Biology subjects

Linnertz, C. L.

Publications and source records attributed to Linnertz, C. L..

6 recordsLinked to original sources

bioRxiv2026

Cross-coronavirus host susceptibility loci influence disease severity through immune mediators

Severe disease following infection with SARS-CoV or SARS-CoV-2 is driven in part by genetically regulated immune responses that promote lung injury. Previously, we showed that genetic risk for severe disease is conserved across viruses and between mouse and human, identifying the HrS43 locus as a shared determinant of severity. Here, to resolve immune pathways linking host loci to disease outcomes, we apply an integrative statistical framework combining Bayesian identification of predictive immune traits with QTL mapping and mediation analysis across infection conditions. This approach identifies immune predictors of disease severity across both viruses, reveals extensive genetic control of the immune system at homeostasis and during infection, and supports locus-specific causal mechanisms of immunopathology. Notably, HrS43 appears to influence disease severity through distinct immune mediators in SARS-CoV versus SARS-CoV-2, demonstrating that conserved genetic susceptibility can drive virus-specific immunopathology with translational relevance across species.

genetics↗

bioRxiv2023

Sarbecovirus disease susceptibility is conserved across viral and host models

Coronaviruses have caused three severe epidemics since the start of the 21st century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing likelihood of future coronavirus outbreaks motivates greater understanding of factors leading to severe coronavirus disease. We screened ten strains from the Collaborative Cross mouse genetic reference panel and identified strains CC006/TauUnc (CC006) and CC044/Unc (CC044) as coronavirus-susceptible and resistant, respectively, as indicated by variable weight loss and lung congestion scores four days post-infection. We generated a genetic mapping population of 755 CC006xCC044 F2 mice and exposed the mice to one of three genetically distinct mouse-adapted coronaviruses: clade 1a SARS-CoV MA15 (n=391), clade 1b SARS-CoV-2 MA10 (n=274), and clade 2 HKU3-CoV MA (n=90). Quantitative trait loci (QTL) mapping in SARS-CoV- and SARS-CoV-2-infected F2 mice identified genetic loci associated with disease severity. Specifically, we identified seven loci associated with variation in outcome following infection with either virus, including one, HrS45, that is present in both groups. Three of these QTL, including HrS45, were also associated with HKU3-CoV MA outcome. HrS45 overlaps with a QTL previously reported by our lab that is associated with SARS-CoV outcome in CC011xCC074 F2 mice and is also syntenic with a human chromosomal region associated with severe COVID-19 outcomes in humans GWAS. The results reported here provide: (a) additional support for the involvement of this locus in SARS-CoV MA15 infection, (b) the first conclusive evidence that this locus is associated with susceptibility across the Sarbecovirus subgenus, and (c) demonstration of the relevance of mouse models in the study of coronavirus disease susceptibility in humans.

genetics↗

bioRxiv2023

A mutation in Themis contributes to peanut-induced oral anaphylaxis in CC027 mice

BackgroundThe development of peanut allergy is due to a combination of genetic and environmental factors, although specific genes have proven difficult to identify. Previously, we reported that peanut- sensitized CC027/GeniUnc (CC027) mice develop anaphylaxis upon oral challenge to peanut, unlike C3H/HeJ (C3H) mice. ObjectiveTo determine the genetic basis of orally-induced anaphylaxis to peanut in CC027 mice. MethodsA genetic mapping population between CC027 and C3H mice was designed to identify the genetic factors that drive oral anaphylaxis. A total of 356 CC027xC3H backcrossed mice were generated, sensitized to peanut, then challenged to peanut by oral gavage. Anaphylaxis and peanut-specific IgE were quantified for all mice. T-cell phenotyping was conducted on CC027 and five additional CC strains. ResultsAnaphylaxis to peanut was absent in 77% of backcrossed mice, with 19% showing moderate anaphylaxis, and 4% having severe anaphylaxis. A total of eight genetic loci were associated with variation in response to peanut challenge, six associated with anaphylaxis (temperature decrease) and two associated with peanut-specific IgE levels. There were two major loci that impacted multiple aspects of the severity of acute anaphylaxis, at which the CC027 allele was associated with worse outcome. At one of these loci, CC027 has a private genetic variant in the Themis (thymocyte-expressed molecule involved in selection) gene. Consistent with Themis described functions, we found that CC027 have more immature T cells with fewer CD8+, CD4+, and CD4+CD25+CD127- regulatory T cells. ConclusionOur results demonstrate a key role for Themis in the orally-reactive CC027 mouse model of peanut allergy.

