Correlation between natural killer cell activation in the bone marrow and haemopoietic dysfunction following cytomegalovirus infection of mice.

We describe here the activation of natural killer (NK) cells in the bone marrows and spleens of mice infected with murine cytomegalovirus (MCMV). NK activity at these sites peaked at day 2 to 3 post-infection (p.i.) and declined between days 6 and 10 p.i. in BALB/c and C57BL/6 mice. In BALB/c mice, the increases in NK activity coincided with depletion of colony-forming units of the granulocyte-monocyte lineage (CFU-GM) from the marrow. CFU-GM depletion in MCMV-infected C57BL/6 mice was less severe, despite the presence of activated NK cells in the marrow. Treatment of BALB/c mice with anti-asialo GM1 prior to MCMV infection resulted in less severe CFU-GM depletion at day 2 p.i. than infection with MCMV alone. When homozygous C57BL/6 or CBA/CaH bg/bg mice were infected with MCMV, depletion of marrow CFU-GM was more severe than in their heterozygous littermates. Finally, we observed some inhibition of colony formation when marrow cells from MCMV-infected and uninfected BALB/c donors were mixed and incubated prior to the CFU-GM assay. These results suggest that activated NK cells may contribute to depletion of haemopoietic cells soon after MCMV infection of BALB/c mice, but may limit the loss of these cells in C57BL/6 and CBA/CaH mice.     

Thy 1+ asialo GM 1 + dendritic epidermal cells in skin defense mechanisms of vaccinia virus-infected mice

Summary To define different growths of vaccinia virus (VV) in the footpad, ear and tail skin of ddY and BALB/c mice, we investigated the roles of Ia⁺ Langerhans cells (LC) and Ia^– dendritic epidermal cells (DEC) in the skin defense mechanisms. With respect to LC obtained from the footpad, ear and tail skin of BALB/c mice, the level of lysosomal enzyme, phagocytic, antigen-presenting and antiviral activities were almost the same. Footpad DEC exhibited higher natural killer (NK)-like lysis activity against YAC-1 target cells than ear and tail DEC. The NK-like lysis activity of footpad DEC was also seen in athymic nude mice (BALB/c nu/nu) but not in NK cell-defective beige mice (C57BL/6 bg/bg). The footpad DEC activity was completely abolished by in vitro and in vivo treatment with anti-Thy 1.2 or anti-asialo GM₁ antibody, and VV replicated in the footpad 10³ fold more than in the untreated group, but not by treatment with anti-Ia^d antibody. When footpad Thy 1.2⁺ asialo GM ₁ ⁺ DEC were adoptively transferred to the tail skin of syngeneic mice, followed by intradermal challenge of the mice with VV, viral replication in the tail skin was markedly suppressed. These results indicated that the pathogenicity of VV in the skin is affected by Thy 1.2⁺ asialo GM ₁ ⁺ DEC rather than by Ia⁺ LC.     

Absence of a role for natural killer cells in the control of acute infection by Toxoplasma gondii oocysts.

The active phase of primary and challenge oral infections of Toxoplasma gondii was investigated with respect to natural killer (NK) activity against YAC-1 tumour cell targets in vitro and serum interferon (IFN) titres. Primary (non-lethal) oral infection of BALB/c mice with Me49 oocysts resulted in a rapid increase of serum IFN titres, followed by augmented NK activity. NK levels became depressed, rising again by 15 days after infection to normal levels, again preceded by elevated IFN titres. In challenge infections NK was not augmented and IFN titres rose only if a high dose of oocysts was given. IFN activity was pH2-labile in all cases and considered to be due to IFN-gamma. Cold target inhibition studies indicated that T. gondii did not bind to NK cells. A bioassay for the effects of NK cells on T. gondii tachyzoites was developed and there was no evidence of killing in vitro by cells with NK function; T. gondii survived better when cultured with NK cells than when cultured alone. Studies using C57BL/6bg/bg,bg/+ and +/+ mice showed that there was no difference in mean time to death after administration of a lethal ME49 oocyst infection by mouth. Cytotoxicity against YAC-1 in both spleen and mesenteric lymph node (MLN) cell populations was highly augmented in bg/+ and +/+, but not in bg/bg mice. Genetic deficiency of NK activity had no effect on survival of mice after infection. Therefore NK has at best a minimal role to play in protection during the acute phase of Toxoplasma infection.     

