Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
- Duke University, United States
- University of Massachusetts Medical School, United States
- Weill Cornell Medical College, United States
- Michigan State University, United States
- University of North Carolina at Chapel Hill, United States
- Texas A&M University, United States
Abstract
The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen's ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of Mtb transposon mutant fitness (TnSeq) across the CC panel revealed that many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen's genome that has been maintained to ensure fitness in a diverse population. Both immunological and bacterial traits can be associated with genetic variants distributed across the mouse genome, making the CC a unique population for identifying specific host-pathogen genetic interactions that influence pathogenesis.
Data availability
All relevant data to support the findings of this study are located within the paper and supplemental files. Genome sequence data is deposited in the NCBI Gene Expression Omnibus (GEO), accession number GSE164156. All raw phenotype values and QTL mapping objects are located on GitHub @sassettilab in the Smith_et_al_CC_TnSeq repository
Article and author information
Author details
Michelle M Bellerose
Christopher M Sassetti
Funding
National Institute of Allergy and Infectious Diseases (AI132130)
- Fernando Pardo-Manuel de Villena
- Christopher M Sassetti
National Institute of Allergy and Infectious Diseases (U19AI100625)
- Fernando Pardo-Manuel de Villena
- Martin T Ferris
Howard Hughes Medical Institute (A20-0146)
- Brea K Hampton
National Human Genome Research Institute (U24HG010100)
- Fernando Pardo-Manuel de Villena
Bank of America (Charles H King Postdoctoral Fellowship)
- Clare M Smith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mouse studies were performed in strict accordance using the recommendations from the Guide for the Care and Use of Laboratory Animals of the National Institute of Health and the Office of Laboratory Animal Welfare. Mouse studies at the University of Massachusetts Medical School (UMASS) were performed using protocols approved by the UMASS Institutional Animal Care and Use Committee (IACUC) (Animal Welfare Assurance Number A3306-01) in a manner designed to minimize pain and suffering in Mtb-infected animals. Any animal that exhibited severe disease signs was immediately euthanized in accordance with IACUC approved endpoints. All mouse studies at UNC (Animal Welfare Assurance #A3410-01) were performed using protocols approved by the UNC Institutional Animal Care and Use Committee (IACUC).
Copyright
© 2022, Smith et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 734
- downloads
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
eLife 11:e74419.
https://doi.org/10.7554/eLife.74419
Further reading
-
- Developmental Biology
- Genetics and Genomics
Asthenoteratozoospermia, a prevalent cause of male infertility, lacks a well-defined etiology. DNAH12 is a special dynein featured by the absence of a microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-exome sequencing and subsequent Sanger sequencing on infertile patients and fertile controls from six distinct families, we unveiled six biallelic mutations in DNAH12 that co-segregate recessively with male infertility in the studied families. Transmission electron microscopy (TEM) revealed pronounced axonemal abnormalities, including inner dynein arms (IDAs) impairment and central pair (CP) loss in sperm flagella of the patients. Mouse models (Dnah12-/- and Dnah12mut/mut) were generated and recapitulated the reproductive defects in the patients. Noteworthy, DNAH12 deficiency did not show effects on cilium organization and function. Mechanistically, DNAH12 was confirmed to interact with two other IDA components DNALI1 and DNAH1, while disruption of DNAH12 leads to failed recruitment of DNALI1 and DNAH1 to IDAs and compromised sperm development. Furthermore, DNAH12 also interacts with radial spoke head proteins RSPH1, RSPH9, and DNAJB13 to regulate CP stability. Moreover, the infertility of Dnah12-/- mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. Collectively, DNAH12 plays a crucial role in the proper organization of axoneme in sperm flagella, but not cilia, by recruiting DNAH1 and DNALI1 in both humans and mice. These findings expand our comprehension of dynein component assembly in flagella and cilia and provide a valuable marker for genetic counseling and diagnosis of asthenoteratozoospermia in clinical practice.
-
- Genetics and Genomics
We report our attempt to replicate reports of transgenerational epigenetic inheritance in Caenorhabditis elegans. Multiple laboratories report that C. elegans adults and their F1 embryos exposed to the pathogen Pseudomonas aeruginosa show pathogen aversion behavior and increased daf-7/TGFβ reporter gene expression. However, results from one group show persistence of both through the F4 generation. We failed to consistently detect either the avoidance response or elevated daf-7 expression beyond the F1 generation. We confirmed that the dsRNA transport proteins SID-1 and SID-2 are required for intergenerational (F1) inheritance of pathogen avoidance, but not for the F1 inheritance of elevated daf-7 expression. Reanalysis of RNA seq data provides additional evidence that this intergenerational inherited PA14 response may be mediated by small RNAs. The experimental methods are well-described, the source materials are readily available, including samples from the reporting laboratory, and we explored a variety of environmental conditions likely to account for lab-to-lab variability. None of these adjustments altered our results. We conclude that this example of transgenerational inheritance lacks robustness, confirm that the intergenerational avoidance response, but not the elevated daf-7p::gfp expression in F1 progeny, requires sid-1 and sid-2, and identify candidate siRNAs and target genes that may mediate this intergenerational response.
