NHR-49/PPAR-α and HLH-30/TFEB cooperate for C. elegans host defense via a flavin-containing monooxygenase
Abstract
The model organism Caenorhabditis elegans mounts transcriptional defense responses against intestinal bacterial infections that elicit overlapping starvation and infection responses, the regulation of which is not well understood. Direct comparison of C. elegans that were starved or infected with Staphylococcus aureus revealed a large infection-specific transcriptional signature, which was almost completely abrogated by deletion of transcription factor hlh-30/TFEB, except for six genes including a flavin-containing monooxygenase (FMO) gene, fmo-2/FMO5. Deletion of fmo-2/FMO5 severely compromised infection survival, thus identifying the first FMO with innate immunity functions in animals. Moreover, fmo-2/FMO5 induction required the nuclear hormone receptor, NHR-49/PPAR-α, which controlled host defense cell non-autonomously. These findings reveal an infection-specific host response to S. aureus, identify HLH-30/TFEB as its main regulator, reveal FMOs as important innate immunity effectors in animals, and identify the mechanism of FMO regulation through NHR-49/PPAR-α during S. aureus infection, with implications for host defense and inflammation in higher organisms.
Data availability
RNA-seq reads are deposited in SRA (NCBI/NIH)
Article and author information
Author details
Funding
National Institute of General Medical Sciences (GM101056)
- Javier E Irazoqui
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Scott F Leiser, University of Michigan, United States
Version history
- Received: September 4, 2020
- Accepted: April 29, 2021
- Accepted Manuscript published: May 12, 2021 (version 1)
- Accepted Manuscript updated: May 17, 2021 (version 2)
- Version of Record published: May 21, 2021 (version 3)
Copyright
© 2021, Wani 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
-
- 2,276
- Page views
-
- 300
- Downloads
-
- 18
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
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)
Further reading
-
- Immunology and Inflammation
The co-expression of inhibitory receptors (IRs) is a hallmark of CD8+ T-cell exhaustion (Tex) in people living with HIV-1 (PLWH). Understanding alterations of IRs expression in PLWH on long-term antiretroviral treatment (ART) remains elusive but is critical to overcoming CD8+ Tex and designing novel HIV-1 cure immunotherapies. To address this, we combine high-dimensional supervised and unsupervised analysis of IRs concomitant with functional markers across the CD8+ T-cell landscape on 24 PLWH over a decade on ART. We define irreversible alterations of IRs co-expression patterns in CD8+ T cells not mitigated by ART and identify negative associations between the frequency of TIGIT+ and TIGIT+ TIM-3+ and CD4+ T-cell levels. Moreover, changes in total, SEB-activated, and HIV-1-specific CD8+ T cells delineate a complex reshaping of memory and effector-like cellular clusters on ART. Indeed, we identify a selective reduction of HIV-1 specific-CD8+ T-cell memory-like clusters sharing TIGIT expression and low CD107a that can be recovered by mAb TIGIT blockade independently of IFNγ and IL-2. Collectively, these data characterize with unprecedented detail the patterns of IRs expression and functions across the CD8+ T-cell landscape and indicate the potential of TIGIT as a target for Tex precision immunotherapies in PLWH at all ART stages.
-
- Genetics and Genomics
- Immunology and Inflammation
Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood-borne immune cell types (naive B, naive CD4+ and CD8+ T cells, granulocytes, monocytes, and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousands of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1β) and REST transcription factor (TF) motifs, respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to TF motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.