key: cord-0919217-159b1nux
authors: Ahmed, Shiek S. S. J.; Paramasivam, Prabu; Kamath, Manjunath; Sharma, Ashutosh; Rome, Sophie; Murugesan, Ram
title: Genetic Exchange of Lung-Derived Exosome to Brain Causing Neuronal Changes on COVID-19 Infection
date: 2021-07-27
journal: Mol Neurobiol
DOI: 10.1007/s12035-021-02485-9
sha: d15ea2805d2223ee5f2d835a80fc7c842ea21e90
doc_id: 919217
cord_uid: 159b1nux

The pandemic of novel coronavirus 2 (SARS-CoV-2) has made global chaos for normal human living. Despite common COVID-19 symptoms, variability in clinical phenotypes was reported worldwide. Reports on SARS-CoV-2 suggest causing neurological manifestation. In addition, the susceptibility of SARS-CoV-2 in patients with neurodegenerative diseases and its complexity are largely unclear. Here, we aimed to demonstrate the possible transport of exosome from SARS-CoV-2–infected lungs to the brain regions associated with neurodegenerative diseases using multiple transcriptome datasets of SARS-CoV-2–infected lungs, RNA profiles from lung exosome, and gene expression profiles of the human brain. Upon transport, the transcription factors localized in the exosome regulate genes at lateral substantia nigra, medial substantia nigra, and superior frontal gyrus regions of Parkinson’s disease (PD) and frontal cortex, hippocampus, and temporal cortex of Alzheimer’s disease (AD). On SARS-CoV-2 infection, BCL3, JUND, MXD1, IRF2, IRF9, and STAT1 transcription factors in the exosomes influence the neuronal gene regulatory network and accelerate neurodegeneration. STAT1 transcription factor regulates 64 PD genes at lateral substantia nigra, 65 at superior frontal gyrus, and 19 at medial substantia nigra. Similarly, in AD, STAT1 regulates 74 AD genes at the temporal cortex, 40 genes at the hippocampus, and 16 genes at the frontal cortex. We further demonstrate that dysregulated neuronal genes showed involvement in immune response, signal transduction, apoptosis, and stress response process. In conclusion, SARS-CoV-2 may dysregulate neuronal gene regulatory network through exosomes that attenuate disease severity of neurodegeneration. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-021-02485-9.

Exosomes are one of the extracellular vesicles secreted by most of the multi-cellular organisms for their intercellular communication. Exosomes carry various biomolecules like nucleotide molecules, including RNA, miRNAs, lncRNA, proteins, and metabolites from the originating cells to target cells [1, 2] . Initially, exosomes were considered to be involved in removing waste molecules from the cells [3] . Advance in the research suggests that exosomes deliver micro-and macromolecules to communicate and regulate the recipient cells during physiological and pathological processes. It is proven that exosomes are involved in cancer progression [4] , cardiovascular diseases [5] , neurodegeneration [6] , and even in microbial and viral infections [7, 8] . Interestingly, exosomes released from the virus-infected cells carry the viral particles to reprogram the target cells and spread pathogenesis [9] .

Recently, the SARS-CoV-2 (COVID-19) infection has become a pandemic affecting millions of people worldwide. An increased vulnerability is reported in patients with chronic diseases like diabetes and hypertension [10, 11] . SARS-CoV-2 infects lower respiratory tracts and progresses toward multi-organ failure [12] . Currently, there is no specific treatment available to treat COVID-19. Social distancing and vaccination are helpful to protect the spreading of disease among the population. However, there is an urgent need to develop a drug to treat this disease. Understanding the disease mechanism may contribute to the development of a potential drug for SARS-CoV-2 infection. Many viruses, including the RNA of SARS-CoV-2, are known to enter the exosome that enables intra-host spreading [13] . Studies showed presence of SARS-CoV-2 viral particles within exosomes [14, 15] . Besides, SARS-CoV-2 was noticed within host cells' vacuoles in the histopathological analysis [16, 17] . These findings suggested a possible involvement of exosomal intercellular communication on SARS-CoV-2 infection from the primary lung site to other communicating organs in the human system.

