scholarly journals A novel murine model for assessing fetal and birth outcomes following transgestational maternal malaria infection

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Catherine D. Morffy Smith ◽  
Brittany N. Russ ◽  
Alicer K. Andrew ◽  
Caitlin A. Cooper ◽  
Julie M. Moore
Keyword(s):  
Malaria Infection ◽  
Inbred Mouse ◽  
Parasite Burden ◽  
Postnatal Growth ◽  
Mouse Strains ◽  
Heme Oxygenase 1 ◽  
Human Populations ◽  
Chronic Infections ◽  
Early Gestation ◽  
Maternal Illness

AbstractPlasmodium falciparum infection during pregnancy is a major cause of severe maternal illness and neonatal mortality. Mouse models are important for the study of gestational malaria pathogenesis. When infected with Plasmodium chabaudi chabaudi AS in early gestation, several inbred mouse strains abort at midgestation. We report here that outbred Swiss Webster mice infected with P. chabaudi chabaudi AS in early gestation carry their pregnancies to term despite high parasite burden and malarial hemozoin accumulation in the placenta at midgestation, with the latter associated with induction of heme oxygenase 1 expression. Infection yields reduced fetal weight and viability at term and a reduction in pup number at weaning, but does not influence postnatal growth prior to weaning. This novel model allows for the exploration of malaria infection throughout pregnancy, modeling chronic infections observed in pregnant women prior to the birth of underweight infants and enabling the production of progeny exposed to malaria in utero, which is critical for understanding the postnatal repercussions of gestational malaria. The use of outbred mice allows for the exploration of gestational malaria in a genetically diverse model system, better recapitulating the diversity of infection responses observed in human populations.

scholarly journals Terc Gene Cluster Variants Predict Liver Telomere Length in Mice

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2623
Author(s):  
Dana Zeid ◽  
Sean Mooney-Leber ◽  
Laurel R. Seemiller ◽  
Lisa R. Goldberg ◽  
Thomas J. Gould
Keyword(s):  
Linkage Disequilibrium ◽  
Telomere Length ◽  
Gene Cluster ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Chromosome 3 ◽  
Human Populations ◽  
Nucleotide Polymorphisms ◽  
Initial Finding

Variants in a gene cluster upstream-adjacent to TERC on human chromosome 3, which includes genes APRM, LRRC31, LRRC34 and MYNN, have been associated with telomere length in several human populations. Currently, the mechanism by which variants in the TERC gene cluster influence telomere length in humans is unknown. Given the proximity between the TERC gene cluster and TERC (~0.05 Mb) in humans, it is speculated that cluster variants are in linkage disequilibrium with a TERC causal variant. In mice, the Terc gene/Terc gene cluster are also located on chromosome 3; however, the Terc gene cluster is located distantly downstream of Terc (~60 Mb). Here, we initially aim to investigate the interactions between genotype and nicotine exposure on absolute liver telomere length (aTL) in a panel of eight inbred mouse strains. Although we found no significant impact of nicotine on liver aTL, this first experiment identified candidate single nucleotide polymorphisms (SNPs) in the murine Terc gene cluster (within genes Lrrc31, Lrriq4 and Mynn) co-varying with aTL in our panel. In a second experiment, we tested the association of these Terc gene cluster variants with liver aTL in an independent panel of eight inbred mice selected based on candidate SNP genotype. This supported our initial finding that Terc gene cluster polymorphisms impact aTL in mice, consistent with data in human populations. This provides support for mice as a model for telomere dynamics, especially for studying mechanisms underlying the association between Terc cluster variants and telomere length. Finally, these data suggest that mechanisms independent of linkage disequilibrium between the Terc/TERC gene cluster and the Terc/TERC gene mediate the cluster’s regulation of telomere length.

Integrative analysis reveals mouse strain-dependent responses to acute ozone exposure associated with airway macrophage transcriptional activity

2021 ◽  
Author(s):  
Adelaide Tovar ◽  
Wesley L. Crouse ◽  
Gregory J. Smith ◽  
Joseph M. Thomas ◽  
Benjamin P. Keith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Inbred Mouse ◽  
Chromatin Accessibility ◽  
Ozone Exposure ◽  
Mouse Strains ◽  
Human Populations ◽  
Transcriptional Responses ◽  
Adult Mice ◽  
Strain Dependent

