Proteomics study of <i>Mycoplasma pneumoniae</i> pneumonia reveals the Fc fragment of the IgG-binding protein as a serum biomarker and implicates potential therapeutic targets

doi:10.1007/s11684-021-0840-y

Front. Med.

2022, Vol. 16

Issue (3) : 378-388 https://doi.org/10.1007/s11684-021-0840-y

RESEARCH ARTICLE

Proteomics study of Mycoplasma pneumoniae pneumonia reveals the Fc fragment of the IgG-binding protein as a serum biomarker and implicates potential therapeutic targets

Jinrong Liu¹, Rongfang Shen², Lin Feng², Shujun Cheng², Jun Chen³(

), Ting Xiao²(

), Shunying Zhao¹(

)

¹. Department of Respiratory Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China
². State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
³. Beijing Engineering Research Center of Pediatric Surgery, Engineering and Transformation Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing 100045, China

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Abstract

Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP (SMPP). SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans. Therefore, identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency. In this study, serum samples were collected from patients with general MPP (GMPP) and SMPP to conduct proteomics profiling. The Fc fragment of the IgG-binding protein (FCGBP) was identified as the most promising indicator of SMPP. Biological enrichment analysis indicated uncontrolled inflammation in SMPP. ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP. Furthermore, the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression. Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment. Among them, a mechanistic target of rapamycin kinase (mTOR) inhibitor, which is a macrolide compound and a cell proliferation inhibitor, was the most promising candidate for targeting SMPP. To our knowledge, this study was the first proteomics-based characterization of patients with SMPP and GMPP.

Keywords severe Mycoplasma pneumoniae pneumonia children proteomics Fc fragment of the IgG-binding protein mechanistic target of rapamycin kinase inhibitor

Corresponding Author(s): Jun Chen,Ting Xiao,Shunying Zhao

Just Accepted Date: 27 May 2021 Online First Date: 13 July 2021 Issue Date: 18 July 2022

Cite this article:

Jinrong Liu,Rongfang Shen,Lin Feng, et al. Proteomics study of Mycoplasma pneumoniae pneumonia reveals the Fc fragment of the IgG-binding protein as a serum biomarker and implicates potential therapeutic targets[J]. Front. Med., 2022, 16(3): 378-388.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0840-y
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I3/378

Tab.1 Detailed clinical characteristic of children enrolled in proteomics analysis

Tab.2 Clinical characteristics of patients enrolled in ELISA

Fig.1 Biological differences between general Mycoplasma pneumoniae pneumonia (GMPP) and severe Mycoplasma pneumoniae pneumonia (SMPP). (A) 2D scatter plot of the proteins identified in patients with GMPP and SMPP. Proteins with log₂FC>0.5 were considered to be differentially expressed proteins and are shaded in blue or red. Corresponding gene symbols of proteins with log₂FC>1.5 are labeled in the plot. The label-free quantification (LFQ) intensity represents the protein quantification level. (B, C) Gene ontology enrichment analysis results of the dysregulated genes enriched in patients with SMPP (B) and GMPP (C). Top 15 GO terms with the most significant enrichment results for each category (biological process, molecular function, and cellular component). (D) Kyoto Encyclopedia of Genes and Genomes analysis results for the dysregulated genes enriched in patients with SMPP (top) and GMPP (bottom). All enrichment terms that reached significance are shown. (E) Overview of the complement and coagulation cascade pathways. The colored boxes (green, gray, and red) are the identified proteins in these pathways. The color intensity represents the corresponding log₂FC level; and increase in color intensity indicates an increase in enrichment in patients with SMPP (red) and GMPP (green).

Fig.2 Fc fragment of the IgG-binding protein (FCGBP) is a promising indicator for the progression to severe Mycoplasma pneumoniae pneumonia (SMPP). The serum concentration of FCGBP identified by ELISA in patients with general Mycoplasma pneumoniae pneumonia (GMPP) and SMPP on the 1st day of admission (A) and 5–7 days after admission (B). Statistical significance level of comparisons and fold change level (SMPP vs. GMPP) are indicated in the text. (C) Pairwise comparison of FCGBP serum concentrations in the GMPP group for treatment-naïve patients on the 1st day of admission and after 5–7 days of admission. (D) Pairwise comparison of FCGBP serum concentrations in the SMPP group for the patients on the 1st day of admission and after 5–7 days of admission. The statistical significance level of pairwise comparisons is indicated in the text.

Fig.3 Potential transcription factors (TFs) that regulate the expression of IgG-binding protein Fc fragment. (A) Predictive value of FCGBP serum levels in the early, late, and all stages. (B) Top 20 TFs with the highest regulatory potential scores. The regulatory potential score estimates the possibility that a factor can regulate a gene. Factor names are placed on the x-axis. Dots on the same vertical line with the same color represent the same factor. Each dot represents ChIP-Seq data.

Fig.4 Promising therapeutic drugs that inhibit progression to severe Mycoplasma pneumoniae pneumonia. (A) A bar graph of candidate perturbations inferred from connectivity map analyses. The top 10 compounds with the most positive and most negative connectivity scores are shown. (B) Connectivity map (CMap) mode-of-action analyses of the 25 selected drugs with connectivity scores<-70. Potential mechanisms and inhibitors are placed in the right and upper panels. The perturbations’ modes of action are indicated by black dots. (C) CMap gene target analyses of the 25 selected drugs. Identified target genes and inhibitors are placed in the right and upper panels. The perturbations’ target genes are indicated by black dots. (D) Protein–protein interaction network of the target genes inferred from CMap gene target analysis. The relationships between these proteins are inferred from STRING.

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