Acute infection with the intestinal parasite Trichuris muris has long-term consequences on mucosal mast cell homeostasis and epithelial integrity

A hallmark of parasite infection is the accumulation of innate immune cells, notably granulocytes and mast cells, at the site of infection. While this is typically viewed as a transient response, with the tissue returning to steady state once the infection is cleared, we found that mast cells accumulated in the large-intestinal epithelium following infection with the nematode Trichuris muris and persisted at this site for several months after worm expulsion. Mast cell accumulation in the epithelium was associated with the induction of type-2 immunity and appeared to be driven by increased maturation of local progenitors in the intestinal lamina propria. Furthermore, we also detected increased local and systemic levels of the mucosal mast cell protease MCPt-1, which correlated highly with the persistent epithelial mast cell population. Finally, the mast cells appeared to have striking consequences on epithelial barrier integrity, by regulation of gut permeability long after worm expulsion. These findings highlight the importance of mast cells not only in the early phases of infection but also at later stages, which has functional implications on the mucosal tissue

Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation

RIPK1 regulates cell death and inflammation through kinase-dependent and -independent mechanisms. As a scaffold, RIPK1 inhibits caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis. As a kinase, RIPK1 paradoxically induces these cell death modalities. The molecular switch between RIPK1 pro-survival and pro-death functions remains poorly understood. We identify phosphorylation of RIPK1 on Ser25 by IKKs as a key mechanism directly inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1-dependent cell death. Mimicking Ser25 phosphorylation (S > D mutation) protects cells and mice from the cytotoxic effect of TNF in conditions of IKK inhibition. In line with their roles in IKK activation, TNF-induced Ser25 phosphorylation of RIPK1 is defective in TAK1- or SHARPIN-deficient cells and restoring phosphorylation protects these cells from TNF-induced death. Importantly, mimicking Ser25 phosphorylation compromises the in vivo cell death-dependent immune control of Yersinia infection, a physiological model of TAK1/IKK inhibition, and rescues the cell death-induced multi-organ inflammatory phenotype of the SHARPIN-deficient mice

Minor alterations in the intestinal microbiota composition upon Rotavirus infection do not affect susceptibility to DSS colitis

Viral triggers at the intestinal mucosa can have multiple global effects on intestinal integrity, causing elevated intestinal barrier strength and relative protection from subsequent inflammatory bowel disease (IBD) induction in various models. As viruses can interfere with the intestinal immune system both directly and indirectly through commensal bacteria, cause-effect relationships are difficult to define. Due to the complexity of putatively causative factors, our understanding of such virus-mediated protection is currently very limited. We here set out to better understand the impact that adult enteric infection with rotavirus (RV) might have on the composition of the intestinal microbiome and on the severity of IBD. We found that RV infection neither induced significant long-lasting microbiota community changes in the small or large intestine nor affected the severity of subsequent dextran sulfate sodium-induced colitis. Hence, adult murine RV infection does not exert lasting effects on intestinal homeostasis

Data from: Chronic Trichuris muris Infection Decreases Diversity of the Intestinal Microbiota and Concomitantly Increases the Abundance of Lactobacilli

The intestinal microbiota is vital for shaping the local intestinal environment as well as host immunity and metabolism. At the same time, epidemiological and experimental evidence suggest an important role for parasitic worm infections in maintaining the inflammatory and regulatory balance of the immune system. In line with this, the prevalence of persistent worm infections is inversely correlated with the incidence of immune-associated diseases, prompting the use of controlled parasite infections for therapeutic purposes. Despite this, the impact of parasite infection on the intestinal microbiota, as well as potential downstream effects on the immune system, remain largely unknown. We have assessed the influence of chronic infection with the large-intestinal nematode Trichuris muris, a close relative of the human pathogen Trichuris trichiura, on the composition of the murine intestinal microbiota by 16S ribosomal-RNA gene-based sequencing. Our results demonstrate that persistent T. muris infection dramatically affects the large-intestinal microbiota, most notably with a drop in the diversity of bacterial communities, as well as a marked increase in the relative abundance of the Lactobacillus genus. In parallel, chronic T. muris infection resulted in a significant shift in the balance between regulatory and inflammatory T cells in the intestinal adaptive immune system, in favour of inflammatory cells. Together, these data demonstrate that chronic parasite infection strongly influences the intestinal microbiota and the adaptive immune system. Our results illustrate the complex interactions between these factors in the intestinal tract, and contribute to furthering the understanding of this interplay, which is of crucial importance considering that 500 million people globally are suffering from these infections and their potential use for therapeutic purposes

