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Fungal adhesion protein guides community behaviors and autoinduction in a paracrine manner.

ABSTRACT: Microbes live mostly in a social community rather than in a planktonic state. Such communities have complex spatiotemporal patterns that require intercellular communication to coordinate gene expression. Here, we demonstrate that Cryptococcus neoformans, a model eukaryotic pathogen, responds to an extracellular signal in constructing its colony morphology. The signal that directs this community behavior is not a molecule of low molecular weight like pheromones or quorum-sensing molecules but a secreted protein. Znf2, a master regulator of morphogenesis in Cryptococcus, is necessary and sufficient for the production of this signal protein. Cfl1, a prominent Znf2-downstream adhesion protein (adhesin), was identified to be responsible for the paracrine communication. Consistent with its role in communication, Cfl1 is highly induced during mating colony differentiation, and some of the Cfl1 proteins undergo shedding and are released from the cell wall. The released Cfl1 is enriched in the extracellular matrix and acts as an autoinduction signal to stimulate neighboring cells to phenocopy Cfl1-expressing cells via the filamentation-signaling pathway. We further demonstrate the importance of an unannotated and yet conserved domain in Cfl1's signaling activity. Although adhesion proteins have long been considered to be mediators of microbial pathogenicity and the structural components of biofilms, our work presented here provides the direct evidence supporting the signaling activation by microbial adhesion/matrix proteins.

SUBMITTER: Wang L

PROVIDER: S-EPMC3710841 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Fungal adhesion protein guides community behaviors and autoinduction in a paracrine manner.

Wang Linqi L Tian Xiuyun X Gyawali Rachana R Lin Xiaorong X

Proceedings of the National Academy of Sciences of the United States of America 20130624 28

Microbes live mostly in a social community rather than in a planktonic state. Such communities have complex spatiotemporal patterns that require intercellular communication to coordinate gene expression. Here, we demonstrate that Cryptococcus neoformans, a model eukaryotic pathogen, responds to an extracellular signal in constructing its colony morphology. The signal that directs this community behavior is not a molecule of low molecular weight like pheromones or quorum-sensing molecules but a s ...[more]

PMID: 23798436

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Project description:Increased mortality in COVID-19 cases is often associated with microvascular complications. We have recently shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein promotes an inflammatory cytokine interleukin 6 (IL-6)/IL-6R-induced trans signaling response and alarmin secretion. Virus-infected or spike-transfected human epithelial cells exhibited an increase in senescence, with a release of senescence-associated secretory phenotype (SASP)-related inflammatory molecules. Introduction of the bromodomain-containing protein 4 (BRD4) inhibitor AZD5153 to senescent epithelial cells reversed this effect and reduced SASP-related inflammatory molecule release in TMNK-1 or EAhy926 (representative human endothelial cell lines), when cells were exposed to cell culture medium (CM) derived from A549 cells expressing SARS-CoV-2 spike protein. Cells also exhibited a senescence phenotype with enhanced p16, p21, and senescence-associated β-galactosidase (SA-β-Gal) expression and triggered SASP pathways. Inhibition of IL-6 trans signaling by tocilizumab and inhibition of inflammatory receptor signaling by the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib, prior to exposure of CM to endothelial cells, inhibited p21 and p16 induction. We also observed an increase in reactive oxygen species (ROS) in A549 spike-transfected and endothelial cells exposed to spike-transfected CM. ROS generation in endothelial cell lines was reduced after treatment with tocilizumab and zanubrutinib. Cellular senescence was associated with an increased level of the endothelial adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), which have in vitro leukocyte attachment potential. Inhibition of senescence or SASP function prevented VCAM-1/ICAM-1 expression and leukocyte attachment. Taken together, we identified that human endothelial cells exposed to cell culture supernatant derived from SARS-CoV-2 spike protein expression displayed cellular senescence markers, leading to enhanced leukocyte adhesion. IMPORTANCE The present study was aimed at examining the underlying mechanism of extrapulmonary manifestations of SARS-CoV-2 spike protein-associated pathogenesis, with the notion that infection of the pulmonary epithelium can lead to mediators that drive endothelial dysfunction. We utilized SARS-CoV-2 spike protein expression in cultured human hepatocytes (Huh7.5) and pneumocytes (A549) to generate conditioned culture medium (CM). Endothelial cell lines (TMNK-1 or EAhy926) treated with CM exhibited an increase in cellular senescence markers by a paracrine mode and led to leukocyte adhesion. Overall, the link between these responses in endothelial cell senescence and a potential contribution to microvascular complication in productively SARS-CoV-2-infected humans is implicated. Furthermore, the use of inhibitors (BTK, IL-6, and BRD4) showed a reverse effect in the senescent cells. These results may support the selection of potential adjunct therapeutic modalities to impede SARS-CoV-2-associated pathogenesis.

Dataset Information

Fungal adhesion protein guides community behaviors and autoinduction in a paracrine manner.

Publications

Fungal adhesion protein guides community behaviors and autoinduction in a paracrine manner.

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