Genetic resistance of mice to Mycobacterium paratuberculosis is influenced by Slc11a1 at the early but not at the late stage of infection

We have recently described the development of a luminescent Mycobacterium paratuberculosis strain of bovine origin expressing the luxAB genes of Vibrio harveyi. With this luminescent isolate, fastidious and costly enumeration of CFU by plating them on agar can be replaced by easy and rapid luminometry. Here, we have reevaluated the effect of Slc11a1 (formerly Nramp1) polymorphism on susceptibility to M. paratuberculosis, using this luminometric method. A series of inbred mouse strains were infected intravenously with luminescent M. paratuberculosis S-23 and monitored for bacterial replication in spleen, liver, and lungs for 12 weeks. The results indicate that, as for Mycobacterium avium subsp. avium, innate resistance to infection is genetically controlled by Slc11a1. In BALB/c, congenic BALB.B10-H2(b) (BALB/c background; H-2(b)), C57BL/6, and beige C57BL/6(bg/)(bg) mice (all Slc11a1(s)), bacterial numbers in spleen and liver remained unchanged during the first 4 weeks of infection, whereas in DBA/2 and congenic BALB/c.DBA/2 (C.D2) mice (both Slc11a1(r)) and in (C57BL/6 x DBA/2)F(1) mice (Slc11a1(s/r)), the bacterial numbers had decreased more than 10-fold at 4 weeks postinfection in both male and female mice. At later time points, additional differences in bacterial replication were observed between the susceptible mouse strains, particularly in the liver. Whereas bacterial numbers in the liver gradually decreased more than 100-fold in C57BL/6 mice between week 4 and week 12, bacterial numbers were stable in livers from BALB/c and beige C57BL/6(bg/)(bg) mice during this period. Mycobacterium-specific gamma interferon responses developed earlier and to a higher magnitude in C57BL/6 mice than in BALB/c mice and were lowest in resistant C.D2 mice.     

Cytomegalovirus hepatitis: characterization of the inflammatory infiltrate in resistant and susceptible mice.

Mice susceptible and resistant to murine cytomegalovirus (MCMV) were infected with this virus and livers were harvested after 2-231 days. Cryostat sections were stained to visualize cells bearing CD4, CD8 or Mac-1 antigens. Mac-1+ cells were prevalent in inflammatory foci after 2 days. These cells persisted in susceptible BALB/c and A/J mice, but disappeared from livers of resistant C57Bl/6 and CBA/CaH mice by day 28. T cell inflammation peaked on days 7-11. This declined by day 56 in C57Bl/6 and CBA/CaH mice, but persisted in BALB/c and A/J mice for at least 231 days. Persistent CD8+ cells were dispersed throughout the parenchyma. More CD8+ cells were observed 7-14 days after infection in the livers of bg/bg (natural killer (NK) cell-deficient) C57Bl/6 and CBA mice, and in C57Bl/6 mice depleted of NK1.1 cells by MoAb. Thus, mice of strains susceptible to MCMV exhibit hepatitis characterized by persistence of dispersed CD8+ cells. This phenomenon may be limited by NK cells in resistant strains.     

Natural killer cells appear to play no role in the recovery of mice from Sindbis virus infection.

Previous studies have suggested that non-specific defence mechanisms may be important in the development of age-dependent resistance to fatal Sindbis-virus infection and in the recovery of adult mice from non-fatal infection. In these studies, natural killer (NK) cell induction was studied in 7-day-old susceptible mice and 28-35-day-old resistant mice. It was found that Sindbis virus infection induced NK cells in both the young and older mice, suggesting that NK cells were not important in the acquisition of resistance to fatal Sindbis-virus infection. Transfer of 10(8) lymph node cells from adult, mice, at the peak of NK cell activity, did not protect young mice from fatal infections, supporting the in vitro findings. The pathogenesis of Sindbis virus infection in C57BL/6J bg/bg (NK-cell deficient) and bg/+ (NK-cell normal) mice was also studied. Despite a defect in the induction of NK cells by Sindbis virus infection in the bg/bg mice, there were no significant differences in the pathogenesis of either peripheral or intracerebral infection in these strains of mice. These studies suggest that although NK cells are induced, they may not be important in the recovery of mice from Sindbis virus infection.     

