Investigating the human protein-host protein interactome of SARS-CoV-2 infection in the small intestine

Abstract

Aim: The present study aimed to identify human protein-host protein interactions of SARS-CoV-2 infection in the small intestine to discern the potential mechanisms and gain insights into the associated biomarkers and treatment strategies.

Background: Deciphering the tissue and organ interactions of the SARS-CoV-2 infection can be important to discern the potential underlying mechanisms. In the present study, we investigated the human protein-host protein interactions in the small intestine.

Methods: Public databases and published works were used to collect data related to small intestine tissue and SARS-CoV-2 infection. We constructed a human protein-protein interaction (PPI) network and showed interactions of host proteins in the small intestine. Associated modules, biological processes, functional pathways, regulatory transcription factors, disease ontology categories, and possible drug candidates for therapeutic targets were identified.

Results: Thirteen primary protein neighbors were found for the SARS-CoV-2 receptor ACE2. ACE2 and its four partners were observed in a highly clustered module; moreover, 8 host proteins belonged to this module. The protein digestion and absorption as a significant pathway was highlighted with enriched genes of ACE2, MEP1A, MEP1B, DPP4, and XPNPEP2. The HNF4A, HNF1A, and HNF1B transcription factors were found to be regulating the expression of ACE2. A significant association with 12 diseases was deciphered and 116 drug-target interactions were identified.

Conclusion: The protein-host protein interactome revealed the important elements and interactions for SARS-CoV-2 infection in the small intestine, which can be useful in clarifying the mechanisms of gastrointestinal symptoms and inflammation. The results suggest that antiviral targeting of these interactions may improve the condition of COVID-19 patients.

Keywords: Drug targets; Interactome; Protein interaction network; Regulatory network; SARS-CoV-2; Small intestine.

Figure 1

Top 10 tissue-specific expression categories with FDR-corrected p-value <. 05. 176 genes for small intestine tissue were enriched with FDR-corrected p-value = 5.10E-12, of which 108 genes were common with the host protein list

Figure 2.

(A). PPI Network of the 176 small intestine-specific proteins (146 nodes and 366 edges). Red nodes: host proteins (91 proteins). Blue edges: ACE2-first neighbor interactions. Red edges: ACE2-second neighbor interactions. (B). ACE2 interaction network in the small intestine including ACE2, the first interacting protein neighbors of ACE2 (13 proteins), and second neighbor host proteins (16 proteins)

Figure 3

Skeletal structure of 6 clusters. Red nodes: host proteins

Figure 4

Cross-talk among the clusters through ACE2 in the network. Red nodes: host proteins

Figure 5

Transcription factor-target gene regulatory network. Hexagon nodes represent the 8 enriched transcription factors. Yellow nodes: host proteins

Figure 6

Disease-gene network. Yellow nodes represent the 7 overlapping diseases with 176 genes. Red nodes: host proteins

Figure 7

Drug-protein interaction network. Violet nodes represent the 60 drugs. Red nodes: host proteins