Acute ozone (O3) exposure is associated with multiple adverse cardiorespiratory outcomes, the severity of which varies across individuals in human populations and inbred mouse strains. However, molecular determinants of response, including susceptibility biomarkers that distinguish who will develop severe injury and inflammation, are not well characterized. We and others have demonstrated that airway macrophages (AMs) are an important resident immune cell type that are functionally and transcriptionally responsive to O3 inhalation. Here, we sought to explore influences of strain, exposure, and strain-by-O3 exposure interactions on AM gene expression and identify transcriptional correlates of O3-induced inflammation and injury across 6 mouse strains, including 5 Collaborative Cross (CC) strains. We exposed adult mice of both sexes to filtered air (FA) or 2 ppm O3 for 3 hours, and measured inflammatory and injury parameters 21 hours later. Mice exposed to O3 developed airway neutrophilia and lung injury with strain-dependent severity. In AMs, we identified a common core O3 response signature across all strains, as well as a set of genes exhibiting strain-by-O3 exposure interactions. In particular, a prominent gene expression contrast emerged between a low- (CC017/Unc) and high-responding (CC003/Unc) strain, as reflected by cellular inflammation and injury. Further inspection indicated that differences in their baseline gene expression and chromatin accessibility profiles likely contributes to their divergent post-O3 exposure transcriptional responses. Together, these results suggest that aspects of O3-induced respiratory responses are mediated through altered AM transcriptional signatures, and further confirms the importance of gene-environment interactions in mediating differential responsiveness to environmental agents.

scholarly journals Aurothioglucose does not improve alveolarization or elicit sustained Nrf2 activation in C57BL/6 models of bronchopulmonary dysplasia

2018 ◽  
Vol 314 (5) ◽  
pp. L736-L742 ◽  
Author(s):  
Qian Li ◽  
Rui Li ◽  
Stephanie B. Wall ◽  
Katelyn Dunigan ◽  
Changchun Ren ◽  
...  
Keyword(s):  
Lung Development ◽  
Inbred Mouse ◽  
Thioredoxin Reductase ◽  
Differential Sensitivity ◽  
Mouse Strains ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Protective Effects ◽  
Quinone Oxidoreductase ◽  
Nrf2 Activation

We previously showed that the thioredoxin reductase-1 (TrxR1) inhibitor aurothioglucose (ATG) improves alveolarization in hyperoxia-exposed newborn C3H/HeN mice. Our data supported a mechanism by which the protective effects of ATG are mediated via sustained nuclear factor E2-related factor 2 (Nrf2) activation in hyperoxia-exposed C3H/HeN mice 72 h after ATG administration. Given that inbred mouse strains have differential sensitivity and endogenous Nrf2 activation by hyperoxia, the present studies utilized two C57BL/6 exposure models to evaluate the effects of ATG on lung development and Nrf2 activation. The first model (0–14 days) was used in our C3H/HeN studies and the 2nd model (4–14 days) is well characterized in C57BL/6 mice. ATG significantly inhibited lung TrxR1 activity in both models; however, there was no effect on parameters of alveolarization in C57BL/6 mice. In sharp contrast to C3H/HeN mice, there was no effect of ATG on pulmonary NADPH quinone oxidoreductase-1 ( Nqo1) and heme oxygenase-1 ( Hmox1) at 72 h in either C57BL/6 model. In conclusion, although ATG inhibited TrxR1 activity in the lungs of newborn C57BL/6 mice, effects on lung development and sustained Nrf2-dependent pulmonary responses were blunted. These findings also highlight the importance of strain-dependent hyperoxic sensitivity in evaluation of potential novel therapies.

scholarly journals Multiple trait measurements in 43 inbred mouse strains capture the phenotypic diversity characteristic of human populations

2007 ◽  
Vol 102 (6) ◽  
pp. 2369-2378 ◽  
Author(s):  
Karen L. Svenson ◽  
Randy Von Smith ◽  
Phyllis A. Magnani ◽  
Heather R. Suetin ◽  
Beverly Paigen ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Phenotypic Diversity ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Human Populations ◽  
Large Set ◽  
Inbred Mouse Strains ◽  
High Fat ◽  
Mineral Density

