Biology subjects

Wisniewski, S.

Publications and source records attributed to Wisniewski, S..

4 recordsLinked to original sources

bioRxiv2026

Evolution of SARS-CoV-2 reshapes upper airway immunity in children

Children were relatively protected from severe COVID-19 during the early pandemic a phenomenon linked to rapid and heightened innate immune responses in the upper-airways. Although adult upper-airway antiviral responses varied across successive SARS-CoV-2 waves, whether viral evolution similarly reshaped pediatric mucosal immunity remains unclear. Here we used single-cell transcriptomics to profile 229,533 upper-airway cells from 68 unvaccinated children including 17 uninfected controls, spanning the wild-type SARS-CoV-2, Alpha, Delta and Omicron waves. Epithelial interferon responses were primarily determined by time since symptom onset but were, unlike in adults, independent of disease severity. During early infection, anti-viral responses differed across variants without following a progressive pattern of attenuation. Alpha and Delta elicited the strongest interferon programs across epithelial and immune cell populations, whereas Omicron exhibited a shift towards macrophage cytokine signaling and T-cell cytotoxicity. These findings reveal variant-specific remodeling of pediatric upper-airway immunity that fundamentally differs from that described in adults.

immunology↗

bioRxiv2024

Rewired type I IFN signaling is linked to age-dependent differences in COVID-19

Advanced age is the most important risk factor for severe disease or death from COVID-19, but a thorough mechanistic understanding of the molecular and cellular underpinnings is lacking. Multi-omics analysis of samples from SARS-CoV-2 infected persons aged 1 to 84 years, revealed a rewiring of type I interferon (IFN) signaling with a gradual shift from signal transducer and activator of transcription 1 (STAT1) to STAT3 activation in monocytes, CD4+ T cells and B cells with increasing age. Diversion of interferon IFN signaling was associated with increased expression of inflammatory markers, enhanced release of inflammatory cytokines, and delayed contraction of infection-induced CD4+ T cells. A shift from IFN-responsive germinal center B (GCB) cells towards CD69high GCB and atypical B cells corresponded to the formation of IgA in children while complement fixing IgG was dominant in adults. Our data provide a mechanistic basis for inflammation-prone responses to infections and associated pathology during aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/619479v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@723896org.highwire.dtl.DTLVardef@e12b2aorg.highwire.dtl.DTLVardef@d8de22org.highwire.dtl.DTLVardef@1df96ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners

ObjectiveDysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context. MethodsWe used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth. ResultsInhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice. ConclusionOur findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming.

cell biology↗

bioRxiv2022

Helix 8 in chemotactic receptors of the complement system.

Host response to infection involves activation of the complement system leading to producing of anaphylotoxins C3a and C5a. A complement factor C5a exerts its effect through activation of C5aR1, chemotactic receptor 1, and triggers the G protein-coupled signaling cascade. Orthosteric and allosteric antagonists of C5aR1 are a novel strategy for anti-inflammatory therapies. Here, we discuss recent crystal structures of inactive C5aR1 in terms of an inverted orientation of helix H8, unobserved in other GPCR structures. Analysis of mutual interactions of subunits in the C5aR1 - G protein complex has provided new insights into the activation mechanism of this distinct receptor. By comparison of C5aR1 and its homolog C5aR2 we explained differences between their signaling pathways on the molecular level. A comparison of microsecond MD trajectories started from active and inactive receptor conformations also enabled to elucidate details of local and global changes in the transmembrane domain induced by interactions with the G subunit and to explain the impact of inverted H8 on the receptor activation.

immunology↗