The host plays an essential role in parasite transmission. The viability of the host–parasite relationship depends upon development of immune resistance and the induction of disease tolerance. Here I ...propose that pathogen coevolution of avirulence factors promoting host disease tolerance is an essential feature of the parasitic lifestyle.
Paneth cells are post-mitotic intestinal epithelial cells supporting the stem cell niche and mucosal immunity. Paneth cell pathologies are observed in various gastrointestinal diseases, but their ...plasticity and response to genomic and environmental challenges remain unclear. Using a knockin allele engineered at the mouse Lyz1 locus, we performed detailed Paneth cell-lineage tracing. Irradiation induced a subset of Paneth cells to proliferate and differentiate into villus epithelial cells. RNA sequencing (RNA-seq) revealed that Paneth cells sorted from irradiated mice acquired a stem cell-like transcriptome; when cultured in vitro, these individual Paneth cells formed organoids. Irradiation activated Notch signaling, and forced expression of Notch intracellular domain (NICD) in Paneth cells, but not Wnt/β-catenin pathway activation, induced their dedifferentiation. This study documents Paneth cell plasticity, particularly their ability to participate in epithelial replenishment following stem cell loss, adding to a growing body of knowledge detailing the molecular pathways controlling injury-induced regeneration.
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•Irradiation induced a subset of Paneth cells to acquire multipotency•Irradiated Paneth cells had a stem cell-like transcriptome and organoid-forming ability•Forced activation of the Notch pathway induced Paneth cell fate change•Constitutive activation of the Wnt/β-catenin pathway did not induce dedifferentiation
Using a knockin allele engineered at the mouse Lyz1 locus, Yu et al. report that irradiation induces a subset of Paneth cells to dedifferentiate. This process can also be induced by expressing active Notch1 in this cell type. The study documents Paneth cell plasticity, expanding current understanding of intestinal regeneration.
Growth differentiation factor 15 (GDF-15) is a cytokine that is widely used as a biomarker for the severity of diverse disease states. It also has been shown to play a protective role after tissue ...injury and to promote a negative energy balance during obesity and diabetes. In addition to its metabolic effects, GDF-15 also regulates the host's immune responses to infectious and noninfectious diseases. GDF-15 can suppress a type 1 and, in contrast, promote a type 2 inflammatory response. In this brief review, we discuss how GDF-15 affects the effector function and recruitment of immune cells, the pathways that induce its expression, and the diverse mechanisms by which it is regulated during inflammation and infection. We further highlight outstanding questions that should be the focus of future investigations in this emerging field.
Helminth infections are ubiquitous worldwide and can trigger potent immune responses that differ from and potentially antagonize host protective responses to microbial pathogens. In this Review we ...focus on the three main killers in infectious disease-AIDS, tuberculosis and malaria-and critically assesses whether helminths adversely influence host control of these diseases. We also discuss emerging concepts for how M2 macrophages and helminth-modulated dendritic cells can potentially influence the protective immune response to concurrent infections. Finally, we present evidence advocating for more efforts to determine how and to what extent helminths interfere with the successful control of specific concurrent coinfections.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Innate cells are responsible for the rapid recognition of infection and mediate essential mechanisms of pathogen elimination, and also facilitate adaptive immune responses. We review here the ...numerous intricate interactions among innate cells that initiate protective immunity. The efficient eradication of pathogens depends on the coordinated actions of multiple cells, including innate cells and epithelial cells. Rather than acting as isolated effector cells, innate cells are in constant communication with other responding cells of the immune system, locally and distally. These interactions are critically important for the efficient control of primary infections as well for the development of 'trained' innate cells that facilitate the rapid elimination of homologous or heterologous infections.
Polymeric guanylate-binding proteins (GBPs) physically dismember the vacuole membrane formed by Toxoplasma gondii while nitric oxide (NO) poisons and inhibits parasite replication within interferon ...(IFN)-γ activated macrophages. Zhao et al. report a novel mechanism for synergy between these classical microbicidal and microbistatic effectors in cell-autonomous immunity to the intracellular parasites.
Polymeric guanylate-binding proteins (GBPs) physically dismember the vacuole membrane formed by Toxoplasma gondii while nitric oxide (NO) poisons and inhibits parasite replication within interferon (IFN)-γ activated macrophages. Zhao et al. report a novel mechanism for synergy between these classical microbicidal and microbistatic effectors in cell-autonomous immunity to the intracellular parasites.
Globally, cryptosporidiosis is a leading cause of childhood diarrheal disease and is a major risk factor for malnutrition and impairment of growth and cognitive development. In this issue of Cell ...Host & Microbe, Maradana et al. identify a target for dietary enhancement of innate immune defenses against cryptosporidiosis.
Paneth cells are the primary source of C-type lysozyme, a β-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ...ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn’s disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1−/− hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.