Porphyromonas gingivalisvirulence in a murine lesion model: effects of immune alterations

This study utilized various mouse strains with documented alterations in immune system components to assess their contribution to modify the virulence ofPorphyromonas gingivalis. P. gingivalisW50 was cultivated on blood agar plates, harvested and used to challenge mice by subcutaneous injection on the dorsolateral surface of the back. Soft tissue lesion development was estimated by measuring the area of the spreading lesion formed by this microorganism over a period of 15 days. Challenge of various normal inbred and outbred mouse strains including: BALB/cN, BALB/cJ, BALB/c nu/+, ICR, B10.A(4R), B10.MBR, A/J, C57BL/6J, CBA/CaH, C.B-17/Icv Tacf DF and C3H/HeN with 2×10¹⁰bacteria showed similar lesion size among these strains (400 mm²). Genetically deficient mouse strains [C.B-17/Icr Tac (SCID); DBA/2 (C5 deficient); BALB/c nu/nu (T cell deficient); CBA/CaHN-XID/J (B cell deficient) and C3H/HeJ (LPS hyporesponsive)] demonstrated a lesion size which was similar to normal animals. C57BL/6J-BgJ (NK cell deficient) mice exhibited a significantly more severe lesion than the other strains tested. Following healing of the lesions, we initiated a secondary infection of the surviving animals to estimate the acquisition of protective immunity following recovery from the primary infection. Normal mice demonstrated a delayed onset and decrease in lesion size of 15 to 30% compared with the primary infection. In contrast, each of the immunodeficient strains appeared unable to develop immune protection to the secondary challenge. The findings suggest that protection against primary infections withP. gingivalisare mediated by innate immune mechanisms (PMN. NK cells). Additionally, it appears that T-cell-dependent humoral responses are critical to developing immunity to subsequentP. gingivalisinfection.     

Response of scid mice to establishment of Leishmania major infection.

The initiation of Leishmania major infection in susceptible BALB/c mice is regulated by interferon-gamma (IFN-gamma). To examine further the mechanisms of IFN-gamma-dependent regulation of the establishment of L. major, we studied the characteristics of the infection in severe combined immunodeficient (scid) mice. In the first 2 weeks of infection, we observed a delay in the development of the lesions in the footpads and lower numbers of parasites in scid compared with BALB/c mice. By week 5 after infection, the size of the leishmanial lesion was similar in both strains of mice, but the number of parasites in scid mice was 100-fold higher than in BALB/c. Treatment with anti-IFN-gamma during the establishment of L. major did not alter the course of infection in scid mice, while it exacerbated lesion development in BALB/c mice. Macrophages from scid mice were unable to kill L. major when stimulated with IFN-gamma in vitro, and produced lower levels of nitric oxide compared with macrophages from susceptible BALB/c or the resistant C57Bl/6 mice. We examined whether delayed lesion development in scid mice was due to their inability to mount appropriate inflammatory responses. While significantly fewer nucleated cells were present in the footpads of scid mice compared with BALB/c, 2 and 3 weeks after infection, no difference in inflammatory response between scid and BALB/c mice was observed in response to L. major antigen in the footpads. In contrast, there was a dramatic increase in the number of cells in the popliteal lymph nodes of BALB/c mice. Decreased inflammatory responses of scid mice in the footpad (at the site of infection) may contribute to slower development of leishmanial lesions during the first 2 weeks of infection.     

Modulation of Mouse Natural Killer Cell Activity by the Serum Thymic Factor

After mice had been treated with serum thymic factor (FTS). we observed an increase or a decrease in the NK activity, depending on the duration of treatment and mouse strain: an increase for C57BL/6, BALB/c, A, and nu/nu and a decrease for NZB and CBA mice. The fact that treatment of C57BL/6 mice with FTS produces the same effect as thymeciomy—that is, an increase -on the NK activity and returns the augmented NK activity of thymeclomized mice to normal levels suggests that FTS has multiple effects with different results depending on the level of differentiation of the target cells. Different mechanisms of action of FTS on NK cells are discussed.     