genetics↗

bioRxiv2022

Forward genetic screen of homeostatic antibody levels in the Collaborative Cross identifies MBD1 as a novel regulator of B cell homeostasis

Variation in immune homeostasis, the state in which the immune system is maintained in the absence of stimulation, is highly variable across populations. This variation is attributed to both genetic and environmental factors. However, the identity and function of specific regulators have been difficult to identify in humans. We evaluated homeostatic antibody levels in the serum of the Collaborative Cross (CC) mouse genetic reference population. We found heritable variation in all antibody isotypes and subtypes measured. We identified 4 quantitative trait loci (QTL) associated with 3 IgG subtypes: IgG1, IgG2b, and IgG2c. While 3 of these QTL maps to known immunologically important regions of the genomes, Qih1 (associated with variation in IgG1) mapped to a novel locus on Chromosome 18. We further associated this locus with B cell proportions in the spleen and show that Methyl-CpG binding domain protein 1 is a novel regulator of homeostatic IgG1 levels in the serum and marginal zone B cells (MZB) in the spleen, consistent with a role in MZB differentiation to antibody secreting cells. SummaryHomeostatic antibody levels are highly variable between Collaborative Cross (CC) mouse strains. This forward genetic screen in the CC identifies Methyl-CpG binding domain protein 1 (MBD1) as a regulator of homeostatic IgG1 levels and marginal zone B cell differentiation.

genetics↗

bioRxiv2021

Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice

Variation in immune homeostasis, immune system stability, in organ systems such as the lungs is likely to shape the host response to infection at these exposed tissues. We evaluated immune homeostasis in immune cell populations in the lungs of the Collaborative Cross (CC) mouse genetic reference population. We found vast heritable variation in leukocyte populations with the frequency of many of these cell types showing distinct patterns relative to classic inbred strains C57BL/6J and BALB/cJ. We identified 28 quantitative trait loci (QTL) associated with variation in baseline lung immune cell populations, including several loci that broadly regulate the abundance of immune populations from distinct developmental lineages, and found that many of these loci have predictive value for influenza disease outcomes, demonstrating that genetic determinants of homeostatic immunity in the lungs regulate susceptibility to virus-induced disease. All told, we highlight the need to assess diverse mouse strains in understanding immune homeostasis and resulting immune responses.

genetics↗

bioRxiv2020

Content and performance of the MiniMUGA genotyping array, a new tool to improve rigor and reproducibility in mouse research

The laboratory mouse is the most widely used animal model for biomedical research, due in part to its well annotated genome, wealth of genetic resources and the ability to precisely manipulate its genome. Despite the importance of genetics for mouse research, genetic quality control (QC) is not standardized, in part due to the lack of cost effective, informative and robust platforms. Genotyping arrays are standard tools for mouse research and remain an attractive alternative even in the era of high-throughput whole genome sequencing. Here we describe the content and performance of a new Mouse Universal Genotyping Array (MUGA). MiniMUGA, an array-based genetic QC platform with over 11,000 probes. In addition to robust discrimination between most classical and wild-derived laboratory strains, MiniMUGA was designed to contain features not available in other platforms: 1) chromosomal sex determination, 2) discrimination between substrains from multiple commercial vendors, 3) diagnostic SNPs for popular laboratory strains, 4) detection of constructs used in genetically engineered mice, and 5) an easy to interpret report summarizing these results. In-depth annotation of all probes should facilitate custom analyses by individual researchers. To determine the performance of MiniMUGA we genotyped 6,899 samples from a wide variety of genetic backgrounds. The performance of MiniMUGA compares favorably with three previous iterations of the MUGA family of arrays both in discrimination capabilities and robustness. We have generated publicly available consensus genotypes for 241 inbred strains including classical, wild-derived and recombinant inbred lines. Here we also report the detection of a substantial number of XO and XXY individuals across a variety of sample types, the extension of the utility of reduced complexity crosses to genetic backgrounds other than C57BL/6, and the robust detection of 17 genetic constructs. There is preliminary but striking evidence that the array can be used to identify both partial sex chromosome duplication and mosaicism, and that diagnostic SNPs can be used to determine how long inbred mice have been bred independently from the main stock for a significant action of the genotyped inbred samples. We conclude that MiniMUGA is a valuable platform for genetic QC and important new tool to the increase rigor and reproducibility of mouse research.

genetics↗