Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota

BACKGROUND: Helminth parasites have been reported to have beneficial immunomodulatory effects in patients with allergic and autoimmune conditions and detrimental consequences in patients with tuberculosis and some viral infections. Their role in coinfection with respiratory viruses is not clear. OBJECTIVE: Here we investigated the effects of strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus (RSV) infection in a mouse model. METHODS: A murine helminth/RSV coinfection model was developed. Mice were infected by means of oral gavage with 200 stage 3 H polygyrus larvae. Ten days later, mice were infected intranasally with either RSV or UV-inactivated RSV. RESULTS: H polygyrus-infected mice showed significantly less disease and pulmonary inflammation after RSV infection associated with reduced viral load. Adaptive immune responses, including TH2 responses, were not essential because protection against RSV was maintained in Rag1-/- and Il4rα-/- mice. Importantly, H polygyrus infection upregulated expression of type I interferons and interferon-stimulated genes in both the duodenum and lung, and its protective effects were lost in both Ifnar1-/- and germ-free mice, revealing essential roles for type I interferon signaling and microbiota in H polygyrus-induced protection against RSV. CONCLUSION: These data demonstrate that a strictly enteric helminth infection can have remote protective antiviral effects in the lung through induction of a microbiota-dependent type I interferon response.

The microbiota provides colonisation resistance against intestinal helminths by regulating intestinal physiology

Luc Xavier Marie Lebon

Intestinal helminth infections are a global health problem affecting particularly people living in poor countries. Heavy worm burdens can lead to nutritional and cognitive deficiencies. Type-two immunity plays a crucial role in promoting tissue repair and limiting parasite burdens; however, our knowledge as to how these responses lead to protection is limited. Moreover, intestinal helminths have co-evolved with their mammalian hosts and are well known to possess potent immuno-modulatory capacities allowing them to establish chronic and repeated infections. As adult worms reside in the gut, we asked whether the presence of intestinal bacterial communities (commonly referred to as the microbiota) impacted on worm burdens or type-two immunity following infection. For this purpose, we infected germ-free (living in a sterile environment) or antibiotic-treated mice with the natural murine parasite Heligmosomoides polygyrus bakeri. As worms are normally hatched from faecal cultures and carry their own microbiota, we first developed a system to generate bacteriologically-sterile (axenic) infective larvae. In germ-free and antibiotic-treated mice, the number of adult worms and their egg production were both increased, despite the presence of a slightly increased helminth-elicited type-two immune response, as shown by cytokine and antibody responses. The increased worm fitness in the absence of microbiota was already detected early following infection and was associated with a more anterior distribution of larvae along the intestinal tract. Thus, we hypothesised that the microbiota may impact on parasite burdens through observed alterations of intestinal physiology, such as increased bile acid production and deregulated smooth muscle cell contractility. To test the importance of these factors, we performed experiments in which we treated mice with an excess of bile acids or altered intestinal transit through drug treatment. Both interventions lead to changes in worm infectivity or location, mirroring different observations generated in our germ-free and antibiotic-treated mice. In summary, our data indicate that a complex microbiota affords 'colonisation resistance' against intestinal helminths, in a manner that is independent of the immune response but dependent on changes to intestinal physiology.

EPFL2017

Mucosal immune responses following intestinal nematode infection

Nicola Harris

In most natural environments, the large majority of mammals harbour parasitic helminths that often live as adults within the intestine for prolonged periods (1-2years) . Although these organisms have been eradicated to a large extent within westernized human populations, those living within rural areas of developing countries continue to suffer from high infection rates. Indeed, recent estimates indicate that approximately 25billion people worldwide, mainly children, currently suffer from infection with intestinal helminths (also known as geohelminths and soil-transmitted helminths) . Paradoxically, the eradication of helminths is thought to contribute to the increased incidence of autoimmune diseases and allergy observed in developed countries. In this review, we will summarize our current understanding of host-helminth interactions at the mucosal surface that result in parasite expulsion or permit the establishment of chronic infections with luminal dwelling adult worms. We will also provide insight into the adaptive immune mechanisms that provide immune protection against re-infection with helminth larvae, a process that is likely to be key to the future development of successful vaccination strategies. Lastly, the contribution of helminths to immune modulation and particularly to the treatment of allergy and inflammatory bowel disease will be discussed.

Wiley-Blackwell2014

Elucidating regulatory mechanisms shaping the transcriptome and proteome of the gut immune response in Drosophila melanogaster

Michael Vincent Frochaux

Work on Drosophila melanogaster paved the way to our current understanding of modern genetics. Since then, this model organism has contributed greatly to various fields such as neurobiology, development, and immunology. The discovery and analysis of the various pathways of the Drosophila immune response led the way to the in-depth characterization of the gut immune response. Furthermore, a genome-wide association study on a population of Drosophila identified resistance to infection by the entomopathogenic bacteria Pseudomonas entomophila (P.e.) as a complex phenotype, with highly resistant and susceptible lines, and highlighted genes and pathways mediating inter-individual differences. However, the molecular mechanisms mediating the resistance to enteric infection remain largely uncharacterized. This study uses the same Drosophila population to analyze what are the molecular mechanisms mediating the resistance to enteric infection. We analyzed the genetic determinants of gene expression variation among the most resistant and susceptible lines in response to infection using expression quantitative trait loci (eQTL) analysis. We also characterized the mode of action of these eQTLs into cis- and trans-acting. Furthermore, we identified the gene nutcracker (ntc) as the only differentially-expressed gene between resistance classes. We then demonstrate that loss of function ntc mutants are significantly more susceptible to infection and then identify a single nucleotide polymorphism (SNP) located in a transcription factor binding site (TFBS) which affects the binding affinity of the transcription factor Broad leading to allele-specific expression variation of the gene ntc. If the transcriptomic response to infection has been thoroughly characterized, it is not the case for the proteomic response. We thus sought to characterize for the first time the proteomic response of the Drosophila to enteric infection. We performed mass spectrometry and RNA sequencing on dissected guts from flies infected by two Gram-negative bacteria, Erwinia carotovora carotovora 15 (Ecc15) or Pseudomonas entomophila, 4h and 16h after infection. We found that a large portion of the measurable proteome (12%) varies after infection and that protein changes are strongly time- and infection-dependent. We showed the relatively poor correlation between gene expression and protein abundance in the Drosophila enteric immune response. Finally, we performed a screen of several proteins that were identified in our proteomics work but had previously not been found when assessing the gene expression response to infection using loss-of-function mutants and identifying 7 genes that modulate overall susceptibility to P.e. infection. In summary, this work analyze the genetic determinants of gene expression variation in the DGRP population upon infection and characterize them according to their mode of action. Furthermore, we describe how a non-coding variant lowers resistance to infection by modulating ntc gene expression through altered Broad repressor binding. Finally, it provides the first comprehensive characterization of the Drosophila gut proteome upon infection by Gram-negative bacteria which can be the basis of future proteomic analysis of the enteric immune response