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Shared molecular signatures between coronavirus infection and neurodegenerative diseases provide targets for broad-spectrum drug development


Overview of the study

The workflow of the study was shown in Fig. 1. Firstly, the viral infection-related genes (VIGs) for three coronaviruses including SARS-CoV-2, SARS-CoV and MERS-CoV, and disease-related genes (DGs) for AD and PD were obtained from databases of H2V, HGMD and DisGeNET, respectively. Then, the common genes and molecular functions between coronavirus infection and neurodegenerative diseases were obtained. Finally, the tissue expression specificity of the common genes were analyzed based on the Expression Atlas database; the interactions between these genes and other viruses besides coronaviruses were analyzed based on protein–protein interactions derived from the HVIDB database; the drugs targeting these genes were obtained from the DGIdb database.

Figure 1
figure 1

The workflow of the study. The database names were shown in italic and colored in red.

Integration of viral infection-related and disease-related genes from multi-omics data

The VIGs were obtained for three deadly coronaviruses including the SARS-CoV-2, SARS-CoV and MERS-CoV from the H2V database (Table S1) (Materials and Methods). The VIGs included seven kinds of genes from multi-omics data: the differentially expressed genes (DEGs), differentially expressed proteins (DEPs), differentially phosphorylated proteins (DPPs), differentially translated proteins (DTPs), differentially ubiquitinated proteins (DUPs), proteins that participate in human-virus protein–protein interactions (P-PPIs), and disease severity associated proteins (SAPs) (Table 1). For the SARS-CoV-2, VIGs included 810 DEGs, 171 DEPs, 1,987 DPPs, 111 DTPs, 267 DUPs, 1,257 P-PPIs and 335 SAPs. Only a few genes overlapped between different kinds of VIGs (Table S2). For example, only 13 genes were observed in both the DEGs and DEPs. This suggested that different kinds of VIGs capture complementary aspects of the viral infection. Therefore, seven kinds of VIGs from multi-omics data were incorporated for a better understanding of the pathogenesis of coronavirus infection.

Table 1 The number of different kinds of VIGs in SARS-CoV-2, SARS-CoV and MERS-CoV.

For the SARS-CoV, 2,488 VIGs were obtained which included 1,487 DEGs, 51 DEPs and 998 P-PPIs; for the MERS-CoV, 9,038 VIGs were obtained which included 8,895 DEGs and 292 P-PPIs (Table 1). Only a few genes overlapped between different kinds of VIGs for both SARS-CoV and MERS-CoV.

The DGs for both AD and PD were obtained from the HGMD and DisGeNET databases (Materials and Methods). A total of 886 DGs for AD were obtained which included 105 and 852 genes obtained from the HGMD and DisGeNET databases, respectively (Table S1). A total of 481 DGs for PD were obtained which included 85 and 450 genes obtained from the HGMD and DisGeNET databases, respectively (Table S1).

The inflammation and stress response-related molecular functions were common in coronavirus infection and AD

The enriched gene ontology (GO) terms and KEGG pathways in the VIGs of three coronaviruses and DGs of two neurodegenerative diseases were obtained firstly (Table S3). Then, the common genes and functions between VIGs of all three coronaviruses and DGs of AD were analyzed. 38 genes were found to be involved in infection of three coronaviruses and AD (Fig. 2 and Table S4). A total of 8 KEGG pathways, and 95, 5, 25 GO terms in the domain of Biological Process, Molecular Function, Cellular Component, respectively, were observed between the enriched functions in VIGs of three coronaviruses and DGs of AD (Fig. 2 and Table S5).

Figure 2
figure 2

The common molecular signatures between three coronaviruses (SARS-CoV-2, SARS-CoV and MERS-CoV) and two neurodegenerative diseases (AD and PD). (A) The overlapped genes between VIGs and DGs; (BE) The overlapped KEGG pathways (B) and GO terms in domains of Biological Process (C), Molecular Function (D) and Cellular Component (E).

In the shared KEGG pathways, six pathways were connected in the pathway network (Fig. 3A). Three pathways including the “MAPK signaling pathway”, “TNF signaling pathway” and “NF-kappa B signaling pathway” were reported to be involved in inflammation and immune response. Among them, the “MAPK signaling pathway” was the hub node in the pathway network and connected to four pathways. Interestingly, two virus infection-related pathways including “Coronavirus disease” and “Epstein-Barr virus infection” were enriched in DGs of AD, while two neurodegenerative disease-related pathways including “Amyotrophic lateral sclerosis” and “Lipid and atherosclerosis” were enriched in VIGs of three coronaviruses.

