investigated by using H-2 congenic strains on BALB and B10 backgrounds. Resistance was assessed by counting the organisms present at the infection site in the footpad and in the draining (right popliteal) lymph node 20 weeks after infection. When mice of BALB and B10 backgrounds with the same H-2 haplotype were compared, the BALB mice were always more susceptible. However, BALB/K (H-2k) mice were more susceptible than BALB/B (H-2b) mice, and BALB/B mice were more susceptible than BALB/c (H-2d) mice. There was no detectable difference in the resistance of B10.D2/n (H-2d) mice and B10 (H-2b) mice, but B10.BR (H-2k) mice were more susceptible than mice of the other two B10 strains. BALB/K was the only strain in which a high proportion of mice showed significant dissemination of organisms to the liver and spleen.