Varying susceptibility of pulmonary cytokine production to lipopolysaccharide in mice

Objectives: The lipopolysaccharide (LPS)-induced acute lung injury (ALI) model has been widely applied for pathophysiological and pharmacological research. The aim of present study is to understand the variation of acute pulmonary inflammation between mouse strains. Methods: The present study investigated the susceptibility of acute production of inflammatory mediators, e.g. cytokines, chemokines and others, to LPS in C57BL/6J, Balb/cJ, DBA/1J, CD-1, NMRI, DBA/2J, A/J, and C3H/HeN mice. Results: The susceptibility to intra-tracheal challenge with LPS varied between measured variables, durations and strains. General lung hyper-reactive susceptibility to LPS-induced pulmonary production of 6–8 inflammatory mediators followed the order NMRI, Balb/cJ, C3H/HeN, A/J, C57BL/6J, DBA/1J, DBA/2J and CD-1 mice at 4 h, and A/J, C3H/HeN, CD-1, NMRI, C57BL/6J, Balb/cJ, DBA/2J and DBA/1J mice at 24 h. Conclusions: Our data provide information for scientists to consider the proper strain of mice for the measurement of specific inflammatory mediators and to select sensitive or resistant mouse strains for understanding genetic variation in the pathogenesis and for the screening of target-oriented drug development.     

Immune complexes, but not streptococcal cell walls or zymosan, cause chronic arthritis in mouse strains susceptible for collagen type II auto-immune arthritis

In this study we investigated mechanisms involved in the chronic character of experimental collagen type II induced arthritis (CIA). We compared the knee joints of mouse strains which are prone to develop this autoimmune disease (DBA/1,B10RIII) with other nonsusceptible mouse strains (C57Bl/6,BALB/c) in their reaction to different stimuli: immune complexes (IC), zymosan and streptococcal cell walls (SCW). Inflammation was evaluated by(99m)Tc uptake measurements and in haematoxylin- and eosin-stained knee-joint sections. Passively induced immune complex mediated arthritis (ICA) in knee joints of C57Bl/6 and BALB/c mice, showed moderate cell influx at day 3, whereas at day 7 only minor amounts of inflammatory cells were observed. In contrast, in arthritic DBA/1 and, to a lesser extent, in B10.RIII joints, a tremendous cell influx was observed at day 3 and even at day 14 there was still significant synovitis. In contrast, if arthritis was elicited by intra-articular injection of zymosan or SCW in C57Bl/6 and DBA/1, the course of inflammation was similar in both strains and no chronic inflammation developed. In line with severe arthritis, chemotactic factor production was dramatically enhanced in ICA in DBA/1 mice, and a prolonged production of IL-1 was evident. When IL-1 was neutralized before or during the ICA using specific anti-IL-1alpha,beta antibodies, inflammation could be blocked completely. Single or multiple injection of IL-1 in the knee joint of C57Bl/6 or DBA/1 showed comparable inflammation, indicating that the chemotactic response per se is comparable in both strains. No prolonged production of IL-1 was found during zymosan or SCW arthritis. Selective removal of macrophages from the synovial intima prior to ICA induction (using clodronate-containing liposomes) prevented the onset of inflammation in C57Bl/6 and DBA/1 mice. It can be concluded that immune complexes, but not zymosan or SCW, cause a more severe and chronic arthritis in mouse strains which are susceptible for collagen type II autoimmune arthritis. This is due to higher and prolonged expression of IL-1 and chemotactic factors, caused by stimulation with immune complexes. The interaction of IC with lining macrophages probably plays a dominant role in development of chronicity.     

