Biology subjects

Nejsum, P.

Publications and source records attributed to Nejsum, P..

7 recordsLinked to original sources

bioRxiv2025

Transglutaminase 2 predicts parasitic worm-mediated protection against hepatic steatosis in obese mice

Parasitic worm infection can mitigate high fat diet-induced chronic inflammation in obese mice by reducing hepatic fat accumulation and improving insulin sensitivity. However, the molecular alterations during infection-mediated regulation of hepatic steatotic events in obesity remain poorly understood. Here, we integrated proteomic and metabolomic analyses of infected obese mice, a functional deworming and interleukin-4c (IL-4c) treated animal model, and an obese patient cohort before and after bariatric surgery to uncover molecular targets/pathways indicative of the regulation of hepatic steatosis by gut Heligmosomoides polygyrus bakeri (H. p. bakeri) helminth infection. Proteomic analysis identified alterations in several molecules related to metabolism and showed elevated levels of transglutaminase 2 (TGM2) proportionate with an infection-regulated lipid load in diet-induced obese (DIO) mice. The role of TGM2 as a reliable predictor of hepatic steatosis was validated using deworming experiments which revealed a decrease in the liver tissue levels of Tgm2 following removal of H. p. bakeri. Further validation showing increase in Tgm2 levels in IL-4c treated mice confirmed its relevance as a general response indicator of type 2 immune response induced by helminth infection. Assessment of circulating TGM2 levels in matched obese patients before and after bariatric surgery revealed no change, indicating that differential expression of TGM2 is a unique functional response to regulation of hepatic steatosis by H. p. bakeri infection. Together, our data show that TGM2 is a unique predictive marker of improvement in hepatic lipid profile and provides additional evidence that parasitic worm infection protects against hepatic steatosis in DIO mice. These findings pave the way for novel therapeutic opportunities to resolve hepatic steatosis and prevent its progression to severe forms of metabolic dysfunction-associated steatotic liver disease, based on TGM2 coupled with mimetics of H. p. bakeri-derived products. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/689654v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1cae718org.highwire.dtl.DTLVardef@9ec0aorg.highwire.dtl.DTLVardef@1679b1corg.highwire.dtl.DTLVardef@f86bc9_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Host microbiome determines host specificity of the human whipworm, Trichuris trichiura

Long-term whipworm-host co-evolution has resulted in tropism for the caecum of specific hosts, an organ with the densest microbial population in the body. Here, we demonstrate that the host specificity of human whipworms (Trichuris trichiura) is host microbiome-driven. We successfully establish a T. trichiura infection in a non-primate host using a humanised-microbiota mouse model. We further show, in vitro, that hatching of T. trichiura was triggered by mucosal scrapings of the caecum of human microbiota-associated mice, but not from wild-type mice, which only induced T. muris hatching. Comparative metagenomic analysis of the murine versus humanised microbiomes directly implicated specific bacterial species in T. trichiura egg hatching. Additionally, we demonstrate that host tissue does not directly determine host specificity, as T. trichiura readily infected mouse caecaloids. Our findings indicate that host-microbiome-whipworm co-evolution has resulted in exquisite bacterial-whipworm egg interactions critical for hatching and development of these parasites in their definitive hosts.

microbiology↗

bioRxiv2023

Migratory pattern of zoonotic Toxocara cati and T. canis in experimentally infected pigs

Over a billion people are infected with Toxocara canis or T. cati, the roundworms of dogs and cats. Historically, T. canis has been considered the main responsible of human toxocarosis but as serodiagnosis cannot discriminate the two species, this remains unresolved. We assessed the migratory pattern of T. cati and T. canis in a pig model and found them to be equally infective. Overall, they had a similar migration pattern reaching multiple organs and tissues, including mesenteric lymph nodes, liver, lungs and diaphragm. We recovered larvae of both species in the brain, suggesting that T. cati also can cause neurological toxocarosis in humans. Both species induced systemic eosinophilia and histopathological changes in lungs, livers and mesenteric lymph nodes. This study emphasizes the importance of T. cati as a zoonotic agent and the need to develop diagnostic methods that can differentiate between sources of infection in humans.

microbiology↗

bioRxiv2023

Bacterial contact induces polar plug disintegration to mediate whipworm egg hatching

