Majer, M. | Search bioRxiv

bioRxiv2026

Schistosoma mansoni Granulin binds the human neutrophil receptor CD177 and modulates neutrophil activation

To establish chronic infection in the vasculature of their infected host, schistosomes have developed multifaceted strategies of immune subversion. Extracellular parasite proteins are believed to play immunomodulatory functions, but their mode of action remains largely elusive. To investigate whether proteins secreted by the Schistosoma mansoni parasite have the potential to directly interact with host immune receptors, we performed a large-scale protein:protein interaction study between selected parasite proteins sharing structural similarities with known host immune effectors and a protein array of over 750 full-length human ectodomains mostly expressed by immune cells. We identified CD177 as a neutrophil receptor for S. mansoni Granulin (SmGrn). SmGrn exclusively bound the surface of CD177+ human neutrophils and led to cellular hyporesponsiveness following stimulation with LPS as evidenced by decreases in surface markers of activation, delayed reactive oxygen species production and reduced IL-8 release. In addition, human neutrophils exposed to SmGrn showed delayed apoptosis and morphological changes compatible with a more quiescent state as well as transcriptional upregulation of negative regulators of interferon signalling. These data suggest that SmGrn dampens human neutrophil response to stimulation and may lead to suboptimal function during schistosome infection.

immunology↗

bioRxiv2019

Comprehensive post mortem brain samples analysis detects global reduction of multiple proteasome subunits expression in schizophrenia

OBJECTIVEA main challenge in the study of schizophrenia is its high heterogeneity. While it is generally accepted that there exist several biological mechanisms that may define distinct schizophrenia subtypes, they havent been identified yet. We applied comprehensive gene expression analysis, searching for molecular signals that differentiate patients with schizophrenia from healthy controls, and examined whether the identified signal characterizes a particular subgroup of the patients. METHODSWe performed transcriptome sequencing of 14 superior temporal gyrus (STG) samples of relatively young (mean age: 44) subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute. Analyses of differential expression and pathway enrichment were applied and the results were compared with those obtained from an independent cohort of elderly (mean age: 74) patients. Replicability was then tested on six additional independent datasets of various brain regions. RESULTSThe two STG cohorts of relatively young and elderly subjects showed high replicability. Pathway enrichment analysis of the down-regulated genes pointed to proteasome-related pathways. Meta-analysis of differential expression identified down-regulation of 12 of 39 proteasome subunits in schizophrenia. Down-regulation of multiple proteasome subunits was replicated in six additional datasets (overall 8 cohorts, with 267 schizophrenia and 266 control samples, from 5 brain regions, were studied). This signal was concentrated in a subgroup of the patients. CONCLUSIONSWe detect global down-regulation of proteasome subunits in a subgroup of the patients with schizophrenia. The proteasome is a major intracellular protein degradation system, where ubiquitinated proteins (proteins bound by the small protein called ubiquitin) are targeted for degradation. We hypothesize that the down-regulation we detect leads to proteasome dysfunction that causes accumulation of ubiquitinated proteins. Such accumulation has recently been identified, also in a subgroup of the studied patients with schizophrenia. Thus, down-regulation of proteasome subunits might define a biological subtype of schizophrenia.

neuroscience↗