Among various affected organs, limited research has been carried out to study the COVID-19 pathogenesis in the brain. Besides the cardinal symptoms, neurological changes have also been reported in 36.4% of cases COVID-19 [18] . Notably, some COVID-19 recovered patients show significant memory loss and cognitive disability [19] . Recently, Singh et al. suggested that COVID-19 may affect the central nervous system (CNS) [20] . Particularly, a few studies suggest COVID-19 may accelerate neurodegeneration in Parkinson's (PD) and Alzheimer's (AD) disease [21, 22] . A study by Pavel et al. suggests COVID-19 causes selective vulnerability in PD by activation of α-synucleinopathies in the CNS [21] . Also, the survey conducted by Brown et al. reports the worsening of PD symptoms on COVID-19 infection [23] . Similarly, Naughton et al. demonstrate the possible role of COVID-19 infection in patients with AD [24] . Moreover, Heneka et al. suggest that COVID-19 patients are at high risk of developing AD [25] .

Herein, we postulate that exosomes may be involved in the transport molecules from the infected lungs to the brain region by crossing the blood-brain barrier (BBB) that leads to neurological manifestation. Elevated levels of exosomes in the peripheral circulatory system were noticed during lung inflammation [26] . Indeed, previous studies have demonstrated the exosomal transport between the lungs to BBB and BBB to other neuronal regions [27] [28] [29] [30] [31] [32] . In general, BBB is a vascular structure composed of brain microvascular endothelial cells (BMECs), which act as a barrier between the CNS and peripheral circulatory system that allows exosomes in and out from blood to the brain. Studies suggest exosomal transport occurs by endocytosis of BMEC's transcellular mechanism or diffusion through tight junctions between BMECs [33, 34] . Recently, Reynolds et al. suggest the ability of SARS-COV-2 to alter tight junction (TJ) proteins that cause disruption of BBB integrity which allows neuro-invasion of molecules [35] . Chen et al. demonstrate exosomes crossing BBB through transcellular BMEC endocytosis in stroke [36] . Similarly, Matsumoto et al. report the transport of exosomes from the peripheral circulatory to CNS through BBB during the inflammatory condition [37] .

In the present study, we have developed a systems biological framework to demonstrate the role of exosomecarried mRNAs that encode transcription factors from infected lungs to the brain. We investigated multiple transcriptome datasets of SARS-CoV-2-infected lungs, RNA profiles of lung-derived exosomes, and gene expression profiles of various human brain regions. In addition, the exosomal intercellular network between lungs and brain regions was constructed for neurodegenerative diseases based on literature evidence. Our data identify the transcription factors (TF) from the lungs regulating gene expression in the brain regions, which accelerate PD and AD on COVID-19 infection.

The RNA-Seq dataset related to SARS-CoV-2 infection in the lungs were retrieved from Sequence Read Archive (SRA), NCBI database by using a combination of key terms including "SARS-CoV-2" and "Human host." The dataset (GSE147507) containing the RNA-Seq profile of 110 samples at various experimental conditions of SARS-CoV-2 infection was retrieved [38] . Among 110 samples, two healthy lung biopsies (GSM4462413 and GSM4462414) and two SARS-CoV-2-infected lung (GSM4462415 and GSM4462416) samples were selected and utilized for our downstream analysis. These selected samples have no previous history of disease including neuropathology.

FastQC v0.11.5 was used to assess the quality of data. Then, reads were trimmed by using Trimmomatic v0.32. The qualified reads were aligned to the HG19 human genome. Reads count for each transcript was normalized, and the up-regulated genes on SARS-CoV-2 infection compared to healthy lungs were captured using the DESeq method. Significant up-regulated genes were identified based on false discovery rate (FDR), p < 0.05.

The GSE121307 microarray dataset [39] describing the exosomal shuttle RNA (esRNA) in respiratory tract-derived exosomes was collected from NCBI, Gene Expression Omnibus (GEO) database. Exosomal shuttle mRNA (esRNA) predominantly expressed in GSE121307 lung data were identified and mapped with the overexpressed genes on SARS-CoV-2 infection. The mapped overexpressed genes were assumed to be packed into exosome as esRNA during SARS-CoV-2 infection. Among them, mRNA encoding transcription factor was identified using the Molecular Signatures (https:// www. gsea-msigdb. org/ gsea/ msigdb) and TcoF-DB (https:// tools. sschm eier. com/ tcof) databases.