A comparison of morphine-induced locomotor activity and mesolimbic dopamine release in C57BL6, 129Sv and DBA2 mice

Inbred mouse strains show marked variations in morphine-induced locomotion and reward behaviors. As increases in mesolimbic dopamine release and locomotion have been implicated as being critical aspects of drug-seeking and reward-related behaviors, the present study sought to determine the relationship between morphine-induced changes in locomotion and mesolimbic dopamine release. Freely moving microdialysis of the ventral striatum was performed in mouse strains chosen on the basis of their documented differences in locomotor and reward response to morphine (C57BL6 and DBA2) and use in the production of genetically modified mice (129Sv). Both C57BL6 and 129Sv mice showed significant increases in locomotion and ventral striatal extracellular dopamine levels following subcutaneous morphine administration (3 mg/kg), with the former strain showing the largest increase in both parameters. Ventral striatal extracellular DA levels increased in DBA2 mice to a similar extent as 129Sv mice following morphine administration, despite this strain showing no locomotor response. Intra-strain analysis found no correlation between morphine-induced locomotion and mesolimbic dopamine release in any of the strains studied. Thus, no universal relationship between morphine-induced mesolimbic dopamine release and locomotion exists between, and particularly within, inbred mouse strains. Furthermore, morphine-induced increases in mesolimbic activity correlate negatively with the rewarding potential of morphine described in previously reported conditioned place preference studies.     

Strain specificity and cholinergic modulation of visuospatial attention in three inbred mouse strains

The tremendous increase in the use of mouse inbred strains and mutant mice to study the molecular basis of psychiatric disorders urges for a better understanding of attentional performance in mice. To this aim, we investigated possible strain differences in performance and cholinergic modulation of visuospatial attention in three widely used mouse inbred strains (129S2/SvHsd, C57BL/6JOlaHsd and DBA/2OlaHsd) in the five-choice serial reaction time task. Results indicated that after extended training, performance of 129S2/SvHsd mice was superior to that of C57BL/6JOlaHsd and DBA/2OlaHsd mice in terms of attention, omission errors, inhibitory control and latencies to correct choice. Increasing the attentional load resulted in comparable decrements in attention in all strains and inhibitory control impairments that were most pronounced in DBA/2OlaHsd mice. Further pharmacological evaluation indicated that all strains showed attentional impairments after treatment with the muscarinic and nicotinic antagonists scopolamine and mecamylamine, respectively. 129S2/SvHsd mice were less sensitive, whereas DBA/2OlaHsd mice appeared more sensitive to the detrimental effects of mecamylamine. In addition, subchronic, but not acute, nicotine treatment slightly improved attentional performance in all strains to the same extent. In conclusion, our data indicate strain specificity with particularly good performance of 129S2/SvHsd mice and strong cholinergic involvement in visuospatial attention in mice.     

Differential cardiac histopathology in inbred mouse strains chronically infected with Trypanosoma cruzi.

Seven inbred mouse strains were examined for the presence of chronic Chagas' cardiomyopathy in postacute Trypanosoma cruzi infection. DBA/1, DBA/2, BALB/c, B10.T (6R), B10.Q, B10.D2, and B6 mice were infected for 100 days with the Brazil strain of T. cruzi. Standard histologic examination of cardiac tissue from these mice revealed the following relationship among the different strains based on the severity of observed inflammation (myocarditis): BALB/c, DBA/1, and DBA/2 were the most inflamed; B10.T (6R) and B10.Q were intermediate; and B6 and B10.D2 showed the least inflammation. Examination of these tissues for characteristics of myocardiopathy such as cell swelling, edema, vacuolization, necrosis, myocytolysis, connective tissue infiltration, and thinning of the right ventricular wall indicated a relative relationship among the different strains relative to the severity of cardiomyopathy as follows: BALB/c, DBA/2, and DBA/1 showed the most cardiopathy (pathopermissive); B10.T (6R) and B10.Q showed intermediate pathology; and B6 and B10.D2 showed the least involvement (pathoresistant). Anti-heart antibody present in the sera of all these mice showed specific reactivity in western blots to a 43-kDa glycoprotein from normal heart tissue. Also, anti-heart antibody enzyme-linked immunosorbent assay titers for all mouse strains were similar and showed no correlation with the severity of tissue damage. The fact that different inbred strains show various degrees of myocarditis and cardiomyopathy may be useful in the study of pathogenesis of chronic Chagas' disease. Results from this limited list of inbred strains suggest that background genes, rather than the major histocompatibility complex, play the major role in the expression of cardiac pathogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Allelic variation on murine chromosome 11 modifies host inflammatory responses and resistance to Bacillus anthracis

