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Elucidating Mechanisms of Tolerance to Salmonella Typhimurium Across Long-Term Infections Using the Collaborative Cross

View ORCID ProfileKristin Scoggin, Jyotsana Gupta, View ORCID ProfileRachel Lynch, View ORCID ProfileAravindh Nagarajan, View ORCID ProfileManuchehr Aminian, Amy Peterson, View ORCID ProfileL. Garry Adams, Michael Kirby, View ORCID ProfileDavid W. Threadgill, View ORCID ProfileHelene L. Andrews-Polymenis
doi: https://doi.org/10.1101/2022.04.11.487981
Kristin Scoggin
1Interdisciplinary Program in Genetics, Texas A&M University, College Station, Texas, United States of America
2Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas, United States of America
3Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, United States of America
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  • ORCID record for Kristin Scoggin
Jyotsana Gupta
3Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, United States of America
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Rachel Lynch
2Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas, United States of America
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  • ORCID record for Rachel Lynch
Aravindh Nagarajan
1Interdisciplinary Program in Genetics, Texas A&M University, College Station, Texas, United States of America
3Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, United States of America
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Manuchehr Aminian
4Department of Mathematics, Colorado State University, Fort Collins, Colorado, United States of America
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  • ORCID record for Manuchehr Aminian
Amy Peterson
4Department of Mathematics, Colorado State University, Fort Collins, Colorado, United States of America
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L. Garry Adams
5Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M, College Station, Texas, United States of America
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  • ORCID record for L. Garry Adams
Michael Kirby
4Department of Mathematics, Colorado State University, Fort Collins, Colorado, United States of America
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  • For correspondence: dwthreadgill@tamu.edu handrews@tamu.edu Michael.Kirby@colostate.edu
David W. Threadgill
1Interdisciplinary Program in Genetics, Texas A&M University, College Station, Texas, United States of America
2Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas, United States of America
6Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, Texas, United States of America
7Department of Biochemistry & Biophysics and Department of Nutrition, Texas A&M University, College Station, Texas, United States of America
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  • For correspondence: dwthreadgill@tamu.edu handrews@tamu.edu Michael.Kirby@colostate.edu
Helene L. Andrews-Polymenis
1Interdisciplinary Program in Genetics, Texas A&M University, College Station, Texas, United States of America
3Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, Texas, United States of America
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  • For correspondence: dwthreadgill@tamu.edu handrews@tamu.edu Michael.Kirby@colostate.edu
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Abstract

Understanding the molecular mechanisms underlying resistance and tolerance to pathogen infection may present the opportunity to develop novel interventions. Resistance is the absence of clinical disease with low pathogen burden, while tolerance is minimal clinical disease in the face of high pathogen burden. Salmonella is a worldwide health concern. We studied 18 strains of Collaborative Cross mice that survive acute Salmonella Typhimurium (STm) infections. We infected these strains orally and monitored them for three weeks post-infection. Five strains cleared STm by the end of the experiment (resistant), while 6 strains maintained a bacterial load and survived to the end of the experiment (tolerant). The remaining 7 strains survived longer than 7 days but succumbed to infection before the end of the study period and were called “delayed susceptible” to differentiate them from strains that do not survive to day 7 (susceptible). Tolerant strains were colonized in Peyer’s patches, mesenteric lymph node, spleen and liver, while resistant strains had significantly reduced bacterial colonization. Tolerant strains had lower pre-infection core body temperatures than both delayed susceptible and resistant strains and had disrupted circadian patterns of body temperature post-infection sooner than resistant strains. Tolerant strains had higher circulating total white blood cells than resistant strains, driven by increased numbers of neutrophils. Tolerant strains had more severe tissue damage and higher circulating levels of MCP-1 and IFN-γ, but lower levels of ENA-78 than resistant strains. QTL analysis revealed 1 significant association and 6 suggestive associations. RNA-seq analysis identified 22 genes that are differentially regulated in tolerant versus resistant animals that overlapped with the QTLs we identified and allowed us to identify the top 5 canonical pathways. Fibrinogen genes (Fga, Fgb, and Fgg) were found across the QTL, RNA, and top canonical pathways making them the best candidate genes for differentiating tolerance and resistance.

Author Summary An infected host can respond in multiple ways to bacterial infection including resistance and tolerance. Resistance is a decrease in pathogen load, while in tolerance mild clinical signs are present despite high pathogen load. We infected a collection of 18 strains of genetically diverse mice with Salmonella Typhimurium for up to three weeks. Five strains were resistant, 6 strains were tolerant, and the remaining 7 strains survived an intermediate amount of time (“delayed susceptible”). Tolerant strains maintained bacterial load across several organs, while resistant strains reduced bacterial load. Tolerant strains had the lowest pre-infection core body temperatures and the most rapid disruption in circadian patterns of body temperature post-infection. Tolerant strains had higher circulating neutrophils, higher circulating levels of MCP-1 and IFN-γ, but lower levels of ENA-78 than resistant strains, in addition to more severe tissue damage than resistant strains. QTL analysis revealed multiple associated regions, and gene expression analysis identified 22 genes that are differentially regulated in tolerant versus resistant animals in these regions. Fibrinogen genes (Fga, Fgb, and Fgg) were found across the QTL, RNA, and top canonical pathways making them the best candidate genes for differentiating tolerance and resistance.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 12, 2022.
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Elucidating Mechanisms of Tolerance to Salmonella Typhimurium Across Long-Term Infections Using the Collaborative Cross
Kristin Scoggin, Jyotsana Gupta, Rachel Lynch, Aravindh Nagarajan, Manuchehr Aminian, Amy Peterson, L. Garry Adams, Michael Kirby, David W. Threadgill, Helene L. Andrews-Polymenis
bioRxiv 2022.04.11.487981; doi: https://doi.org/10.1101/2022.04.11.487981
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Elucidating Mechanisms of Tolerance to Salmonella Typhimurium Across Long-Term Infections Using the Collaborative Cross
Kristin Scoggin, Jyotsana Gupta, Rachel Lynch, Aravindh Nagarajan, Manuchehr Aminian, Amy Peterson, L. Garry Adams, Michael Kirby, David W. Threadgill, Helene L. Andrews-Polymenis
bioRxiv 2022.04.11.487981; doi: https://doi.org/10.1101/2022.04.11.487981

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