Construction of Unified Human Antimicrobial and Immunomodulatory Peptide Database and Examination of Antimicrobial and Immunomodulatory Peptides in Alzheimer’s Disease Using Network Analysis of Proteomics Datasets

Kumar, Ajneesh; Doan, Vo Minh; Kunkli, Balázs; Csősz, Éva

doi:10.3389/fgene.2021.633050

Cited by 10 publications

(25 citation statements)

References 125 publications

(129 reference statements)

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“…After data integration (Figure 3A), we performed differential gene expression (DEG) analysis (BC subtypes vs normal) to explore upregulated genes encoding immunomodulatory peptides in BC (Figure 3B). AMPs were retrieved from UDAMP (6) (Supplementary Data 1). Ten immunomodulatory peptides were selected for downstream analysis.…”

Section: Resultsmentioning

confidence: 99%

Drug repositioning for immunotherapy in breast cancer using single-cell and spatial transcriptomics analysis

Mohammadi

Jin

Zhang

et al. 2022

Preprint

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Immunomodulatory peptides are capable of stimulating or suppressing the immune system. Hence, deregulation of them can be considered as an immunotherapy approach. These peptides may have dual behavior in response to different infections. For instance, an antimicrobial peptide may act as an anticancer, tumor marker or even cause cancer progression. In this study, we used single-cell RNA sequencing analysis to investigate the deregulation of immunomodulatory peptides in malignant versus normal human breast epithelial cells. We validated the obtained results in chromatin accessibility level. Furthermore, we used a drug repositioning approach to change the expression of these peptides based on their role in cancer biology. As a result, ten immunomodulatory peptides were upregulated in breast cancer versus normal. Chromatin was more accessible for these peptides in cancer cell lines versus normal. Among these ten peptides, five of them were tumor drivers (i.e., BST2, GAPDH, S100A8, S100A9 and HMGB1), three of them were anticancer (i.e., H2AFJ, SCGB2A1 and HMGN2), S100A7 had dual behavior in different cancers and ZG16B was a tumor marker. Using the LINCS L1000 database, we proposed a list of drugs that can deregulate the candidate peptides according to their role in the progression of malignancy. In conclusion, immunomodulatory peptides can be considered as drug targets based on their role in cancer biology.

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Section: Resultsmentioning

confidence: 99%

Drug repositioning for immunotherapy in breast cancer using single-cell and spatial transcriptomics analysis

Mohammadi

Jin

Zhang

et al. 2022

Preprint

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“…Currently, the hypothesis that links microbial insults to immune system activation in AD, which ultimately leads to the production of antimicrobial peptides (AMPs), has been strengthened ( 46 ). To explore the distribution of proteins with antimicrobial activities across the four brain regions and their changes in expression and/or post-translational modification status, we compared our complete proteomic data set with the recently published UDAMP database ( 47 ). A total of 39 AMPs were detected, 26 of which were found in all brain regions ( Figure 7A ).…”

Section: Resultsmentioning

confidence: 99%

“…The analysis of proteins with potential AMP functions displays a similar distribution across the AD-brain areas. AMPs have a dual role related to pro-inflammation and immunomodulation ( 46 , 47 ). Interestingly, the alteration in their abundance is more prominent in the HP, the brain region characterized by a pro-inflammatory profile.…”

Section: Discussionmentioning

confidence: 99%

Topological Dissection of Proteomic Changes Linked to the Limbic Stage of Alzheimer’s Disease

et al. 2021

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Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. In AD, neurodegeneration spreads throughout different areas of the central nervous system (CNS) in a gradual and predictable pattern, causing progressive memory decline and cognitive impairment. Deposition of neurofibrillary tangles (NFTs) in specific CNS regions correlates with the severity of AD and constitutes the basis for disease classification into different Braak stages (I-VI). Early clinical symptoms are typically associated with stages III-IV (i.e., limbic stages) when the involvement of the hippocampus begins. Histopathological changes in AD have been linked to brain proteome alterations, including aberrant posttranslational modifications (PTMs) such as the hyperphosphorylation of Tau. Most proteomic studies to date have focused on AD progression across different stages of the disease, by targeting one specific brain area at a time. However, in AD vulnerable regions, stage-specific proteomic alterations, including changes in PTM status occur in parallel and remain poorly characterized. Here, we conducted proteomic, phosphoproteomic, and acetylomic analyses of human postmortem tissue samples from AD (Braak stage III-IV, n=11) and control brains (n=12), covering all anatomical areas affected during the limbic stage of the disease (total hippocampus, CA1, entorhinal and perirhinal cortices). Overall, ~6000 proteins, ~9000 unique phosphopeptides and 221 acetylated peptides were accurately quantified across all tissues. Our results reveal significant proteome changes in AD brains compared to controls. Among others, we have observed the dysregulation of pathways related to the adaptive and innate immune responses, including several altered antimicrobial peptides (AMPs). Notably, some of these changes were restricted to specific anatomical areas, while others altered according to disease progression across the regions studied. Our data highlights the molecular heterogeneity of AD and the relevance of neuroinflammation as a major player in AD pathology. Data are available via ProteomeXchange with identifier PXD027173.

