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A novel model of pulmonary KPC infection reveals critical roles of NK cell and group 3 ILC cytokines in host resistance

ABSTRACT: Both NK cells and group 3 ILCs play key roles and that effector cytokines made by these cells can provide immunoprophylaxis against Carbapenem resistant K. pneumoniae infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE130045 | GEO | 2020/05/13

REPOSITORIES: GEO

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A novel model of pulmonary KPC infection reveals critical roles of NK cell and group 3 ILC cytokines in host resistance

Project description:A novel model of pulmonary KPC infection reveals critical roles of NK cell and group 3 ILC cytokines in host resistance

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Systemic human ILC precursors provide a substrate for tissue ILC differentiation

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Clarification of human blood ILC subtype interrelatedness and discovery of amphiregulin production by human NK cells shed light on HIV-1 pathogenesis

Project description:Human blood innate lymphoid cells (ILCs), which include ILCs and natural killer (NK) cells, derive from a common CD117+ILC precursor (ILCP). Yet, the relationship among the ILC subsets remains unclear. Bulk and single cell RNA-Seq and ATAC-Seq showed that blood ILC subsets cluster into ILC2s, ILCPs, a mixed cluster of CD56dim and CD56– NK cells, and a separate cluster of CD56hiNK cells that shares features with both ILCs and CD56dim/–NK cells. In surprising contrast to mice, tissue repair protein amphiregulin (AREG) was produced by human NK cells, with even higher levels in CD56hiNK cells than in ILCs. AREG expression in NK cells was driven by TCF7/WNT signaling and inhibited by TGFB1, a cytokine elevated in HIV-1+ people. Knockout of RUNX3, a WNT antagonist acting downstream of TGFB1, increased AREG production. Consistent with these findings, AREG+NK cells were decreased in people living with HIV-1. Additionally, functionally defective CD56–NK cells expanded in HIV-1+ people, in inverse correlation with CD56dimNK cells, ILCs, and CD4+T cells. Experiments in tissue culture and in humanized mice showed that CD56–NK cells derive from the epigenetically similar CD56dimNK cells, and that stimulation of MTOR by CD4+T cells or exogenous IL-2 prevents their expansion. These findings clarify how ILC subsets are related to each other and provide insight into how HIV-1 infection disrupts ILC homeostasis and contributes to pathology

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Intermediate GATA3 expression renders a noncanonical ILC population in skin essential for hair follicle recycling

Project description:We find that the expression of GATA3 in skin ILCs is significantly lower than in conventional ILC2s of other tissues, indicating that the regulatory role of GATA3 may be different. Indeed, skin ILCs are still maintained after inducing Gata3 depletion in Gata3fl/flCreERT2 mice, when all ILC2s were gone. In addition, about 70% skin ILCs are found to experience RORγt expression as reflected by RORγt fate-mapping. And, conditional Gata3 depletion in the RORγt fate-mapped skin ILCs does not affect their number as well. Therefore, in contrast to conventional ILC2s, GATA3 is not required for skin ILCs for their maintenance. The RORγt fate-mapped skin ILCs have exhibited ILC3-like features. Single-cell transcriptome analysis further reveals that skin ILCs converge on a Ccr6+ ILC3-like state and an Il1rl1+ ILC2-like state. The regulatory role of GATA3 is crucial in the ILC3-like skin ILCs. It promotes the expression of their featured genes, while suppresses the expression of ILC2-like skin ILC featured genes. These ILC3-like skin ILCs locate in close proximity to hair follicles. During hair follicle recycling they migrate from isthmus to suprabulbar to promote the hair follicle growth. Whereas in absence of Gata3, the ILC3-like skin ILCs exhibit defective migration to the suprabulbar and reduced expression of the featured genes in this process. Together, our study evidence that skin ILCs are alternative to conventional ILC2s. In particular, we shed light on the function of GATA3 in promoting the specific gene expression in ILC3-like skin ILCs and regulating their crucial roles in hair follicle recycling, which will improve our knowledge about the involvement of ILCs in maintaining homeostasis of skin.

2022-02-05 | GSE195973 | GEO

RNAseq transcriptome analysis of K. pneumoniae MS6671 and E. coli MS8345 treated with PBT2

Project description:The emergence of colistin resistance in carbapenem-resistant and extended-spectrum ß-lactamase (ESBL)-producing bacteria is a significant threat to human health, and new treatment strategies are urgently required. Here we investigated the ability of the safe-for-human use ionophore PBT2 to restore antibiotic sensitivity in several polymyxin-resistant, ESBL-producing, carbapenem resistant Gram-negative human pathogens. PBT2 was observed to resensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including a ‘next generation’ polymyxin derivative, FADDI-287. To gain additional insight into the potential mechanism of action of PBT2, we analyzed the transcriptome of K. pneumoniae and E. coli in the presence of sub-inhibitory concentrations of PBT2. Treatment with PBT2 was associated with multiple stress responses in both K. pneumoniae and E. coli. Significant changes in the transcription of transition metal ion homeostasis genes were observed in both strains.

2019-06-13 | GSE132637 | GEO

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