Anthrax is a potentially fatal disease resulting from infection with Bacillus anthracis. The outcome of infection is influenced by pathogen-encoded virulence factors such as lethal toxin (LT), as well as by genetic variation within the host. To identify host genes controlling susceptibility to anthrax, a library of congenic mice consisting of strains with homozygous chromosomal segments from the LT-responsive CAST/Ei strain introgressed on a LT-resistant C57BL/6 (B6) background was screened for response to LT. Three congenic strains containing CAST/Ei regions of chromosome 11 were identified that displayed a rapid inflammatory response to LT similar to, but more severe than that driven by a LT-responsive allele of the inflammasome constituent NRLP1B. Importantly, increased response to LT in congenic mice correlated with greater resistance to infection by the Sterne strain of B. anthracis. The genomic region controlling the inflammatory response to LT was mapped to 66.36-74.67 Mb on chromosome 11, a region that encodes the LT-responsive CAST/Ei allele of Nlrp1b. However, known downstream effects of NLRP1B activation, including macrophage pyroptosis, cytokine release, and leukocyte infiltration could not fully explain the response to LT or the resistance to B. anthracis Sterne in congenic mice. Further, the exacerbated response in congenic mice is inherited in a recessive manner while the Nlrp1b-mediated response to LT is dominant. Finally, congenic mice displayed increased responsiveness in a model of sepsis compared with B6 mice. In total, these data suggest that allelic variation of one or more chromosome 11 genes in addition to Nlrp1b controls the severity of host response to multiple inflammatory stimuli and contributes to resistance to B. anthracis Sterne. Expression quantitative trait locus analysis revealed 25 genes within this region as high priority candidates for contributing to the host response to LT.     

Genetic analysis of the diabetes-prone C57BLKS/J mouse strain reveals genetic contribution from multiple strains

The C57BLKS/J (BKS) inbred mouse strain is a widely used animal model of type 2 diabetes. In the presence of the diabetes (db) mutation, obese BKS-db mice develop severe diabetes. Genetic studies of diabetes-susceptibility in this strain are facilitated by the fact that BKS is a genetic composite between the diabetes-resistant C57BL/6J (B6) and susceptible DBA/2J (DBA) strains. On this basis, it has been hypothesized that diabetes-susceptibility in BKS is conferred by DBA-derived alleles. However, recent studies revealed non-B6/non-DBA genetic material in BKS. To identify the origin of this genetic component, we generated a genomic map of BKS using 537 microsatellite markers. Our results demonstrate that, in addition to B6 and DBA, BKS contains alleles from at least three other strains, including 129, C57BL/10 and an unidentified mouse strain. We also analyzed two congenic strains, B6-db and BKS-db, which are widely used for the genetic mapping of diabetes-susceptibility loci. We identified several donor-derived genomic regions introduced during the generation of these congenic strains. In summary, our study reveals novel aspects of the genetic fine-structure of BKS and related strains and facilitates the identification of diabetes-susceptibility loci in this mouse model.     

Behavioral differences among fourteen inbred mouse strains commonly used as disease models

We compared the behavior of 14 inbred mouse strains and an F1 hybrid commonly used in transgenic and knockout production. These strains were 129P3/J, 129S1/SvImJ, 129S6/SvEvTac, 129T2/SvEmsJ, 129X1/SvJ (formerly 129/J, 129/Sv-p+Tyr+Kitl+/J, 129/SvEvTac, 129SvEmsJ, and 129/SvJ, respectively), A/JCrTac, BALB/cAnNTac, C3H/HeNTac, C57BL/6J, C57BL/6NTac, DBA/2NTac, FVB/NTac, NOD/MrkTac, SJL/JCrNTac, and the hybrid B6129S6F1Tac. Performance in three behavioral tests (rotorod, open-field activity-habituation, and contextual and cued fear conditioning) was determined. On the rotorod assay, SJL/JCrNTac mice had the shortest latencies to fall on the first day of testing, and DBA/2NTac mice showed impaired motor learning. Open-field behavior was analyzed using the parameters total distance, center distance, velocity, and vertical activity. 129T2/EvEmsJ and A/JCrTac were least active in the open field, whereas NOD/MrkTac mice were most active. Contrary to earlier studies, we found that all strains habituated to the open field in at least one of these parameters. In contextual and cued fear conditioning, all strains displayed activity suppression. However, FVB/NTac mice reacted less strongly to both context and cue than did most of the other strains. There were no significant behavioral differences between C57BL/6J and C57BL/6NTac, except for higher open-field activity in C57BL/6J female mice. These findings illustrate the importance of the appropriate selection of background strain for transgenic, gene targeting, or drug research.     