Data from: Chronic Trichuris muris Infection Decreases Diversity of the Intestinal Microbiota and Concomitantly Increases the Abundance of Lactobacilli

The intestinal microbiota is vital for shaping the local intestinal environment as well as host immunity and metabolism. At the same time, epidemiological and experimental evidence suggest an important role for parasitic worm infections in maintaining the inflammatory and regulatory balance of the immune system. In line with this, the prevalence of persistent worm infections is inversely correlated with the incidence of immune-associated diseases, prompting the use of controlled parasite infections for therapeutic purposes. Despite this, the impact of parasite infection on the intestinal microbiota, as well as potential downstream effects on the immune system, remain largely unknown. We have assessed the influence of chronic infection with the large-intestinal nematode Trichuris muris, a close relative of the human pathogen Trichuris trichiura, on the composition of the murine intestinal microbiota by 16S ribosomal-RNA gene-based sequencing. Our results demonstrate that persistent T. muris infection dramatically affects the large-intestinal microbiota, most notably with a drop in the diversity of bacterial communities, as well as a marked increase in the relative abundance of the Lactobacillus genus. In parallel, chronic T. muris infection resulted in a significant shift in the balance between regulatory and inflammatory T cells in the intestinal adaptive immune system, in favour of inflammatory cells. Together, these data demonstrate that chronic parasite infection strongly influences the intestinal microbiota and the adaptive immune system. Our results illustrate the complex interactions between these factors in the intestinal tract, and contribute to furthering the understanding of this interplay, which is of crucial importance considering that 500 million people globally are suffering from these infections and their potential use for therapeutic purposes

Immune raw data

Immune raw dat

Chronic <i>T</i>. <i>muris</i> infection affects the composition of the microbiota.

<p>Taxa summary plots at family level showing (A) changes in microbiota composition of faecal samples from the infected mice from day 0 to day 35, and (B) the microbiota composition of uninfected and infected mice at day 35 for faecal and caecal samples. “Unknown” refers to OTUs that we were unable to classify. Data represent mean relative abundance.</p

Bacterial taxa that differed significantly within faecal samples after <i>T</i>. <i>muris</i> infection.

<p>List of significantly (adj. p-value <0.05) increased or decreased abundance of bacteria at multiple taxonomic ranks when comparing infected with uninfected samples at the given time points. Data are illustrated with the prevalence for each given bacteria, absolute counts, and relative abundance. Significantly increased or decreased bacterial groups are depicted in bold letters with up- or down arrows, respectively. Statistics were performed using metagenomeSeq[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125495#pone.0125495.ref046" target="_blank">46</a>].</p><p>Bacterial taxa that differed significantly within faecal samples after <i>T</i>. <i>muris</i> infection.</p

Chronic <i>T</i>. <i>muris</i> infection alters the relative abundance of multiple genera.

<p>(A) Heat-map illustrating changes over time in mean relative abundance at genus level for faecal samples from infected mice. Data are log₁₀ transformed and colour-scaled in the horizontal direction. Blue indicates low values and red indicates high values. Dendrograms are based on hierarchical cluster analysis with Bray-Curtis dissimilarity indices. (B) Log₁₀ fold change between infected and uninfected faecal samples from day 35. (*) Indicates that the genus was undetected in either infected or uninfected samples. Detected only in uninfected: <i>Robinsoniella</i> (0.003%), <i>Sporobacter</i> (0.06%). Detected only in infected: <i>Escherichia/Shigella</i> (0.06%), <i>Enterococcus</i> (0.04%).</p