The breadth of genetic and phenotypic variation among inbred strains is often underappreciated because assessments include only a limited number of strains. Evaluation of a larger collection of inbred strains provides not only a greater understanding of this variation but collectively mimics much of the variation observed in human populations. We used a high-throughput phenotyping protocol to measure females and males of 43 inbred strains for body composition (weight, fat, lean tissue mass, and bone mineral density), plasma triglycerides, high-density lipoprotein and total cholesterol, glucose, insulin, and leptin levels while mice consumed a high-fat, high-cholesterol diet. Mice were fed a chow diet until they were 6–8 wk old and then fed the high-fat diet for an additional 18 wk. As expected, broad phenotypic diversity was observed among these strains. Significant variation between the sexes was also observed for most traits measured. Additionally, the response to the high-fat diet differed considerably among many strains. By the testing of such a large set of inbred strains for many traits, multiple phenotypes can be considered simultaneously and thereby aid in the selection of certain inbred strains as models for complex human diseases. These data are publicly available in the web-accessible Mouse Phenome Database ( http://www.jax.org/phenome ), an effort established to promote systematic characterization of biochemical and behavioral phenotypes of commonly used and genetically diverse inbred mouse strains. Data generated by this effort builds on the value of inbred mouse strains as a powerful tool for biomedical research.

scholarly journals High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 296
Author(s):  
Andrea Zelmer ◽  
Lisa Stockdale ◽  
Satria A. Prabowo ◽  
Felipe Cia ◽  
Natasha Spink ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tissue Distribution ◽  
Inbred Mouse ◽  
Subcutaneous Administration ◽  
Mouse Strains ◽  
Human Populations ◽  
Early Assessment ◽  
Vaccine Candidates ◽  
Immunological Mechanisms ◽  
Tissue Homogenates

Background:The only available tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG), has variable efficacy. New vaccines are therefore urgently needed. Why BCG fails is incompletely understood, and the tools used for early assessment of new vaccine candidates do not account for BCG variability. Taking correlates of risk of TB disease observed in human studies and back-translating them into mice to create models of BCG variability should allow novel vaccine candidates to be tested early in animal models that are more representative of the human populations most at risk. Furthermore, this could help to elucidate the immunological mechanisms leading to BCG failure. We have chosen the monocyte to lymphocyte (ML) ratio as a correlate of risk of TB disease and have back-translated this into a mouse model.Methods: Four commercially available, inbred mouse strains were chosen. We investigated their baseline ML ratio by flow cytometry; extent of BCG-mediated protection from Mycobacterium tuberculosisinfection by experimental challenge; vaccine-induced interferon gamma (IFNγ) response by ELISPOT assay; and tissue distribution of BCG by plating tissue homogenates.Results:The ML ratio varied significantly between A/J, DBA/2, C57Bl/6 and 129S2 mice. A/J mice showed the highest BCG-mediated protection and lowest ML ratio, while 129S2 mice showed the lowest protection and higher ML ratio. We also found that A/J mice had a lower antigen specific IFNγ response than 129S2 mice. BCG tissue distribution appeared higher in A/J mice, although this was not statistically significant.Conclusions:These results suggest that the ML ratio has an impact on BCG-mediated protection in mice, in alignment with observations from clinical studies. A/J and 129S2 mice may therefore be useful models of BCG vaccine variability for early TB vaccine testing. We speculate that failure of BCG to protect from TB disease is linked to poor tissue distribution in a ML high immune environment.

scholarly journals High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 296 ◽  
Author(s):  
Andrea Zelmer ◽  
Lisa Stockdale ◽  
Satria A. Prabowo ◽  
Felipe Cia ◽  
Natasha Spink ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tissue Distribution ◽  
Inbred Mouse ◽  
Subcutaneous Administration ◽  
Mouse Strains ◽  
Human Populations ◽  
Early Assessment ◽  
Vaccine Candidates ◽  
Immunological Mechanisms ◽  
Tissue Homogenates

Background: The only available tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG), has variable efficacy. New vaccines are therefore urgently needed. Why BCG fails is incompletely understood, and the tools used for early assessment of new vaccine candidates do not account for BCG variability. Taking correlates of risk of TB disease observed in human studies and back-translating them into mice to create models of BCG variability should allow novel vaccine candidates to be tested early in animal models that are more representative of the human populations most at risk. Furthermore, this could help to elucidate the immunological mechanisms leading to BCG failure. We have chosen the monocyte to lymphocyte (ML) ratio as a correlate of risk of TB disease and have back-translated this into a mouse model. Methods: Four commercially available, inbred mouse strains were chosen. We investigated their baseline ML ratio by flow cytometry; extent of BCG-mediated protection from Mtb infection by experimental challenge; vaccine-induced interferon gamma (IFNγ) response by ELISPOT assay; and tissue distribution of BCG by plating tissue homogenates. Results: The ML ratio varied significantly between A/J, DBA/2, C57Bl/6 and 129S2 mice. A/J mice showed the highest BCG-mediated protection and lowest ML ratio, while 129S2 mice showed the lowest protection and higher ML ratio. We also found that A/J mice had a lower antigen specific IFNγ response than 129S2 mice. BCG tissue distribution appeared higher in A/J mice, although this was not statistically significant. Conclusions: These results suggest that the ML ratio has an impact on BCG-mediated protection in mice, in alignment with observations from clinical studies. A/J and 129S2 mice may therefore be useful models of BCG vaccine variability for early TB vaccine testing. We speculate that failure of BCG to protect from TB disease is linked to poor tissue distribution in a ML high immune environment.