Listeriosis in beige mice and their heterozygous littermates.

The ability to resist the facultative intracellular bacterium Listeria monocytogenes was not impaired in the beige mutants of C57BL/6J mice which are known to be deficient in a number of immune functions. The intravenous LD50 of Listeria in beige (bg/bg) mice and their normal heterozygous (bg +) littermates was approximately 5 X 10(5). Growth of Listeria in the spleen and liver during primary and secondary infections was similar in the two groups of mice, and each was able to act efficiently in adoptive transfer of immunity. Histological examination showed a normal accumulation of polymorphonuclear and mononuclear cells at foci of infection in the liver, while in the spleen the previously described depletion of T cells 2-4 days after infection was observed in both groups. In-vitro 18-hr cytotoxicity of peritoneal cells for P815 targets, a function usually attributed to macrophages, was increased 2 days after infection in both bg/bg and bg/+ mice. In contrast, 4 hr cytotoxicity of spleen cells for YAC-1 targets, considered typical of natural killer (NK) cells, was depressed in uninfected bg/bg mice and only slightly raised during infection. This compared with a normal NK activity in uninfected bg/+ mice which was markedly increased during infection.     

Natural Killer Cell Response to Lymphocytic Choriomeningitis Virus in Beige Mice

Lymphocytic choriomeningitis virus (LCMV) induced low levels of natural killer (NK) tell activity in C57BL6 mutant beige (bg/bg) mice, which had previously been reported to have no cytotoxic NK cells. NK cell-mediated lysis by bg/bg splenocytes was observed against a cell line (YAC-I) very sensitive to NK cell cytotoxicity, but not appreciably against a less scum live cell line (L-929), The bg/bg mutant mice with this very low NK cell activity and control stains of mice (bg/+, C57BL6) with high NK cell activity synthesized comparable amounts of virus and interferon in the spleen, suggesting that NK cells may not play a significant role in curtailing viral synthesis before the advent of the specific immune response mechanisms     

Genotype-dependent characteristics of behavior in mice in cognitive tests. The effects of Noopept

Male C57BL/6J, BALB/c, and DBA/2J mice showed differences in their abilities to perform two cognitive tests. C57BL/6J mice had good learning ability and memory trace retention (at 10 days) in a simplified Morris maze, while BALB/c mice had low levels of memory trace retention and DBA/2J mice had low learning ability in this test. I.p. administration of the nootropic agent Noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) at a dose of 0.5 mg/kg 15 min before the start of the test induced significant improvements in long-term memory in this test in BALB/c mice but no further improvement in C57BL/6J mice, and had no effect in DBA/2J mice. On testing the ability to extrapolate the direction of movement of a stimulus, administration of Noopept increased the proportion of correct responses in C57BL/6J and BALB/c mice, but had no effect in DBA/2J mice. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 57, No. 6, pp. 721–728, November–December, 2007.     

Regulation by protein kinase of phagocytosis of Mycobacterium leprae by macrophages

Mycobacterium leprae multiplies within host macrophages. The mechanism of internalisation of the bacteria by the phagocytic cells is unknown. In this study, M. leprae was purified from the foot pads of experimentally infected nu/nu mice. Peritoneal macrophages were harvested from BALB/c mice or C57 beige (bg/bg) mice. The effect of protein kinase inhibitors (erbstatin, genistein or staurosporine for BALB/c and bg/bg mice, plus herbimycin for bg/bg mice) on phagocytosis of the mycobacteria by the macrophage monolayers was tested. The untreated (control) macrophages phagocytosed M. leprae. Phagocytosis by BALB/c macrophages was inhibited by erbstatin and staurosporine but not by genistein; all the protein kinase inhibitors prevented uptake of M. leprae by bg/bg cells. The results demonstrate that protein kinase regulates phagocytosis of M. leprae by macrophages. The mechanism might prove to be a rational drug target for mycobacteria that multiply intracellularly.     

The role of natural killer cells in resistance to coccidiosis: investigations in a murine model.