The Qinsight text mining tool (https:// quert le. com/) was used to construct an exosome-cell communication network. Qinsight allows us to collect more precise literature for the key terms from patents, clinical trials, and journals, including original research, reviews, and case reports based on biospecific artificial intelligence methods. We constructed the exosome communication network by literature search with the relevant keywords to establish the exosome connection between (1) lungs to the BBB and (2) BBB to the neuronal regions associated to PD and AD. At the initial phase of exosome communication network construction, anatomical neuronal connectivity between the brain regions and BBB was verified. In the second phase, the report suggesting the transport of exosomes between the lungs and the BBB and subsequent transfer of exosomes from the BBB to neuronal regions was accessed. In both phases, two different investigators (M.K. and P.P.) independently collected the supporting literature using Qinsight. The collected data were cross-verified by the two investigators (S.S.S.J.A. and A.S.). If any, discrepancy in the collected data was resolved during group discussion. Finally, based on the literature evidence, an exosome communication network was constructed.

The Parkinson's gene expression microarray dataset of human lateral substantia nigra, medial substantia nigra, and superior frontal gyrus regions was retrieved from the Gene Expression Omnibus (GSE8397) [40] . For AD, the gene expression dataset of human frontal cortex, hippocampus, and temporal cortex was collected with accession GSE36980 [41] . The sample characteristics of both datasets (GSE8397 and GSE36980) were assessed from the literature [40, 41] . In the PD dataset (GSE8397), all control samples were reported free from neurological diseases and PD cases were assessed by neurological rating scale and histologically confirmed [40] . Particularly, the multiple sclerosis-specific control sample in the GSE8397 dataset was excluded during analysis. Similarly in the AD dataset (GSE36980), Binswanger's disease and non-AD vascular dementia were excluded to select control samples that are free from neurological diseases [41] , whereas the AD samples were pathologically assessed based on the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and the Braak stage positive. In addition, the AD was confirmed with immunostaining against phosphorylated microtubule-associated protein tau [41] . All selected samples from the datasets were log-transformed and analyzed with a limma 3.26.8 library package using the R program to identify significantly overexpressed genes (DEG) with a t test statistical significance of p ≤ 0.05.

Next, we assumed that exosome-transported mRNA encoding TF would be readily translated into protein by the host translational machinery and activate its target genes in neurons. These activated genes may be associated with neurodegenerative diseases. We use the Coexpedia database (http:// www. coexp edia. org/) to look for overexpressed PD and AD genes that are co-expressed with each TF identified in the exosomes during SARS-CoV-2 infection. The regulatory relationships were determined between these TFs with overexpressed PD and AD genes using iRegulon plugin (version 1.3) in Cytoscape software [42] with NEScore > 3 and FDR < 0.001 set as a threshold [43] .

Molecular enrichments were carried out to evaluate the TF's target genes' functions and relevance for the PD and AD pathology. The biological process of the genes in the regulatory network was determined by using the BiNGO module [44] with a p value < 0.05 cut-off in Cytoscape software. The regulatory network was also analyzed based on molecular pathways derived using the Reactome database (www. react ome. org/).

Lung RNA-Seq data on SARS-CoV-2 infection and their controls were analyzed. Of 21,797 transcripts, 731 (431 up and 300 down) were differentially regulated on SARS-CoV-2 infection with FDR, p < 0.05. We then mapped the 431 overexpressed genes with GSE121307 esRNA data to confirm their lung-derived exosome. We believe that the flooding of overexpressed genes in the lungs in SARS-CoV-2 infection may be packed into exosomes and transported to the target cell. Among 431 overexpressed genes, 267 were sorted into exosomes. For example, GSK3B, DPP4, SMAD3, PARP1, and IKBKB are the inflammatory genes (mRNA) noticed as an outcome of cytokine storm in the lungs that may be carried as esRNA to target cells by the exosome. Of 267 overexpressed esRNA, 19 encode TFs identified using the Molecular Signatures and TcoF-DB v2 databases (Table 1) .