scholarly journals Coupling between tolerance and resistance for two related Eimeria parasite species

2020 ◽  
Author(s):  
Alice Balard ◽  
Víctor Hugo Jarquín-Díaz ◽  
Jenny Jost ◽  
Vivian Mittné ◽  
Francisca Böhning ◽  
...  
Keyword(s):  
Parasite Species ◽  
Inbred Mouse ◽  
Relative Weight ◽  
Parasite Burden ◽  
F1 Hybrids ◽  
Mouse Strains ◽  
Mus Musculus Domesticus ◽  
Relative Weight Loss ◽  
Host Parasite ◽  
Immune Defences

AbstractResistance (host capacity to reduce parasite burden) and tolerance (host capacity to reduce impact on its health for a given parasite burden) manifest two different lines of defence. Tolerance can be independent from resistance, traded-off against it, or the two can be positively correlated because of redundancy in underlying (immune) processes. We here tested whether this coupling between tolerance and resistance could differ upon infection with closely related parasite species. We tested this in experimental infections with two parasite species of the genus Eimeria. We measured proxies for resistance (the (inverse of) number of parasite transmission stages (oocysts) per gram of feces at the day of maximal shedding) and tolerance (the slope of maximum relative weight loss compared to day of infection on number of oocysts per gram of feces at the day of maximal shedding for each host strain) in four inbred mouse strains and four groups of F1 hybrids belonging to two mouse subspecies, Mus musculus domesticus and M. m. musculus. We found a negative correlation between resistance and tolerance against E. falciformis, while the two are uncoupled against E. ferrisi. We conclude that resistance and tolerance against the first parasite species might be traded off, but evolve more independently in different mouse genotypes against the latter. We argue that evolution of the host immune defences can be studied largely irrespective of parasite isolates if resistance-tolerance coupling is absent or weak (E. ferrisi) but host-parasite coevolution is more likely observable and best studied in a system with negatively correlated tolerance and resistance (E. falciformis).

scholarly journals Comparative Evaluation of Two Vaccine Candidates against Experimental Leishmaniasis Due to Leishmania major Infection in Four Inbred Mouse Strains

2009 ◽  
Vol 16 (11) ◽  
pp. 1529-1537 ◽  
Author(s):  
Fouad Benhnini ◽  
Mehdi Chenik ◽  
Dhafer Laouini ◽  
Hechmi Louzir ◽  
Pierre André Cazenave ◽  
...  
Keyword(s):  
Mouse Strain ◽  
Leishmania Major ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Human Populations ◽  
Inbred Mouse Strains ◽  
Vaccine Candidates ◽  
Preclinical Evaluation ◽  
Protein Disulfide

ABSATRCT Experimental leishmaniasis in BALB/c and C57BL/6 mice are the most investigated murine models that were used for the preclinical evaluation of Leishmania vaccine candidates. We have previously described two new inbred mouse strains named PWK and MAI issued from feral founders that also support the development of experimental leishmaniasis due to L. major. In this study, we sought to determine whether different mouse inbred strains generate concordant or discordant results when used to evaluate the potential of Leishmania proteins to protect against experimental leishmaniasis. To this end, two Leishmania proteins, namely, LACK (for Leishmania homolog of receptor for activated C kinase) and LmPDI (for L. major protein disulfide isomerase) were compared for their capacity to protect against experimental leishmaniasis in PWK, MAI, BALB/c, and C57BL/6 inbred mouse strains. Our data show that the capacity of Leishmania proteins to confer protection depends on the mouse strain used, stressing the important role played by the genetic background in shaping the immune response against the pathogen. These results may have important implications for the preclinical evaluation of candidate Leishmania vaccines: rather than using a single mouse strain, a panel of different inbred strains of various genetic backgrounds should be tested in parallel. The antigen that confers protection in the larger range of inbred strains may have better chances to be also protective in outbred human populations and should be selected for clinical trials.

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