Arachidonic acid inhibits inflammatory responses by binding to myeloid differentiation factor-2 (MD2) and preventing MD2/toll-like receptor 4 signaling activation

Arachidonic acid (AA) plays a fundamental role in the function of all cells. Metabolites of AA contribute to inflammation as well as for resolving inflammation. Although AA-derived metabolites exhibit well-substantiated bioactivity, it is not known whether AA regulates inflammatory responses independent of its metabolites. With the recent discovery that saturated fatty acids activate toll-like receptor-4 (TLR4), we tested the hypothesis that AA directly regulates inflammatory responses through modulating the activity of TLR4. In cultured cardiomyocytes and macrophages, we found that AA prevents saturated fatty acid-induced TLR4 complex formation with accessory proteins and the induction of proinflammatory cytokines. We discovered that AA directly binds to TLR4 co-receptor, myeloid differentiation factor 2 (MD2) and prevents saturated fatty acids from activating TLR4 pro-inflammatory signaling pathway. Similarly, AA reduced lipopolysaccharide (LPS)-induced inflammation in macrophages and septic death in mice through binding to MD2. In high-fat diet mouse model of obesity and LPS-induced model of acute lung injury, both mediating inflammatory responses through TLR4, treatment with AA prevented MD2/TLR4 dimerization, induction of inflammatory factors, and tissue injuries. In summary, we have discovered that AA interacts with MD2 and disrupts TLR4 activation by LPS and saturated fatty acids. These findings provide experimental evidence for a direct mechanism of AA-induced regulation of inflammation.     

Mouse senile amyloidosis. ASSAM amyloidosis in mice presents universally as a systemic age-associated amyloidosis.

Amyloid deposition in 11 inbred strains of mice (A/J, SJL/J, DDD, C57BL/6J, B10.BR, C57BL/10, B10A/SgSn, C3H/HeMs, B10A(5R), DBA/2 and C57BL/6Cr5/c) was studied using the peroxidase antiperoxidase (PAP) method and antisera against ASSAM and murine protein AA. Among the 170 mice examined, in 77 (45.3%) from the nine strains other than C3H/HeMs and DBA/2, there was evidence of spontaneous amyloid deposits in routine histological sections. Immunohistochemical studies using 54 mice with amyloid deposition, demonstrated ASSAM deposition in 45 mice (83.3%) in all nine strains, although the incidence and intensity of the deposition differed somewhat between strains. SJL/J and A/J had ASSAM deposits from the age of 8 months and the incidence increased with advancing age. In the other seven strains, ASSAM was first deposited at an older age than in the SJL/J and A/J strains. In A J, C57BL/6J, C57BL/10, B10.BR, B10A(5R) and C57BL/6Cr5/c, protein AA often coexisted with ASSAM. The distribution pattern of the ASSAM deposits was similar to that observed among the SAM strains. Thus, ASSAM is an ubiquitously distributed senile amyloid protein in the mouse. Determination of the molecular type of apoA-II, a serum precursor of ASSAM, among all 11 strains using the polymerase chain reaction (PCR) revealed the SAM-P/1 type apoA-II variant in SJL/J and A/J strains with a high susceptibility to ASSAM deposition. We concluded from this study that amino acid substitution in precursor apoA-II may be responsible for the early onset and severe amyloid deposition in the mouse.     

Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcgammaRII

Human autoimmune diseases thought to arise from the combined effects of multiple susceptibility genes include systemic lupus erythematosus (SLE) and autoimmune diabetes. Well-characterised polygenic mouse models closely resembling each of these diseases exist, and genetic evidence links receptors for the Fc portion of immunoglobulin G (FcR) with their pathogenesis in mice and humans [1] [2] [3]. FcRs may be activatory or inhibitory and regulate a variety of immune and inflammatory processes [4] [5]. FcgammaRII (CD32) negatively regulates activation of cells including B cells and macrophages [6]. FcgammaRII-deficient mice are prone to immune-mediated disease [7] [8] [9]. The gene encoding FcgammaRII, Fcgr2, is contained in genetic susceptibility intervals in mouse models of SLE such as the New Zealand Black (NZB) contribution to the (NZB x New Zealand White (NZW)) F1 strain [1] [10] [11] and the BXSB strain [12], and in human SLE [1] [2] [3]. We therefore sequenced Fcgr2 and identified a haplotype defined by deletions in the Fcgr2 promoter region that is present in major SLE-prone mouse strains (NZB, BXSB, SB/Le, MRL, 129 [13]) and non-obese diabetic (NOD) mice but absent in control strains (BALB/c, C57BL/6, DBA/2, C57BL/10) and NZW mice. The autoimmune haplotype was associated with reduced cell-surface expression of FcgammaRII on macrophages and activated B cells and with hyperactive macrophages resembling those of FcgammaRII-deficient mice, and is therefore likely to play an important role in the pathogenesis of SLE and possibly diabetes.     

Strain distribution pattern of susceptibility to immune-mediated nephritis

The genetic basis of immune-mediated nephritis is poorly understood. Recent studies have demonstrated that the NZW mouse strain is more prone to immune-mediated nephritis compared with C57BL/6 and BALB/c strains. The present study extends these findings by challenging 12 additional inbred strains of mice with rabbit anti-mouse glomerular basement membrane (GBM) reactive sera. Compared with control sera-injected mice and anti-GBM-injected A/J, AKR/J, C3H/HeJ, DBA/2J, MRL/MpJ, NOD/LtJ, P/J, SJL/J, and SWR/J mice, the anti-GBM-injected BUB/BnJ, DBA/1J, and 129/svJ mice developed severe proteinuria and azotemia. Their kidneys exhibited pronounced glomerulonephritis, with crescent formation, as well as tubulointerstitial disease, with these phenotypes being particularly profound in 129/svJ mice. However, these strains did not appear to differ in the nature of their xenogeneic immune response to the administered rabbit sera, either quantitatively or qualitatively. Collectively, these findings allude to the presence of genetic elements in the BUB/BnJ, DBA/1J, and 129/svJ genomes that may potentially confer susceptibility to immune-mediated nephritis. Detailed studies to dissect out the immunological and genetic basis of renal disease in these three strains are clearly warranted.     

Behavioral, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains

Food restriction paradigms are widely used in animal studies to investigate systems involved in energy regulation. We have observed behavioral, physiological, and molecular differences in response to food restriction in three inbred mouse strains, C57BL/6J, A/J, and DBA/2J. These are the progenitors of chromosome substitution and recombinant inbred mouse strains used for mapping complex traits. DBA/2J and A/J mice increased their locomotor activity during food restriction, and both displayed a decrease in body temperature, but the decrease was significantly larger in DBA/2J compared with A/J mice. C57BL/6J mice did not increase their locomotor activity and displayed a large decrease in their body temperature. The large decline in body temperature during food restriction in DBA/2J and C57BL/6J strains was associated with a robust reduction in plasma leptin levels. DBA/2J mice showed a marked decrease in white and brown adipose tissue masses and an upregulation of the antithermogenic hypothalamic neuropeptide Y Y(1) receptor. In contrast, A/J mice showed a reduction in body temperature to a lesser extent that may be explained by downregulation of the thermogenic melanocortin 3 receptor and by behavioral thermoregulation as a consequence of their increased locomotor activity. These data indicate that genetic background is an important parameter in controlling an animal's adaptation strategy in response to food restriction. Therefore, mouse genetic mapping populations based on these progenitor lines are highly valuable for investigating mechanisms underlying strain-dependent differences in behavioral physiology that are seen during reduced food availability.     