Next, we constructed an exosomal communication network based on literature evidence. The network demonstrates the exosomal connectivity between the lungs and BBB microendothelial cells [27] [28] [29] [30] [31] [32] . Similarly, the exosome communication between the BBB endothelial cells and various neuronal regions was determined based on literature evidence [27] [28] [29] [30] [31] [32] . Overall, the exosomal network confirms the exosomal connectivity between lungs and neuronal regions associated with neurodegenerative diseases through BBB (Fig. 1 ).

Simultaneously, the collected microarray datasets of PD at lateral substantia nigra, medial substantia nigra, and superior frontal gyrus region were analyzed to identify the overexpressed genes at each neuronal region compared to its control. The overexpressed genes with a p value ≤ 0.05 were selected at each condition across the neuronal regions. For instance, 2495 genes at the lateral substantia nigra, 1088 at the medial substantia nigra, and 790 at the superior frontal gyrus region of PD were overexpressed compared to control. Similarly, the analysis of AD datasets showed 362 genes at the frontal cortex, 1935 in the hippocampus, and 1242 at the temporal cortex were noticed overexpressed in AD.

Transcription factor is a regulatory component involved in regulating cellular gene expression. Here, we built a TF-gene network for 19 TFs regulating the overexpressed PD and AD genes across the brain regions. The acquired TFs from the exosomes will be readily translated into protein by the neuronal translational machinery of targeted neurons. After that, the TFs initiate the transcription of their target genes on binding to their promoter region. We noticed 2758 genes were co-expressed along with the selected 19 TFs (Fig. 2 ). Using iRegulon, the six transcription factors showed regulating the overexpressed genes in neurodegenerative diseases at lateral substantia nigra (Fig. 3) , medial substantia nigra (Fig. 4) , superior frontal gyrus (Fig. 5) , frontal cortex (Fig. 6) , hippocampus (Fig. 7) , and temporal cortex (Fig. 8) . For instance, STAT1 regulates 64 genes associated with PD at lateral substantia nigra. In medial 

We investigated the biological process of each regulatory network in PD (Supplementary Material 1) and AD (Supplementary Material 2), which showed dysregulation in the immune response, signal transduction, apoptosis, and response to stress metabolism. Furthermore, the pathway analysis of the PD regulatory network showed regulating TRAIL signaling pathway, estrogen receptor signaling, Alpha9 beta1 integrin signaling events, LKB1 signaling events, ErbB receptor signaling network, Sphingosine 1-phosphate (S1P) pathway, mTOR signaling pathway, internalization of ErbB1, S1P1 pathway, Arf6 trafficking events, and insulin pathway (Fig. 9) . Similarly, the AD regulatory networks significantly enriched and contributed to the TRAIL signaling pathway, IL5-mediated signaling events, Syndecan-1 signaling, estrogen receptor signaling, proteoglycan, focal adhesion kinase signaling, urokinasetype plasminogen activator (uPA), and uPAR-mediated signaling (Fig. 10 ).

The mechanism of COVID-19 causing neurological manifestation is not clearly understood. The current study suggests that COVID-19 accelerates the immune process and oxidative stress causing difficulty in patients with neurodegenerative diseases [45] . The complexity of the neurodegenerative process and the significant involvement of newly emerged pandemic COVID-19 make it necessary to investigate the association of COVID-19 in PD and AD, the most prevalent neurodegenerative diseases worldwide.

