Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis

Lin, Zhenwu; Thorenoor, Nithyananda; Wu, Rongling; DiAngelo, Susan; Ye, Meixia; Thomas, Neal J.; Liao, Xiaojie; Lin, Tony; Warren, Stuart; Floros, Joanna

doi:10.3389/fimmu.2018.02256

Cited by 40 publications

(69 citation statements)

References 156 publications

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“…The SNPs, rs1124 and rs4715, are exonic splicing enhancers, while rs8192309, rs8192313, rs13248346, rs2070686 and rs4995702 are all transcription factor binding sites, as predicted using the SNPinfo method, as previously reported ( 31 ) ( Table SI ). It has also been reported that the rs4715 SNP was associated with respiratory distress syndrome ( 5 , 14 , 16 ); however, this was not identified in the present study. The results also suggested that the SNP rs1124 may serve an important role in disease development, which was in accordance with the results of previous studies ( 5 , 13 , 14 , 16 ).…”

Section: Discussioncontrasting

confidence: 84%

“…It has also been reported that the rs4715 SNP was associated with respiratory distress syndrome ( 5 , 14 , 16 ); however, this was not identified in the present study. The results also suggested that the SNP rs1124 may serve an important role in disease development, which was in accordance with the results of previous studies ( 5 , 13 , 14 , 16 ). The SNPs, rs4715 and rs1124, are both missense, in which the amino acids 138 (Thr/Asn) and 186 (Ser/Asn) are changed, respectively; however, the potential mechanisms in which they affect function remain unknown.…”

Section: Discussioncontrasting

confidence: 84%

“…Changes in the alveolar lining fluid, including decreased binding ability of SFTPA and SFTPD to Mycobacterium tuberculosis , may increase TB susceptibility ( 29 ). It was reported that SFTPC is a hydrophobic membrane protein and serves a significant role in surfactant function ( 5 ), and mutations in SFTPC may modulate recruitment and activation of key myeloid cell populations in interstitial lung disease ( 30 ). However, there is very little data supporting the effects of SFTPC genetic polymorphisms on predisposition to and the clinical phenotype for TB, which is highly prevalent in China.…”

Section: Discussionmentioning

confidence: 99%

“…Pulmonary surfactant, as a surface-active lipoprotein complex, is composed of 90% lipids and 10% surfactant proteins (SFTPs). Surfactant protein C (SFTPC), a hydrophobic membrane protein, is required for biophysical function, and disruption affects the health of the normal lung ( 5 , 6 ). Therefore, we hypothesized that SFTPC contributes toward the progression of TB.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, Sidobre et al ( 7 ) reported that the mannosylated LAM was a putative ligand for the attachment of the human pulmonary surfactant protein to the pathogenic Mycobacterium tuberculosis . Mutations in the SFTPC gene have been identified in pulmonary surfactant metabolism dysfunction and were associated with interstitial lung diseases ( 5 , 12-17 ), and multiple genetic variants in the SFTP genes were identified in TB ( 18 , 19 ). However, until now, the association between the SFPTC gene and TB has not been investigated in well-defined populations.…”

Section: Introductionmentioning

confidence: 99%

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<em>SFTPC</em> genetic polymorphisms are associated with tuberculosis susceptibility and clinical phenotype in a Western Chinese Han population

et al. 2020

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Tuberculosis (TB) is one of the most common infectious diseases globally. The surfactant protein C (SFTPC), which is involved in innate immunity and surfactant function in the lung, may contribute toward the progression of TB. The aim of the present study was to preliminarily investigate the possible association of single nucleotide polymorphisms (SNPs) in the SFTPC gene with TB susceptibility and clinical phenotypes in a Western Chinese Han population. The improved multiplex ligation detection reaction method was used to genotype 6 SNPs in SFTPC , in 900 patients with TB and 1,534 healthy control subjects. It was found that the A allele for rs1124 and the C allele for rs8192313 were associated with increased susceptibility to TB, P=0.024 and P=0.045, respectively. However, these two P-values were not significant following Bonferroni correction. In all samples, the haplotype [CGA], representing three SFTPC variants, was revealed to increase the risk of TB (P=0.001 and P=0.005, following Bonferroni correction). Furthermore, patients with the AA genotype for rs1124 and with the CC genotype for rs8192313 were associated with higher levels of C-reactive protein (P=0.001 and P=0.005, respectively). The results of the present study indicated that the SFTPC SNPs may increase the susceptibility to TB and the immune response of the host to Mycobacterium tuberculosis and may potentially be novel biomarkers for the pathogenesis of TB.