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•Abnormal production of Paneth cell lysozyme is a feature of human IBD•Intestinal luminal lysozyme determines the abundance of mucolytic commensal bacteria•Processing lysozyme-sensitive bacterial cell wall drives colitis in Lyz1+/+ hosts•Lyz1−/− mice have reduced NLR signaling but an anti-colitogenic type 2 immune response
Paneth cell metaplasia in the colon and rectum and aberrant lysosome production are hallmarks of inflammatory bowel disease in humans. Using mouse models where Lyz1 is deleted or ectopically expressed, Yu et al. show that Paneth cell lysozyme regulates the abundance of mucolytic commensal bacteria and thereby the intestinal inflammatory response.
•IFN-γ is necessary and sufficient to increase systemic GDF-15 levels.•GDF-15 plays an important role in infection-induced weight loss.•GDF-15 is required for infection-induced FGF21 expression in ...the liver.
Infections are often accompanied by weight loss caused by alterations in host behavior and metabolism, also known as sickness behaviors. Recent studies have revealed that sickness behaviors can either promote or impede survival during infections depending on factors such as the type of infectious pathogen. Nevertheless, we have an incomplete understanding of the underlying mechanisms of sickness behaviors. Furthermore, although the host immune responses to infections have long been known to contribute to the induction of sickness behaviors, recent studies have identified emerging cytokines that are also key regulators of host metabolism during infection and inflammation, such as growth differentiation factor 15 (GDF-15). GDF-15 is a distant member of the TGF-β superfamily that causes weight loss by suppressing appetite and food consumption and causing emesis. These effects require activation of neurons that express the only known GDF-15 receptor, the GFRAL receptor. GDF-15 also functions in the periphery including the induction of ketogenesis and immunoregulation. Nevertheless, the functions and regulation of GDF-15 during live infections is not yet known. Murine infection with avirulent Toxoplasma gondii is an established model to understand infection-induced weight loss. Past studies have determined that acute T. gondii infection causes weight loss due to diminished food consumption and increased energy expenditure through unknown mechanisms. Additionally, our lab previously demonstrated that T. gondii causes upregulation in serum GDF-15 in an IFN-γ-dependent manner during the post-acute phase of the infection. In this study, we interrogated the in-vivo functions and immune regulation of GDF-15 during Toxoplasma gondii infection. First, we found that in wild-type mice, acute T. gondii infection caused a significant weight loss that is preceded by elevation of serum levels of IFN-γ and GDF-15. To determine whether IFN-γ regulates GDF-15, we neutralized IFN-γ on days 5 and 6 and measured GDF-15 on day 7 and found that serum but not tissue levels of GDF-15 decreased after IFN-γ neutralization. Additionally, exogenous IFN-γ was sufficient to elevate serum GDF-15 in the absence of infection. Next, we compared the outcomes of T. gondii infection between WT and Gdf15−/− mice. We observed that the weight trajectories were declining in WT mice while they were increasing in Gdf15−/−mice during the acute phase of the infection. This difference in trajectories extended throughout the chronic infection resulting to an overall weight loss relative to initial weights in WT mice but not Gdf15−/−mice. Then, we determined that GDF-15 is not essential for survival and immunoregulation during T. gondii infection. We also demonstrated that GDF-15 is required for the induction of FGF21, stress-induced cytokine with prominent roles in regulating host metabolism. Finally, we discovered a cytokine cascade IFN-γ-GDF-15-FGF21 that is likely involved in the regulation of host metabolism. Overall, our study provides evidence that IFN-γ contributes to the regulation of host metabolism during infection by inducing GDF-15 and FGF21. GDF-15 orchestrates changes in host metabolism that supports the host immune response in clearing the infection. These physiological alterations induce FGF21, which in turn, orchestrates the adaptive responses to the effects of GDF-15, which can be detrimental when protracted.
Anti-helminth responses require robust type 2 cytokine production that simultaneously promotes worm expulsion and initiates the resolution of helminth-induced wounds and hemorrhaging. However, how ...infection-induced changes in hematopoiesis contribute to these seemingly distinct processes remains unknown. Recent studies have suggested the existence of a hematopoietic progenitor with dual mast cell-erythrocyte potential. Nonetheless, whether and how these progenitors contribute to host protection during an active infection remains to be defined. Here, we employed single cell RNA-sequencing and identified that the metabolic enzyme, carbonic anhydrase (Car) 1 marks a predefined bone marrow-resident hematopoietic progenitor cell (HPC) population. Next, we generated a Car1-reporter mouse model and found that Car1-GFP positive progenitors represent bipotent mast cell/erythrocyte precursors. Finally, we show that Car1-expressing HPCs simultaneously support mast cell and erythrocyte responses during Trichinella spiralis infection. Collectively, these data suggest that mast cell/erythrocyte precursors are mobilized to promote type 2 cytokine responses and alleviate helminth-induced blood loss, developmentally linking these processes. Collectively, these studies reveal unappreciated hematopoietic events initiated by the host to combat helminth parasites and provide insight into the evolutionary pressure that may have shaped the developmental relationship between mast cells and erythrocytes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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