Highlights • Th17 responses show protection against both bacterial and fungal pathogens. • Mucosal and systemic vaccines can elicit protective Th17 responses. • Th17 responses can mediate serotype ...immunity against clades of organisms.
Highlights ► Pattern recognition receptors respond to a wide variety of bacterial pathogens in the lung. ► IL-23 stimulates innate production of IL-17 and IL-22 which increase lung defenses. ► CD4+ T ...cell subtypes play a critical role in orchestrating lung immunity. ► Lung epithelia can modulate B cell maturation through BAFF and APRIL.
Fungal infections are of increasing incidence and importance in immunocompromised and immunocompetent patients. Timely diagnosis relies on appropriate use of laboratory testing in susceptible ...patients.
The relevant literature related to diagnosis of invasive pulmonary aspergillosis, invasive candidiasis, and the common endemic mycoses was systematically reviewed. Meta-analysis was performed when appropriate. Recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation approach.
This guideline includes specific recommendations on the use of galactomannan testing in serum and BAL and for the diagnosis of invasive pulmonary aspergillosis, the role of PCR in the diagnosis of invasive pulmonary aspergillosis, the role of β-d-glucan assays in the diagnosis of invasive candidiasis, and the application of serology and antigen testing in the diagnosis of the endemic mycoses.
Rapid, accurate diagnosis of fungal infections relies on appropriate application of laboratory testing, including antigen testing, serological testing, and PCR-based assays.
Abstract The T helper type 17 (Th17) lineage of CD4+ T-cells produce several effector molecules including IL-17A, IL-17F, IL-21, and IL-22. In addition to CD4+, αβ T-cells, these cytokines can be ...produced by natural killer and γδ T-cells. These effector cytokines can be produced rapidly upon infection at mucosal sites and evidence to date strongly implicates that this arm of the immune system plays a critical role in mucosal immunity to many extracellular pathogens. Moreover these cytokines can also coordinate adaptive immunity to some intracellular pathogens. In this review, we will highlight recent progress in our understanding of these cytokines, and mechanisms of their effector function in the mucosa.
Interleukin-17 (IL-17) induces pathology in autoimmunity and infections; therefore, constraint of this pathway is an essential component of its regulation. We demonstrate that the signaling ...intermediate MCPIP1 (also termed Regnase-1, encoded by Zc3h12a) is a feedback inhibitor of IL-17 receptor signal transduction. MCPIP1 knockdown enhanced IL-17-mediated signaling, requiring MCPIP1’s endoribonuclease but not deubiquitinase domain. MCPIP1 haploinsufficient mice showed enhanced resistance to disseminated Candida albicans infection, which was reversed in an Il17ra−/− background. Conversely, IL-17-dependent pathology in Zc3h12a+/− mice was exacerbated in both EAE and pulmonary inflammation. MCPIP1 degraded Il6 mRNA directly but only modestly downregulated the IL-6 promoter. However, MCPIP1 strongly inhibited the Lcn2 promoter by regulating the mRNA stability of Nfkbiz, encoding the IκBζ transcription factor. Unexpectedly, MCPIP1 degraded Il17ra and Il17rc mRNA, independently of the 3′ UTR. The cumulative impact of MCPIP1 on IL-6, IκBζ, and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.
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•MCPIP1 (Regnase-1) is a feedback inhibitor of IL-17 signal transduction•MCPIP1 deficiency enhances immunity to fungi but exacerbates pathology in EAE•MCPIP1 impairs activation of certain IL-17 target promoters by degrading IκBζ mRNA•MCPIP1 degrades transcripts encoding IL-17R subunits independently of the 3′ UTR
Interleukin-17 (IL-17) induces pathology in autoimmunity and infections and therefore its activity must be tightly regulated. Gaffen and colleagues report that the endoribonuclease MCPIP1 degrades IL-17-induced transcripts, including Il6 and Nfkbiz (Iκβζ), to negatively regulate IL-17 receptor signaling both in fungal immunity and experimental autoimmune encephalomyelitis.
Iwanaga and Kolls discuss the study by Schupp et al who performed a single-cell RNAseq analyses in sputum between nine cystic fibrosis (CF) subjects and five healthy control subjects. The authors ...found a cluster of recruited lung mononuclear phagocytes in CF sputum and identified three different archetypes of monocytes: activated monocytes, monocyte-derived macrophages, and heat shock-activated monocytes. Also, the authors observed a complex population of polymorphonuclear neutrophils (PMN) based on the inflammatory genes and genes involved in PMN maturation, which was quite distinct from healthy control subjects.
Importantly, they chose a 14-day time point after Pneumocystis inoculation, as this time point coincided with the induction of adaptive immune responses that are just initializing clearance, yet ...fungal burdens are quite similar between control and steroid-treated animals. ...differences in gene expression largely reflect defects in host immunity and are not skewed by differences in fungal burdens between the groups. A similar defect in T cell priming occurs in mice treated with CD20 (2) or in mice lacking secreted IgM (6). ...in primary infection, B cells appear to be critical to elicit T cell immunity to this infection.
•Polarization of cells dramatically increases cytokine secretion in bronchial epithelial cells.•CFTR F508del mutation itself is sufficient to significantly alter the epigenome and transcriptome of ...epithelial cells.•The F508del mutation is closely associated with immunity-related pathways in the epithelial cells in the absence of infection.•These data may serve as epithelial biomarkers for CFTR mRNA therapies.
Cystic fibrosis (CF) is characterized by chronic inflammation and excessive cytokines secretion in the lung. Isogenic human CF bronchial epithelial (CFBE41o-) cell lines stably expressing wt-CFTR (WTBE) or F508del mutant (CFBE) are widely used tools in understanding responses to stimuli or drugs and CF pathogenesis in vitro. However, the intrinsic cellular differences in culture are unknown.
We performed integrative analyses of these isogenic cells at the protein, mRNA, and chromatin levels in the submerged and air-liquid interface (ALI) conditions to determine cell intrinsic effects of mutant versus complemented CFTR expression.
CFBE and WTBE cells displayed different cytokine secretion patterns, including IL-6, IL-8, CXCL1, CXCL10, and CCL5. The ALI culture dramatically increased cytokine secretion in both cells. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) result showed different chromatin landscapes upon polarization and CFBE cells, compared to WTBE cells, exhibited higher genome-wide chromatin accessibility under both culture methods. At the transcriptome level, differentially expressed genes identified by mRNA sequencing between two cell lines were highly concentrated in immunity-related pathways.
This multilayered study shows that expression of wild-type CFTR has an epithelial cell intrinsic effect on the cell's epigenome and transcriptome particularly in immunity relevant activities. These data will serve as a resource for the CF community and may serve as epithelial biomarkers for CFTR mRNA therapy.
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