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Section: Discussioncontrasting

confidence: 84%

Section: Discussioncontrasting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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<em>SFTPC</em> genetic polymorphisms are associated with tuberculosis susceptibility and clinical phenotype in a Western Chinese Han population

et al. 2020

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Mesenchymal Stem Cell exosome delivered Zinc Finger Protein activation of cystic fibrosis transmembrane conductance regulator

Villamizar

Waters

Scott

et al. 2021

J of Extracellular Vesicle

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Cystic fibrosis is a genetic disorder that results in a multi-organ disease with progressive respiratory decline which leads to premature death. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene disrupts the capacity of the protein to function as a channel, transporting chloride ions and bicarbonate across epithelial cell membranes. Small molecule treatments targeted at potentiating or correcting CFTR have shown clinical benefits, but are only effective for a small percentage of individuals with specific CFTR mutations. To overcome this limitation, we engineered stromal-derived mesenchymal stem cells (MSC) and HEK293 cells to produce exosomes containing a novel CFTR Zinc Finger Protein fusion with transcriptional activation domains VP64, P65 and Rta to target the CFTR promoter (CFZF-VPR) and activate transcription. Treatment with CFZF-VPR results in robust activation of CFTR transcription in patient derived Human Bronchial Epithelial cells (HuBEC). We also find that CFZF-VPR can be packaged into MSC and HEK293 cell exosomes and delivered to HuBEC cells to potently activate CFTR expression. Connexin 43 appeared to be required for functional release of CFZF-VPR from exosomes. The observations presented here demonstrate that MSC derived exosomes can be used to deliver a packaged zinc finger activator to target cells and activate CFTR. The novel approach presented here offers a next-generation genetic therapy that may one day prove effective in treating patients afflicted with Cystic fibrosis. K E Y WO R D S CFTR, exosome, cystic fibrosis, MSC, Zinc Finger Protein  SIGNIFICANCE STATEMENT Exosomes are important mediators that facilitate intercellular communication and transfer of genetic material to recipient cells. Here, we take advantage of this inherent property and engineer MSCs to produce exosomes packaged with a Zinc Finger Activator targeted to the CFTR gene promoter. We find that treatment of CF patient derived HuBEC with the CFZF-VPR containing exosomes results in significant activation of CFTR. The novel approach presented here represents an effective way to deliver therapeutic proteins to patients afflicted with CF. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Molecular and immune signatures, and pathological trajectories of fatal COVID‐19 lungs defined by in situ spatial single‐cell transcriptome analysis

Das

Meng

Liu

et al. 2023

Journal of Medical Virology

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Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID‐19) remain poorly defined. In this study, we investigated the spatial single‐cell molecular and cellular features of postmortem COVID‐19 lung tissues using in situ sequencing (ISS). We detected 10 414 863 transcripts of 221 genes in whole‐slide tissues and segmented them into 1 719 459 cells that were mapped to 18 major parenchymal and immune cell types, all of which were infected by SARS‐CoV‐2. Compared with the non‐COVID‐19 control, COVID‐19 lungs exhibited reduced alveolar cells (ACs) and increased innate and adaptive immune cells. We also identified 19 differentially expressed genes in both infected and uninfected cells across the tissues, which reflected the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that were correlated with high cell densities (HIHD). The HIHD regions expressed high levels of SARS‐CoV‐2 entry‐related factors including ACE2, FURIN, TMPRSS2 and NRP1, and co‐localized with organizing pneumonia (OP) and lymphocytic and immune infiltration, which exhibited increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, mirroring the tissue damage and wound healing processes. Sparse nonnegative matrix factorization (SNMF) analysis of niche features identified seven signatures that captured structure and immune niches in COVID‐19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A primarily progressed with increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B was marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions were marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single‐cell RNA‐seq data (scRNA‐seq) from COVID‐19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations consisting mainly of myofibroblasts. Immunofluorescence staining revealed the activation of IL6‐STAT3 and TGF‐β‐SMAD2/3 pathways in these cells, likely mediating the upregulation of COL1A1 and COL1A2 and excessive fibrosis in the lung tissues. Together, this study provides a spatial single‐cell atlas of cellular and molecular signatures of fatal COVID‐19 lungs, which reveals the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID‐19 lung pathology.

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Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis

Cited by 40 publications

References 156 publications

<em>SFTPC</em> genetic polymorphisms are associated with tuberculosis susceptibility and clinical phenotype in a Western Chinese Han population

<em>SFTPC</em> genetic polymorphisms are associated with tuberculosis susceptibility and clinical phenotype in a Western Chinese Han population

Mesenchymal Stem Cell exosome delivered Zinc Finger Protein activation of cystic fibrosis transmembrane conductance regulator

Molecular and immune signatures, and pathological trajectories of fatal COVID‐19 lungs defined by in situ spatial single‐cell transcriptome analysis

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