Natural killer (NK) activity, detected by the lysis of Yac-1 target cells, was examined in splenic and mesenteric lymph node (MLN) cells throughout the course of infection with Eimeria vermiformis in BALB/c and C57B1/6 (B6) mice. These strains are, respectively, relatively resistant and susceptible to primary infections, which render them equally, and completely, resistant to challenge. Resting levels of NK activity were higher in B6 than in BALB/c, and B6 responded earlier in the course of infection than BALB/c, but splenic peak values were higher in BALB/c; the pattern of response in MLN cells was similar in both strains, but the peak was higher in BALB/c. At the time (7 days p.i.) of peak NK response in BALB/c mice there was, depending upon the choice of NK-resistant/lymphokine-activated killer (LAK)-sensitive target cells, either little (P388D1), or no (P815) splenic LAK activity. Challenge of immunized BALB/c mice did not evoke a detectable NK response. Although the higher NK activity in BALB/c mice correlated with greater control of primary infection, depletion of NK activity (demonstrated in splenic cells) in vivo by treatment with anti-asialo GM1 antibodies did not greatly affect the course of infection. Furthermore, this treatment did not augment the exacerbation of infection produced by treatment with anti-interferon-gamma (IFN-gamma) MoAb, indicating that, at least in this system, NK cells are not a fundamentally important source of this controlling cytokine of eimerian infections. The results suggest that NK cells may not greatly influence the outcome of coccidial infections.     

Innate Resistance to Babesia Infection Is Influenced by Genetic Background and Gender

Infection of severe combined immunodeficient mice with Babesia sp. strain WA1 was studied to assess the contributions of innate and adaptive immunity in resistance to acute babesiosis. The scid mutation showed little effect in genetically susceptible C3H mice and did not decrease the inherent resistance of C57BL/6 mice to the infection, suggesting that innate immunity plays a central role in determining the course of Babesia infection in these strains. In contrast, the scid mutation dramatically impaired resistance in moderately susceptible BALB/c mice, suggesting that acquired immunity may play an important secondary role. In comparison to their female counterparts, male mice of different genetic backgrounds showed increased resistance to the infection, indicating that the gender of the host may influence protection against babesiosis.     

Natural killer cell activity and macrophage-dependent inhibition of growth or killing of Mycobacterium avium complex in a mouse model

Natural killer (NK) cells from spleens of normal and Mycobacterium avium complex (MAC)-infected C57 black mice (C57 BL/6 bg/+) were examined for their capacity to activate splenic and peritoneal macrophages from beige mice to inhibit or kill intracellular MAC. Peritoneal and splenic macrophages from beige mice were exposed in vitro to NK cells obtained from MAC-infected and uninfected black mice. NK cells from uninfected black mice were also treated in vitro with recombinant interleukin-2 (IL-2) for 48 h before incubation with macrophages. While control macrophages supported intracellular growth of MAC, macrophages exposed to unactivated NK cells inhibited growth of the intracellular bacteria, as determined 4 days after infection. IL-2 stimulated NK cells, and NK cells obtained from MAC-infected animals were able to activate murine macrophages in vitro to inhibit growth or kill 40.0 +/- 5% and 61.3 +/- 6% of the intracellular bacteria, respectively. In other experiments, beige mice (C57 BL/6 bg/bg) were treated intraperitoneally with NK cells obtained from MAC-infected and uninfected C57 black mice. Peritoneal macrophages harvested from beige mice treated with NK cells activated in vitro with IL-2 killed 24.4 +/- 4% of intracellular bacteria by day 4 after infection. Macrophages obtained from animals treated with NK cells harvested from MAC-infected black mice killed 58.8 +/- 7% of intracellular bacteria by 4 days after infection, in contrast with intracellular growth observed in macrophages obtained from untreated animals and from animals treated with Hanks' solution or unactivated NK cells. These crossover studies suggest that NK cells may be important in host defense against MAC.     

