ETIDIOH - NEW

  Abstract The severity of influenza is often driven by an excessive host immune response rather than the virus itself , yet the key molecular drivers within specific immune cells remain poorly understood. While recent single-cell RNA sequencing studies have successfully identified immune populations involved, they have largely not identified the upstream drivers modulating their pro-inflammatory functions . Here we employed an integrated single-cell co-expression network to address this gap. Our analysis identified myeloid dendritic cells (mDCs) as central to pro-inflammatory response during infection. Through a multi-layered key driver analysis, we pinpointed C-type lectin , CLEC4E as a top candidate modulating this pathological inflammatory response . The role of CLEC4E was confirmed in an independent single-cell dataset from influenza-infected patients and further validated in vivo. Pharmacological inhibition of CLEC4E in a murine influenza model significantly reduced disease s...

Abstract Exaggerated inflammation and cytokine storm are hallmark features of influenza A virus (IAV)-induced respiratory diseases. While previous studies unequivocally demonstrated the pathophysiological consequences (multiorgan failure) of IAV-associated cytokine storm, it remains unknown if IAV-induced systemic inflammation impacts the fitness and differentiation of immune cells from hematopoietic stem cells (HSCs). Our data on lethal IAV-infected C57BL/6 wildtype mice after 10 days of infection indicated reduced monocyte- and lymphocyte- counts in the peripheral blood, and overall cellularity of spleen, thymus and lymph nodes . IAV- infection resulted in increased numbers of myeloid cells, CD8+ T cells, alveolar macrophages (AVMs), CD11b+ dendritic cells (DCs) & plasmacytoid DCs (pDCs), whereas decreased frequencies of CD103+ DCs, in the lungs of IAV-infected mice. Analysis of spleen and draining lymph nodes indicated reduced absolute numbers of B cells, T cells, monocytes and ...

Abstract The novel H10N3 avian influenza virus (AIV) has infected four individuals since 2021 and caused severe respiratory damage , posing a significant threat to public health . However, its pathogenic mechanisms remain poorly understood. Our findings revealed that H10N3 infection induces severe lung damage and causes death in mice , even at low doses. The elevated levels of multiple pro-inflammatory factors in the bronchoalveolar lavage fluid were significantly increased during infection, displaying hallmarks of a cytokine storm . Transcriptome sequencing further revealed systematic activation of inflammation-related pathways, predicting that viral infection induces multiple forms of programmed cell death , including apoptosis, pyroptosis, and necroptosis . Protein-level validation showed that the activation of key cell death markers, including Caspase-3, GSDMD, and MLKL , significantly increased as the infection progressed, with their dynamic changes correlating strongly with the e...

Abstract In 2020–2021, a “mysterious illness” struck Senegalese fishermen , causing severe acute dermatitis in over one thousand individuals following exposure through drift-net fishing activity . Here, by performing deep analysis of the environmental samples we reveal the presence of the marine dinoflagellate Vulcanodinium rugosum and its associated cyclic imine toxins . Specifically, we show that the toxin PortimineA, strongly enriched in environmental samples, impedes ribosome function in human keratinocytes , which subsequently activates the stress kinases ZAKα and P38 and promotes the nucleation of the human NLRP1 inflammasome, leading to the release of IL-1β/IL-18 pro-inflammatory cytokines and cell death . Furthermore, cell-based models highlight that naturally occurring mutations in the P38-targeted sites of human NLRP1 are unable to respond to PortimineA exposure. Finally, the development and use of human organotypic skins and zebrafish models of PortimineA exposure demonstrat...

Abstract Sepsis , characterized as life-threatening organ dysfunction resulting from dysregulated host responses to infection , remains a significant challenge in clinical practice . Despite advancements in understanding host-bacterial interactions , molecular responses, and therapeutic approaches, the mortality rate associated with sepsis has consistently ranged between 10 and 16%. This elevated mortality highlights critical gaps in our comprehension of sepsis etiology. Traditionally linked to bacterial and fungal pathogens, recent outbreaks of acute viral infections , including Middle East respiratory syndrome coronavirus ( MERS-CoV ), influenza virus, and severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ), among other regional epidemics, have underscored the role of viral pathogenesis in sepsis, particularly when critically ill patients exhibit classic symptoms indicative of sepsis. However, many cases of viral-induced sepsis are frequently underdiagnosed because standar...