The transcription factor ZIP-1 promotes resistance to intracellular infection in Caenorhabditis elegans

Abstract

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts; specifically, the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans remain understudied. Two different types of intracellular pathogens that naturally infect the C. elegans intestine are the Orsay virus, which is an RNA virus, and microsporidia, which comprise a phylum of fungal pathogens. Despite their molecular differences, these pathogens induce a common host transcriptional response called the intracellular pathogen response (IPR). Here we show that zip-1 is an IPR regulator that functions downstream of all known IPR-activating and regulatory pathways. zip-1 encodes a putative bZIP transcription factor, and we show that zip-1 controls induction of a subset of genes upon IPR activation. ZIP-1 protein is expressed in the nuclei of intestinal cells, and is at least partially required in the intestine to upregulate IPR gene expression. Importantly, zip-1 promotes resistance to infection by the Orsay virus and by microsporidia in intestinal cells. Altogether, our results indicate that zip-1 represents a central hub for triggers of the IPR, and that this transcription factor has a protective function against intracellular pathogen infection in C. elegans.

RNA fluorescence in situ hybridization (FISH) to visualize microbial colonization and infection in the Caenorhabditis elegans intestines

“…In the intestine, viral RNA is detected by RIG-I homolog DRH-1 22 , which is required for activation of the transcriptional defense program named the Intracellular Pathogen Response (IPR) 23,24,25 . The transcription of antiviral IPR genes is at least partially controlled by ZIP-1 transcription factor 19 . Here, the expression of ZIP-1::GFP is seen localized in the intestinal nuclei of cells that showing positive Orsay virus FISH staining in the cytoplasm (Figure 3A) 19 .…”

“…The transcription of antiviral IPR genes is at least partially controlled by ZIP-1 transcription factor 19 . Here, the expression of ZIP-1::GFP is seen localized in the intestinal nuclei of cells that showing positive Orsay virus FISH staining in the cytoplasm (Figure 3A) 19 . Multiple animals stained with Orsay-specific FISH are shown to indicate the strength of this signal for easy quantification (Figure 3B).…”

“…(2022). https://doi.org/10.1038/s41467-021-27621-w 19 . The changes were made to the original published image.…”

“…Different colored FISH probes can be used simultaneously, which allows for visual distinction between microbes in wild nematode samples, as well as observation of microbe-microbe dynamics inside a host 15,18 . Furthermore, infection and colonization can be easily quantified manually or through automated approaches 19 .…”

Phagocytosis Is the Sole Arm of Drosophila melanogaster Known Host Defenses That Provides Some Protection Against Microsporidia Infection

“…More recently, a transcriptional immune/stress response called the intracellular pathogen response (IPR) has been shown to be triggered by microsporidia or viral infections as well as by proteotoxic stress and mutations in a purine nucleoside phosphorylase enzyme. These distinct activation pathways converge on the ZIP-1 transcription factor, which likely acts through the gene pals-5 in the intestine ( 28 – 31 ). While these studies constitute major advances in our understanding of defenses against microsporidia in protostomes, the IPR may be specific to nematode worms.…”