Rapid vascular responses to anthrax lethal toxin in mice containing a segment of chromosome 11 from the CAST/Ei strain on a C57BL/6 genetic background

Host allelic variation controls the response to B. anthracis and the disease course of anthrax. Mouse strains with macrophages that are responsive to anthrax lethal toxin (LT) show resistance to infection while mouse strains with LT non-responsive macrophages succumb more readily. B6.CAST.11M mice have a region of chromosome 11 from the CAST/Ei strain (a LT responsive strain) introgressed onto a LT non-responsive C57BL/6J genetic background. Previously, B6.CAST.11M mice were found to exhibit a rapid inflammatory reaction to LT termed the early response phenotype (ERP), and displayed greater resistance to B. anthracis infection compared to C57BL/6J mice. Several ERP features (e.g., bloat, hypothermia, labored breathing, dilated pinnae vessels) suggested vascular involvement. To test this, Evan's blue was used to assess vessel leakage and intravital microscopy was used to monitor microvascular blood flow. Increased vascular leakage was observed in lungs of B6.CAST.11M mice compared to C57BL/6J mice 1 hour after systemic administration of LT. Capillary blood flow was reduced in the small intestine mesentery without concomitant leukocyte emigration following systemic or topical application of LT, the latter suggesting a localized tissue mechanism in this response. Since LT activates the Nlrp1b inflammasome in B6.CAST.11M mice, the roles of inflammasome products, IL-1β and IL-18, were examined. Topical application to the mesentery of IL-1β but not IL-18 revealed pronounced slowing of blood flow in B6.CAST.11M mice that was not present in C57BL/6J mice. A neutralizing anti-IL-1β antibody suppressed the slowing of blood flow induced by LT, indicating a role for IL-1β in the response. Besides allelic differences controlling Nlrp1b inflammasome activation by LT observed previously, evidence presented here suggests that an additional genetic determinant(s) could regulate the vascular response to IL-1β. These results demonstrate that vessel leakage and alterations to blood flow are part of the rapid response in mice resistant to B. anthracis infection.     

Vascular injury response in mice is dependent on genetic background

Mouse models are employed to unravel the pathophysiology of vascular restenosis. Although much effort has been spent on how to apply an adequate arterial injury, the influence of the genetic background of mice has not yet received sufficient consideration. The study presented herein was designed to demonstrate the influence of the mouse strain on vascular injury response. Mice of a defined background (50% 129 strain and 50% DBA strain) were backcrossed into either the 129 strain or the DBA strain. Male offspring were subjected to a femoral artery injury model by applying an electric current. Morphometric analysis revealed that backcrossing into the 129 strain resulted in a significant (P < 0.001) 17-fold increase in neointima formation (n = 17 mice) compared with backcrossing into the DBA strain (n = 19). The values of neointima area were 9.18 x 10(3) +/- 2.13 x 10(3) and 0.54 x 10(3) +/- 0.39 x 10(3) microm2, respectively. In conjunction, the vessel wall area was enhanced by 1.8-fold (P < 0.001). In contrast, no significant differences were found for the areas of the lumen and the tunica media. Similarly, a significant increase in neointima formation was also found for mice of pure 129 strain compared with pure DBA strain. The results underline the importance of the genetic background for studies on vascular injury response. Furthermore, because the mouse genome of the various strains is well defined, serial testing of the genetic background of mice will provide candidate genes and/or genetic modifiers controlling vascular injury response.     