In the present study, the complex systems biological framework was implemented that integrates various transcriptome datasets to demonstrate the influence of exosomal transporting molecules from the lung to the brain on COVID-19 infection. During inflammation, lung cells release exosomes that carry the abundance of signaling molecules to avoid cellular stress. We identified 19 transcription factors (LITAF, IRF2, IRF9, PHF11, ZNF385A, MIER1, Fig. 1 Exosomal communication network. Network representing the exosomal connectivity between lungs to the neuronal regions associated with neurodegenerative diseases through the blood-brain barrier (BBB). The lungs are represented as violet node defining connec-tion with the BBB (green node) by bold dotted edges. BBB connects various brain regions associated with PD (yellow) and AD (red). The gray-colored nodes represent the neurons, orange nodes represent astrocyte, and blue nodes represent microglia cells involved in regulating interferon system with TRIM22 and STAT1 as anti-viral and anti-bacterial components [46, 47] . The IRF9 regulates inflammation and immune cell in autoimmune disease [48] [49] [50] . TRIM22 is the component of TRIM family involved in apoptosis, immune signaling, and antiviral activities [50] . Interestingly, TRIM22 restricts the [51] [52] [53] . Likewise, MXD1 is the MAX dimerization protein 1 transcription factor regulating cell differentiation, proliferation, and apoptosis. MXD1 was noticed up-regulated in CD14 + monocytes and CD4 + T cells on COVID-19 infection [54] . Recently, Mamoor et al. demonstrate the role of MXD1 in host cells' response to COVID-19 infection [55] . Also, Howard et al. reported the influence of MXD1 expression upon H1N1 and H9N2/G1 viral infection in the host [56] . Furthermore, silencing of MXD1 decreases the H9N2 replication process [56] . Similarly, PHF11 is one of the interferon-stimulated genes expressed by a host on viral infections that regulates cytokine genes in T lymphocytes [57, 58] . A study reports enriched cytokines and chemokines in HIV-infected patients' exosomes compared to HIV-negative control [59] . Similarly, lipopolysaccharide (LPS) stimulated RAW 264.7 cells to produce exosomes with increased chemokine and RNA molecules involved in regulating inflammation [60] .

Herein, our RNA-Seq analysis of the GSE121307 dataset showed 19 TFs in the lung-derived exosomes on COVID-19 infection. The lung exosome interacts with brain microvascular endothelial cells that anatomically connect the pathological hotspot of neurodegenerative diseases like AD and PD. The exosomal connectivity between the lungs to BBB and BBB to other neuronal regions was determined based on literature [27] [28] [29] [30] [31] [32] . Exosomal delivery of 19 TFs encoding mRNAs to the neuronal hotspot may get translated into proteins using translational machinery of target cells. Timothy et al. report the functional activity of translated exosome-shuttled mRNA in the target cells [61] . Similarly, Montecalvo et al. and Corrado et al. reported the change in molecular pathways in the target cells on the transfer of exosomal cargoes [62, 63] . Also, Valadi et al. report the cellular modulation in target cell on translating the exosomal mRNA into proteins by the target cell translational machinery [64] . Particularly, Valadi et al. demonstrated the support of translational machinery for the protein synthesis of exosome-transported mRNAs in the target cells using in vitro translation assay [64] .

In the present study, we demonstrated that the translation of these 19 transcription factors will activate their target genes. Among these, six TFs were noticed activating 469 genes associated with AD and PD on binding to their regulatory regions. Most of these activated genes are involved in inflammatory, apoptosis, and other signal transduction processes that contribute to the neurodegeneration process. Although our study identified novel information about the transcription factors regulating neurodegenerative genes on COVID-19 infection, few limitations need to be considered. First, the identified transcriptional regulatory networks were derived using a heterogeneous dataset. Second, no functional exploration was made to understand the significant regulatory network based on COVID-19 infection. Third, difference in regulatory behavior of the network based on gender was not established due to limited samples in dataset that avoid sub-group analysis. Alternatively, the strength of this study need to be acknowledged: (1) This study presents a novel approach of integrating multiple datasets to understand the pathogenesis caused by exosome communication in (2) To the best of knowledge, this is the first study to present a unique exosome communication model that aids in understanding the impact of peripheral exosome on the CNS.

In conclusion, our study explores the behavior of exosomal TF regulating PD and AD causative genes at neuronal regions on SARS-CoV-2 infection. Although the public repository data were used, we implemented several curation levels to achieve the pathologically relevant TF regulatory network associated with neurodegenerative diseases. More particularly, the step-wise procedure implemented in the present study was strategically confirmed at each stage of methodology with biological and literature evidence.

With the rapidly enlarging COVID-19 pandemic, there is an unprecedented level of impact on the research sector and access to laboratory work. Therefore, many research investigations are underway to utilize the publicly available data on SARS-CoV-2 to expand the research efforts to handle the present critical situation. On this basis, the present study enhances the knowledge of COVID-19 influencing neuronal pathogenesis that describes the previously unknown mechanism of the COVID-19 pandemic. However, our hypothesis warrants further investigation.

The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s12035-021-02485-9.

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Acknowledgements All authors thank their institute for the support