Strain-Dependent Differences in Murine Susceptibility to Coccidia

Differences in susceptibility of strains of mice to Eimeria ferrisi were observed by infecting eight strains of mice with six infectious dose levels and comparing the mortality rate among the strains for a period of 12 days. Mice of the C57BL/6 and HA/ICR strains were susceptible, and those of A/He, AKR, BALB/c, CBA, C3H/Anf, and DBA/2 strains were resistant to coccidial infection. Resistance was a dominant genetic expression, as indicated by the resistant response of F(1) hybrids of susceptible C57BL/6 and resistant CBA, C3H/Anf, or DBA/2 strains. An E. ferrisi infection in congenitally athymic nu/nu mice and phenotypically normal heterozygous nu/+ mice was used to determine how thymus-dependent immunoincompetence in cell-mediated immunity of the nu/nu mouse affected resistance to infection in a genetic background of the resistant BALB/c mouse. Results of primary and challenge infections in these two strains of mice suggested that resistance is thymus dependent. Furthermore, impairment of thymus-dependent cell-mediated immunity in resistant AKR mice by treatment with mouse antithymus serum led to partial susceptibility. However, susceptible C57BL/6 and HA/ICR strains are phenotypically normal mice, and previous evidence showed that C57BL/6 mice are not completely immunoincompetent in cell-mediated reactivity to coccidia. Collectively, our data show that cell-mediated immunity is necessary for resistance but may be subjected to modification by genetic expression of the host. The possible role of immune response genes in the control of coccidial immunity is discussed.     

Standardization and performance evaluation of mononuclear cell cytokine secretion assays in a multicenter study

Background

Burkholderia pseudomalleiis the causative agent for melioidosis. For many bacterial infections, cytokine dysregulation is one of the contributing factors to the severe clinical outcomes in the susceptible hosts. The C57BL/6 and BALB/c mice have been established as a differential model of susceptibility in murine melioidosis. In this study, we compared the innate IFN-γ response toB. pseudomalleibetween the C57BL/6 and BALB/c splenocytes and characterized the hyperproduction of IFN-γ in the relatively susceptible BALB/c micein vitro.

Results

Naïve BALB/c splenocytes were found to produce more IFN-γ in response to live bacterial infection compared to C57BL/6 splenocytes. Natural killer cells were found to be the major producers of IFN-γ, while T cells and Gr-1^intermediatecells also contributed to the IFN-γ response. Although anti-Gr-1 depletion substantially reduced the IFN-γ response, this was not due to the contribution of Gr-1^high, Ly-6G expressing neutrophils. We found no differences in the cell types making IFN-γ between BALB/c and C57BL/6 splenocytes. Although IL-12 is essential for the IFN-γ response, BALB/c and C57BL/6 splenocytes made similar amounts of IL-12 after infection. However, BALB/c splenocytes produced higher proinflammatory cytokines such as IL-1β, TNF-α, IL-6, IL-18 than C57BL/6 splenocytes after infection withB. pseudomallei.

Conclusion

Higher percentages of Gr-1 expressing NK and T cells, poorer ability in controlling bacteria growth, and higher IL-18 could be the factors contributing to IFN-γ hyperproduction in BALB/c mice.     

Genetic resistance to murine cryptococcosis: the beige mutation (Chédiak-Higashi syndrome) in mice

The influence of the bgJ and bg2J mutations on the susceptibility of mice to experimental cryptococcosis was studied in inbred mice of the C57BL/6J and C3H/HeJ strains. Although infected animals with the bg/bg genotype had a significantly shorter lifespan than bg/+ or +/+ animals, C3H/He beige-2J mice were less susceptible than C57BL/6 beige-J mice when compared with nonbeige mice of similar background. On days 18 and 19 after infection, quantitation of cryptococci in the brain, liver, and spleen revealed that the overall burden of organisms in infected C57BL/6 beige-J mice was in excess of one log unit above that found in the brain, liver, and spleen of infected C57BL/6 +/+ mice. At that time, C57BL/6 beige-J mice showed a 53% increase in mean brain weight, a 67.8% decrease in mean liver weight, and a 58.6% decrease in mean spleen weight, when compared with uninfected animals of the same age and genetical lineage. The corresponding figures for C57BL/6 +/+ mice were a 32% increase in mean brain weight, a 41.4% decrease in mean liver weight, and a 23.4% decrease in mean spleen weight. From these data, it is concluded that the beige mutation in mice is associated with increased susceptibility to cryptococcosis, the accrued susceptibility of the beige mutant is related to more rapid changes in the weight profile of the target organs as well as to a higher rate of growth or decreased clearance of Cryptococcus neoformans or both, and other autosomal genes are likely to be involved in the genetic control of susceptibility to murine cryptococcosis.     

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.