The bacterial microbiota promotes the life cycle of the intestine-dwelling whipworm Trichuris by mediating hatching of parasite eggs ingested by the mammalian host. Despite the enormous disease burden associated with Trichuris colonization, the mechanisms underlying this transkingdom interaction have been obscure. Here, we used a multiscale microscopy approach to define the structural events associated with bacteria-mediated hatching of eggs for the murine model parasite Trichuris muris. Through the combination of scanning electron microscopy (SEM) and serial block face SEM (SBFSEM), we visualized the outer surface morphology of the shell and generated 3D structures of the egg and larva during the hatching process. These images revealed that exposure to hatching-inducing bacteria catalyzed asymmetric degradation of the polar plugs prior to exit by the larva. Although unrelated bacteria induced similar loss of electron density and dissolution of the structural integrity of the plugs, egg hatching was most efficient in the presence of bacteria that bound poles with high density such as Staphylococcus aureus. Consistent with the ability of taxonomically distant bacteria to induce hatching, additional results suggest chitinase released from larva within the eggs degrade the plugs from the inside instead of enzymes produced by bacteria in the external environment. These findings define at ultrastructure resolution the evolutionary adaptation of a parasite for the microbe-rich environment of the mammalian gut.

microbiology↗

bioRxiv2021

Population genomics of ancient and modern Trichuris trichiura

The neglected tropical disease trichuriasis is caused by the whipworm Trichuris trichiura, a soil-transmitted helminth that has infected humans for millennia. Today, T. trichiura infects as many as 500 million people, predominantly in communities with poor sanitary infrastructure enabling sustained faecal-oral transmission. Using whole-genome sequencing of geographically distributed worms collected from human and other primate hosts, together with ancient samples preserved in archaeologically-defined latrines and deposits dated up to one thousand years old, we present the first population genomics study of T. trichiura. We describe the continent-scale genetic structure between whipworms infecting humans and baboons relative to those infecting other primates. Admixture and population demographic analyses support a stepwise distribution of genetic variation that is highest in Uganda, consistent with an African origin and subsequent translocation with human migration. Finally, genome-wide analyses between human samples and between human and non-human primate samples reveal local regions of genetic differentiation between geographically distinct populations. These data provide insight into zoonotic reservoirs of human-infective T. trichiura and will support future efforts toward the implementation of genomic epidemiology of this globally important helminth.

genomics↗

bioRxiv2021

Parasite-probiotic interactions in the gut: Bacillus sp. and Enterococcus faecium regulate type-2 inflammatory responses and modify the gut microbiota of pigs during helminth infection

Dietary probiotics may enhance gut health by directly competing with pathogenic agents and through immunostimulatory effects. These properties are recognized in the context of bacterial and viral pathogens, but less is known about interactions with eukaryotic pathogens such as parasitic worms (helminths). In this study we investigated whether two probiotic mixtures (comprised of Bacillus amyloliquefaciens, B. subtilis, and Enterococcus faecium [BBE], or Lactobacillus rhamnosus LGG and Bifidobacterium animalis subspecies Lactis Bb12 [LB]) could modulate helminth infection kinetics as well as the gut microbiome and intestinal immune responses in pigs infected with the nodular worm Oesophagostomum dentatum. We observed that neither probiotic mixture influenced helminth infection levels. BBE, and to a lesser extent LB, changed the alpha- and beta-diversity indices of the colon and faecal microbiota, notably including an enrichment of faecal Bifidobacterium spp. by BBE. However, these effects were muted by concurrent O. dentatum infection. BBE (but not LB) significantly attenuated the O. dentatum-induced upregulation of genes involved in type-2 inflammation and restored normal lymphocyte ratios in the ileo-caecal lymph nodes that were altered by infection. Moreover, inflammatory cytokine release from blood mononuclear cells and intestinal lymphocytes was diminished by BBE. Collectively, our data suggest that selected probiotic mixtures can play a role in maintaining immune homeostasis during type 2-biased inflammation. In addition, potentially beneficial changes in the microbiome induced by dietary probiotics may be counteracted by helminths, highlighting the complex inter-relationships that potentially exist between probiotic bacteria and intestinal parasites.

microbiology↗

bioRxiv2019

AFM-based High-Throughput Nanomechanical Screening of Single Extracellular Vesicles

We herein describe an Atomic Force Microscopy (AFM)-based experimental procedure which allows the simultaneous mechanical and morphological characterization of several hundred individual nanosized vesicles within the hour timescale. When deposited on a flat rigid surface from aqueous solution, vesicles are deformed by adhesion forces into oblate spheroids whose geometry is a direct consequence of their mechanical stiffness. AFM image analysis can be used to quantitatively measure the contact angle of individual vesicles, which is a size-independent descriptor of their deformation and, consequently, of their stiffness. The same geometrical measurements can be used to infer vesicle diameter in its original, spherical shape. We demonstrate the applicability of the proposed approach to natural vesicles obtained from different sources, recovering their size and stiffness distributions by simple AFM imaging in liquid. We show how the combined EV stiffness/size readout is able to discriminate between subpopulations of vesicular and non-vesicular objects in the same sample, and between populations of vesicles with similar sizes but different mechanical characteristics. We also discuss a force spectroscopy calibration procedure to quantitatively link the stiffness of EVs to their average contact angle. Finally, we discuss expected extensions and applications of the methodology.

biophysics↗