Figure 3
figure 3

The shared KEGG pathways and biological processes between coronavirus infection and AD. (A) The shared KEGG pathways between coronavirus infection and AD25. (B) Top ten most enriched GO terms in the domain of Biological Processes. The GO terms were sorted by the adjusted p-value of GO terms obtained in AD. The heat map was colored based on the adjusted p-value (shown in the heat map) according to the legend in the top right. (C) Clustering of the shared GO terms in the domain of Biological Process between coronavirus infection and AD. The heat map was colored based on the pairwise similarity of GO terms according to the figure legend in the top right. The words in the right side of the figure referred to top five words which appeared most frequently in the GO terms of the corresponding cluster that were shown in the heat map. The size of words was in proportion to the frequency of them in GO terms of the corresponding cluster.

In the shared GO terms in the domain of Biological Process, when analyzing the top ten GO terms, three of them were related to response to oxidative or chemical stress and five of them were related to regulation of biological processes such as signaling and catabolic process (Fig. 3B). When analyzing all 95 GO terms, they were grouped into 9 clusters (Fig. 3C). The largest cluster was related to responses to signaling, stress, regulations, and so on; the second cluster was related to regulation of biological processes such as signaling and catabolic process; other clusters were related to development, organization, localization, RNA silencing, viral infection, and so on (Fig. 3C). In the shared GO terms in the domain of Molecular Function, all five GO terms were binding-related such as “ubiquitin protein ligase binding” and “chaperone binding” (Table S6). In the shared GO terms in the domain of Cellular Component, most GO terms were related to vesicle-like structures in the cytoplasm such as the vesicle, granule, endosome, vacuole, and so on (Table S6).

Common molecular signatures between coronavirus infection and PD were also observed in AD

Then, the common genes and functions between VIGs of all three coronaviruses and DGs of PD were analyzed. 19 genes were found to be involved in the infection of three coronaviruses and PD (Fig. 2 and Table S4). A total of 7 KEGG pathways, and 97, 5, 22 GO terms in the domain of Biological Process, Molecular Function, Cellular Component, respectively, were observed between the enriched functions in VIGs of three coronaviruses and DGs of PD (Fig. 2 and Table S5). Interestingly, most of the enriched functions shared between coronaviruses and PD were also found in AD (Fig. 2 and Table S5). For example, 100%, 88%, 89% and 91% of enriched KEGG pathways, GO terms in the domain of Biological Process, Molecular Function, Cellular Components shared between the SARS-CoV-2 and PD were also found in AD (Table S5).

Seven genes were involved in infections of three coronaviruses and two neurodegenerative diseases

The common molecular signatures between three coronaviruses and two neurodegenerative diseases were further analyzed. Seven genes were observed to be involved in both infections of three coronaviruses and two neurodegenerative diseases, including the HSP90AA1, ALDH2, CAV1, COMT, MTOR, IGF2R and HSPA1A (Table 2). The expression specificity of these genes in human tissues were analyzed. As shown in Fig. 4, the HSP90AA1 had medium to high expression in several brain tissues such as the Brodmann area 9, cerebellar hemisphere and hypothalamus; the COMT, MTOR and HSPA1A had high expression in one or two brain tissues such as cerebellum; other three genes had low to medium expression in brain tissues. In the lung where three coronaviruses infect, all seven genes had medium expression.

Table 2 Seven genes which were involved in both infections of three coronaviruses and two neurodegenerative diseases, and the drug targeted against these genes.
Figure 4
figure 4

The expression of seven genes in 52 human tissues. The heat map listed the normalized expression value of genes in tissues according to the legend in the top right. The genes were shown in the left side of the figure. The tissues were shown at the bottom of the figure and were organized by systems (colored bars).

A total of 7 KEGG pathways, and 88, 5, 22 GO terms in the domain of Biological Process, Molecular Function, Cellular Component, respectively, were observed between the enriched functions in VIGs of three coronaviruses and DGs of two neurodegenerative diseases (Fig. 2 and Table S5).

Seven genes were involved in infection of multiple viruses

The seven genes identified here can be taken as targets for the development of drugs that may have a broad-spectrum effect on both coronavirus infection and neurodegenerative diseases. Their roles in infections of other viruses were further investigated. Except three coronaviruses used in the study, a total of 21 viruses were reported to interact with these genes based on protein–protein interactions (PPIs) between viral and human proteins (Fig. 5 and Table S8). Notably, the HSP90AA1 and HSPA1A took part in infections of 16 and 12 viruses, respectively. Then, these genes were mapped to public compounds by searching the DGIdb database for drugs targeting these genes. Overall, a total of 28 high-confidence gene-drug interactions were obtained (Table S7). Most genes were targeted by no more than 5 drugs. Interestingly, the COMT could be targeted by more than 10 drugs (Table 2).

Figure 5
figure 5

The interactions between seven genes (red) and viruses (light green). The interactions between three coronaviruses (SARS-CoV-2, SARS-CoV and MERS-CoV) and genes were obtained based on this study, while other interactions were obtained based on PPIs between virus and human (Table S8). The full name of these viruses was listed in Table S9.



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