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“…The list of human AMPs published by Kumar et al. contains 186 peptides and proteins with known antimicrobial and/or immunomodulatory effect ( 35 ). One hundred of them (53.8%) were found in the transcriptomes of the sequenced PFC neurons ( Supplementary Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…To better understand the possible molecular basics of direct neuro-immune interactions and the immunomodulatory potential of cortical neurons, we analyzed the expression pattern of genes encoding AMPs and proteins playing role in immunological processes (T cell dependent B cell activation, T cell independent B cell activation, CD8+ T cell activation, MHC class I antigen presentation, and MHC class II antigen presentation). The list of AMPs was taken from a recently published study ( 35 ), which presents a unified comprehensive human antimicrobial and immunomodulatory protein database constructed by collecting and integrating data from online databases and literature search. Based on this dataset, we searched for AMP transcripts in our normalized sequencing data.…”

Section: Methodsmentioning

confidence: 99%

The Single-Cell Transcriptomic Analysis of Prefrontal Pyramidal Cells and Interneurons Reveals the Neuronal Expression of Genes Encoding Antimicrobial Peptides and Immune Proteins

et al. 2021

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The investigation of the molecular background of direct communication of neurons and immune cells in the brain is an important issue for understanding physiological and pathological processes in the nervous system. Direct contacts between brain-infiltrating immune cells and neurons, and the neuromodulatory effect of immune cell-derived regulatory peptides are well established. Several aspects of the role of immune and glial cells in the direct neuro-immune communication are also well known; however, there remain many questions regarding the molecular details of signaling from neurons to immune cells. Thus, we report here on the neuronal expression of genes encoding antimicrobial and immunomodulatory peptides, as well as proteins of immune cell-specific activation and communication mechanisms. In the present study, we analyzed the single-cell sequencing data of our previous transcriptomic work, obtained from electrophysiologically identified pyramidal cells and interneurons of the murine prefrontal cortex. We filtered out the genes that may be associated with the direct communication between immune cells and neurons and examined their expression pattern in the neuronal transcriptome. The expression of some of these genes by cortical neurons has not yet been reported. The vast majority of antimicrobial (~53%) and immune cell protein (~94%) transcripts was identified in the transcriptome of the 84 cells, owing to the high sensitivity of ultra-deep sequencing. Several of the antimicrobial and immune process-related protein transcripts showed cell type-specific or enriched expression. Individual neurons transcribed only a fraction of the investigated genes with low copy numbers probably due to the bursting kinetics of gene expression; however, the comparison of our data with available transcriptomic datasets from immune cells and neurons suggests the functional relevance of the reported findings. Accordingly, we propose further experimental and in silico studies on the neuronal expression of immune system-related genes and the potential role of the encoded proteins in neuroimmunological processes.

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Construction of Unified Human Antimicrobial and Immunomodulatory Peptide Database and Examination of Antimicrobial and Immunomodulatory Peptides in Alzheimer’s Disease Using Network Analysis of Proteomics Datasets

Cited by 10 publications

References 125 publications

Drug repositioning for immunotherapy in breast cancer using single-cell and spatial transcriptomics analysis

Drug repositioning for immunotherapy in breast cancer using single-cell and spatial transcriptomics analysis

Topological Dissection of Proteomic Changes Linked to the Limbic Stage of Alzheimer’s Disease

The Single-Cell Transcriptomic Analysis of Prefrontal Pyramidal Cells and Interneurons Reveals the Neuronal Expression of Genes Encoding Antimicrobial Peptides and Immune Proteins

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