In the global context, injuries hold the position of being the fourth leading cause of mortality[1].In civilian [12] and military [13] settings, early preventable deaths after injury are mainly caused by uncontrolled hemorrhage [12–17], while later preventable deaths are typically attributed to hypercoagulability [18].After experiencing massive trauma with the presence of shock, hypoperfusion, and vascular damage, TIC (Trauma-Induced Coagulopathy) sets in rapidly. This condition impairs the body's ability to form blood clots and can lead to increased bleeding risks[19].A comprehensive comprehension of TIC pathophysiology is indispensable in the quest to lower trauma-related mortality rates [20].The mechanisms underlying the TIC involve the activation of protein C, disruption of endothelial glycocalyx, decreased levels of fibrinogen, and impaired platelet function [19].Nevertheless, the pathogenesis of TIC remains elusive, and there is a scarcity of effective therapeutic strategies to address the condition. In this context, it is imperative to enhance our comprehension of TIC pathogenesis and actively seek out potential therapeutic targets. Employing various bioinformatics methods, the current study successfully retrieved DEGs from TIC-related microarray datasets sourced from the GEO database. Furthermore, the study encompassed GO enrichment and KEGG pathway enrichment analyses. Subsequently, a PPI network was assembled to identify the top 10 hub genes from the DEGs. Ten hub genes (OAS2, OAS3, IFIT2, IFIT1, IFIT3, HERC5, IFI44, IFI44L, RSAD2, DDX60) were selected for validation of their diagnostic value in TIC patients (P < 0.05). These genes possess significant potential to predict the risk of TIC, making them crucial candidates for further investigation.
Multiple hypotheses have been proposed to explain the underlying mechanisms driving the process, suggesting that tissue injury and shock work in synergy to activate the endothelium, platelets, and the immune system. This activation leads to the production of various mediators that have the combined effect of reducing fibrinogen levels, impairing platelet function, and compromising thrombin generation. As a consequence, these processes ultimately result in inadequate clot formation, leading to compromised hemostasis. During viral infections, similar to bacterial infections, the coagulation system undergoes activation.In the initial stages,the activation of the coagulation cascade could potentially serve as a host defense mechanism, working to impede the spread of the viruses [21].Type I interferons (IFNs) play a crucial role in shaping both innate and adaptive immune responses. The activation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway through type I IFN signaling leads to the transcription of IFN-stimulated genes (ISGs) [22].
The study identifies RSAD2, IFIT1, IFIT2, IFIT3, OAS2, OAS3, IFI44 and IFI44L as the eight hub genes within the ISGs (IFN-stimulated genes). RSAD2, also known as Radical S-adenosyl methionine domain containing 2, is an interferon-stimulated gene that exhibits significant upregulation upon viral infection. It responds to both type I and type II interferon signaling, which occurs through the JAK/STAT pathway [23]. Previous research has demonstrated that RSAD2 exhibits broad antiviral activity against multiple enveloped viruses. Its function as an antiviral agent has been observed in various viral infections, highlighting its potential as a promising therapeutic target in combating enveloped viruses [24].By inhibiting the NF-κB pathway, the suppression of RASD2 can effectively decrease the viability of CD19 + B cells and enhance their apoptosis. Furthermore, this silencing of RASD2 also leads to a reduction in the expression of IL-10[25].
The IFITs (IFN-induced proteins with tetratricopeptide repeats) family is one of the numerous IFN-stimulated gene families. Within this family, there exists a cluster of duplicated loci. Among most mammals, the IFIT1, IFIT2, IFIT3, and IFIT5 genes are present [26].Besides initiating a cytokine storm [27], SARS-CoV-2 infection leads to the activation of the coagulation pathway by causing damage to vascular endothelial cells [28].The presence of SARS-CoV-2 suggests the potential protective effect of IFIT1, IFIT2, and IFIT3 expression in gingival epithelial cells (GECs) against coronavirus infection [29]. Consequently, the expression of the IFITs family may exert an inhibitory effect on the activation of the coagulation pathway.The 2'-5'-oligoadenylate synthetases (OAS), including OAS1, OAS2, and OAS3, are classified as interferon-induced genes that have long been associated with an antiviral function [30].Their downstream products have the ability to trigger the activation of RNase L, an enzyme that facilitates the breakdown of both cellular and viral components[31].The IFI44 gene family is recognized as a newly diversified mediator of immune responses in oysters[32].
DDX60, a novel DEAD-box RNA helicase, has been identified as an upstream regulator of RIG-I in the innate immune response. It was first discovered through microarray research focused on genes induced by measles virus infection in dendritic cells (DCs) [33].We presented experimental findings that support the co-localization of DDX60 with the RIG-I protein, RIG-I ligand, and a stress granule marker known as G3BP. This co-localization provides strong evidence that DDX60 plays a role in the recognition of viral RNA by RIG-I [34].In our study, we discovered that DDX60 is involved in multiple signaling pathways related to immune regulation. Specifically, DDX60 is implicated in the "regulation of immune effector process," "regulation of response to biotic stimulus," and "defense response to virus" signaling pathways (Fig. 5a). These findings highlight the significance of DDX60 in orchestrating immune responses against viral infections.
HECT and RCC1-containing protein 5 (HERC5) are immune proteins with potent antiviral properties. it is specifically induced in response to the signal transduction of IFN-α/β, playing a crucial role in the innate immune response against viral infections [35].HERC5 demonstrates its antiviral efficacy against a wide range of divergent viruses, encompassing retroviruses such as Human Immunodeficiency Virus (HIV) and Simian Immunodeficiency Virus (SIV), as well as papillomaviruses and influenza viruses. Its ability to combat these diverse viral pathogens underscores the broad-spectrum antiviral function of HERC5 [36] [37].In our study, we unraveled the involvement of HERC5 in key signaling pathways associated with immune regulation.
Specifically, we found that HERC5 plays a significant role in the "regulation of response to biotic stimulus" and "defense response to virus" signaling pathways(Fig. 5a). These findings underscore the importance of HERC5 in modulating immune responses to various biotic stimuli, including viral infections.
This study has certain limitations that should be taken into account. Firstly, one of the main limitations of this study is the lack of clinical data support. Furthermore, despite performing a comprehensive bioinformatics analysis in the present study, we regrettably did not proceed with additional experiments. Hence, it is imperative to further investigate the specific mechanisms underlying TIC through in vivo and in vitro experiments.