Sucrose consumption in mice: Major influence of two genetic Loci affecting peripheral sensory responses

Individual variability in sucrose consumption is prominent in humans and other species. To investigate the genetic contribution to this complex behavior, we conducted behavioral, electrophysiological, and genetic studies, using male progeny of two inbred mouse strains (C57BL/6ByJ [B6] and 129/J [129]) and their F₂ hybrids. Two loci on Chromosome (Chr) 4 were responsible for over 50% of the genetic variability in sucrose intake. These loci apparently modulated intake by altering peripheral neural responses to sucrose. One locus affected the response threshold, whereas the other affected the response magnitude. These findings suggest that the majority of difference in sucrose intake between male B6 and 129 mice is due to polymorphisms of two genes that influence receptor or peripheral nervous system activity. Received: 27 January 1997 / Accepted: 17 March 1997     

Genetic background modulates the phenotype of a mouse model of DYT1 dystonia

DYT1 dystonia is a debilitating neurological disease characterized by involuntary twisting movements. The disease is caused by an in-frame deletion (GAG, "ΔE") mutation in the TOR1A gene that encodes the torsinA protein. Intriguingly, only 30% of mutation carriers exhibit motor symptoms despite the fact that functional brain imaging studies show abnormal brain metabolism in all carriers. Because genetic modifiers may be a determinant of this reduced penetrance, we examined the genetic contribution of three different inbred strains of mice on the DYT1 mutation in animals that are homozygous (Tor1a(ΔE/ΔE)) or heterozygous (Tor1a(ΔE/+); disease state) for the disease-causing ΔE mutation. We find that the DBA/2J, C57BL/6J, and CD1-ICR contribution of genes significantly alter lifespan in Tor1a(ΔE/ΔE) mice, which die during the first few days of life on the 129S6/SvEvTac (129) background. The C57BL/6J (B6) strain significantly decreases life expectancy of Tor1a(ΔE/ΔE) animals but, like 129S6/SvEvTac Tor1a(ΔE/+) mice, congenic C57BL/6J Tor1a(ΔE/+) mice do not exhibit any motor abnormalities. In contrast, the DBA/2J (D2) strain significantly increases life expectancy. This effect was not present in congenic DBA/2J Tor1a(ΔE/ΔE) mice, indicating that the extended lifespan of F2 129/D2 mice was due to a combination of homozygous and heterozygous allelic effects. Our observations suggest that genetic modifiers may alter the penetrance of the ΔE mutation, and that mapping these modifiers may provide fresh insight into the torsinA molecular pathway.     

Genetic analysis of intestinal cholesterol absorption in inbred mice.

A genetic mapping strategy was employed to identify chromosomal regions harboring genes that influence the absorption of intestinal cholesterol in the mouse. Analysis of seven inbred strains of male mice (129P3, AKR, BALB/c, C3H/He, C57BL/6, DBA/2, and SJL, all from Jackson Laboratories) revealed substantial differences in their abilities to absorb a bolus of cholesterol delivered by gavage. Crosses between high (AKR, 129) and low (DBA/2, SJL) absorbing strains revealed evidence for the presence of dominant genes that increase and decrease cholesterol absorption. Backcrosses between F1 offspring and parental strains (DBA/2xAKD2F1 and 129xSJL129F1) followed by linkage analyses revealed four quantitative trait loci that influenced cholesterol absorption. Analyses of recombinant inbred strains identified an additional three loci affecting this phenotype. These seven quantitative trait loci, which map to different chromosomes and are termed Cholesterol absorption 1-7 (Chab1-7) loci, together influence the absorption of intestinal cholesterol in mice and are likely to be involved in different steps of this complex pathway.     

The DBA.2 mouse is susceptible to disease following infection with a broad, but limited, range of influenza A and B viruses

We assessed the relative susceptibilities to disease of the DBA.2 and C57BL/6 mouse models upon infection with a range of influenza A and B viruses. DBA.2 mice were more susceptible to disease upon inoculation with human H1N1 influenza A virus strains, several swine influenza viruses, and influenza B viruses but were not overtly susceptible to infection with human seasonal H3N2 strains. Hemagglutination inhibition and immunoglobulin isotype profiling indicated that DBA.2 and C57BL/6 mice generate comparable humoral responses upon equivalent 50% mouse lethal dose (MLD(50)) challenges with influenza virus. Our data demonstrate the utility of DBA.2 mice for the elucidation of influenza virus pathogenicity determinants and the testing of influenza vaccines.