Biology subjects

Loukas, A.

Publications and source records attributed to Loukas, A..

21 records · Page 2Linked to original sources

bioRxiv2018

Hookworm-derived small molecule extracts suppress pathology in a mouse model of colitis and inhibit secretion of key inflammatory cytokines in primary human leukocytes

Iatrogenic hookworm therapy shows promise for treating disorders that result from a dysregulated immune system, including inflammatory bowel disease (IBD). Here we use a metabolomics approach to characterize the non-protein small molecule complement of hookworms. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses of somatic tissue extracts revealed the presence of 52 polar metabolites and 22 non-polar components including short chain fatty acids (SCFA). Several of these small metabolites, notably the SCFA, have been shown to have anti-inflammatory properties in various diseases, including IBD. Using a murine model of colitis and human peripheral blood mononuclear cells, we demonstrate that somatic tissue extracts of the hookworm Ancylostoma caninum contain small molecules with anti-inflammatory activities. Of the five extracts tested, two of them significantly protected mice against T cell-mediated immunopathology and weight loss in a chemically-induced colitis model. Moreover, one of the anti-colitic extracts suppressed ex vivo production of inflammatory cytokines from primary human leukocytes. While the origin of the SCFA (parasite or host microbiota-derived) present in the hookworm somatic tissue extracts cannot be ascertained from this study, it is possible that A. caninum may be actively promoting an anti-inflammatory host microbiome by facilitating immune crosstalk through SCFA production.

microbiology↗

bioRxiv2017

Revisiting The Ancylostoma caninum Secretome Provides New Information On Hookworm-Host Interactions

Hookworm infection is a major tropical parasitic disease affecting almost 500 million people worldwide. These soil-transmitted helminths can survive for many years in the intestine of the host, where they feed on blood, causing iron deficiency anaemia and other complications. To avoid the hosts immune response the parasite releases excretory/secretory products (ESPs), a complex mixture of glycans, lipids and proteins that represent the major host-parasite interface. Using a combination of separation techniques such as SDS-PAGE and OFFGEL electrophoresis, in combination with state-of-the-art mass spectrometry we have reanalysed the dog hookworm, Ancylostoma caninum, ESPs (AcES). We identified 315 proteins present in the AcES, compared with just 105 identified in previous studies. The most highly represented family of proteins is the SCP/TAPs (90 of the 315 proteins), and the most abundant constituents of AcES are homologues of the tissue inhibitors of metalloproteases (TIMP) family. We identified putative vaccine candidates and proteins that could have immunomodulatory effects for treating inflammatory diseases. This study provides novel information about the proteins involved in host-hookworm interactions, and constitutes a comprehensive dataset for the development of vaccines and the discovery of new immunoregulatory biologics.

microbiology↗

bioRxiv2017

Characterisation Of Trichuris muris Secreted Proteins And Extracellular Vesicles Provides New Insights Into Host-Parasite Communication

Whipworms are parasitic nematodes that live in the gut of more than 500 million people worldwide. Due to the difficulty in obtaining parasite material, the mouse whipworm Trichuris muris has been extensively used as a model to study human whipworm infections. These nematodes secrete a multitude of compounds that interact with host tissues where they orchestrate a parasitic existence. Herein we provide the first comprehensive characterisation of the excretory/secretory products of T. muris. We identify 148 proteins secreted by T. muris and show for the first time that the mouse whipworm secretes exosome-like extracellular vesicles (EVs) that can interact with host cells. We use an Optiprep(R) gradient to purify the EVs, highlighting the suitability of this method for purifying EVs secreted by a parasitic nematode. We also characterise the proteomic and genomic content of the EVs, identifying >350 proteins, 56 miRNAs (22 novel) and 475 full-length mRNA transcripts mapping to T. muris gene models. Many of the miRNAs putatively mapped to mouse genes involved in regulation of inflammation, implying a role in parasite-driven immunomodulation. In addition, for the first time to our knowledge, we use colonic organoids to demonstrate the internalisation of parasite EVs by host cells. Understanding how parasites interact with their host is crucial to develop new control measures. This first characterisation of the proteins and EVs secreted by T. muris provides important information on whipworm-host communication and forms the basis for future studies.

microbiology↗