The novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been the catalyst for the global COVID-19 pandemic. SARS-CoV-2 causes COVID-19, a disease that can lead to severe respiratory issues. However, even after the acute phase of COVID-19, many patients report experiencing lingering symptoms. These persistent symptoms, often referred to as long COVID-19 or post-COVID-19 syndrome, include fatigue, shortness of breath, cognitive problems, and gastrointestinal (GI) disorders (Joshee et al., 2022). Notably, GI symptoms such as nausea, vomiting, abdominal pain, loss of taste, anorexia, and diarrhea have been observed in patients suffering from long COVID-19. The rates at which these symptoms occur vary across different studies and are influenced by the size of the cohort being studied. The precise cause of long COVID-19 remains a mystery, but evidence is mounting that suggests SARS-CoV-2 might infect the digestive tract (Crook et al., 2021).
During the acute phase of COVID-19, high levels of SARS-CoV-2 RNA have been found in feces (Guan and Zhong, 2020; Lin et al., 2020; Xiao et al., 2020). The virus not only infects and grows in intestinal epithelial cells in laboratory settings but is also detectable in the stool and intestinal lining of patients long after it has been cleared from the respiratory system (Alvarado et al., 2022). This suggests that the virus might persist in the GI system. Supporting this hypothesis is the detection of residual viral antigens in the GI tissues of recovering patients (Goh et al., 2022). Understanding how the GI tract contributes to long COVID-19 could help develop targeted treatments for the GI symptoms associated with this condition.
Previous research has shown that GI infection caused by SARS-CoV-2 in COVID-19 patients is not uncommon. This expands the understanding of the virus’s impact and highlights the importance of recognizing GI symptoms in COVID-19 patients. GI infection due to SARS-CoV-2 has also been confirmed in animal models, such as nonhuman primates (Jin et al., 2020; Xiao et al., 2020; Jiao et al., 2021). Additionally, it has been discovered that enterocytes (cells lining the intestines) overproduce a protein called vascular endothelial growth factor (VEGF), which increases permeability and promotes inflammation, contributing to disease severity and systemic inflammation (Vahl et al., 1996). Despite the critical role these cells play in the body’s immune response, the cellular and genomic signatures involved in GI inflammation in COVID-19 patients have not been thoroughly studied.
Advanced techniques like single-nucleus RNA sequencing (snRNA-Seq) have revealed significant dysregulation of the immune response in COVID-19 autopsy tissues (Delorey et al., 2021). Multiple studies have shown the presence of infiltrated plasma cells, lymphocytes, and interstitial edema in the lamina propria (a layer of tissue in the stomach, duodenum, and rectum) of COVID-19 patients (Xiao et al., 2020; Livanos et al., 2021). These pathological changes have been confirmed in nonhuman primate models, emphasizing the role of inflammatory cytokines (Jiao et al., 2021). Increased secretion of these cytokines activates monocytes/macrophages and T-cells in an abnormal manner, leading to the migration of epithelial cells into the bloodstream, which accelerates disease progression (Mjösberg and Rao, 2018; Xiao et al., 2020). Dysfunctional intestinal macrophages fail to regulate GI homeostasis, inflammatory responses, gut secretion, and motility effectively (Yip et al., 2021). Additionally, abnormal intraepithelial lymphocytes are less capable of promoting cell-mediated immune responses, which are crucial for controlling viral spread (Niessl et al., 2021). Therefore, investigating the GI immune microenvironment and identifying key immune gene signatures is essential to develop effective treatments for GI symptoms in COVID-19 patients.
To delve deeper into the immune response within the GI tract of COVID-19 patients, researchers used tissue samples from infected patients. Through techniques such as imaging mass cytometry, immunostaining, and transcriptome sequencing, they were able to analyze variations in immune cell populations and identify key signaling pathways. These analyses help define the relationship between GI mucosal damage and tissue immune cells at various stages of COVID-19, which is crucial for optimizing medical management and mitigation efforts.
The angiotensin-converting enzyme 2 (ACE2) is the primary receptor for SARS-CoV-2 entry into cells and is found throughout the entire GI tract. This makes the GI system susceptible to SARS-CoV-2 infection, leading to clinical symptoms (Elmunzer et al., 2023). Studies have detected viral particles and RNA from SARS-CoV-2 in fecal samples, indicating the presence of the virus in the digestive system (Xiao et al., 2020). Moreover, emerging research consistently reports a higher incidence of GI disorders, including irritable bowel syndrome, functional diarrhea, and fecal incontinence, in COVID-19 patients. However, the mechanisms behind the GI functional abnormalities caused by SARS-CoV-2 infection are still not fully understood.
Research has shown that SARS-CoV-2 GI infection stimulates cytokine production, such as VEGF, which might contribute to systemic inflammation and disease progression (Wu et al., 2021; Zeng et al., 2022). The landscape of immune cells present in the stomach, duodenum, and rectum of COVID-19 patients remains unclear. This study comprehensively explored GI tract-infiltrating immune cells in SARS-CoV-2 N protein-positive patient tissues (NP+ tissues) using imaging mass cytometry. A significant expansion of CD68+ macrophages was found in these NP+ tissues. A gene module related to CD68+ macrophages resulted in immune cell infiltration and activation. In COVID-19 patients, abnormal activation of macrophages expressing M1/M2 polarization markers (CD68, CD80, CD163, and CD206) in the lung is associated with cytokine production, including IL-6, IL-10, and TNF-α (Lian et al., 2022). Similar findings have been reported in the neural tissues of severe COVID-19 patients, where activated microglia and cytotoxic T lymphocytes exacerbate neuroinflammation (Ruz-Caracuel et al., 2022). Cardiac tissue infiltration by CD3+ and CD8+ cytotoxic lymphocytes, along with CD68+ macrophages, has also been observed (Maiese et al., 2021). Thus, CD68+ cells, identified in the imaging mass cytometry results, are likely key contributors to GI inflammation and functional abnormalities.
In COVID-19, heightened inflammation in the GI tract is likely to contribute to disease progression, making it a key predictor of disease severity and morbidity. The NF-κB pathway responds to stress stimuli such as cytokines, pathogenic infections, and environmental stress, activating downstream effectors like transcription factors to enhance the production of proinflammatory cytokines (Cuadrado and Nebreda, 2010). Evidence suggests that NF-κB plays a pivotal role in the pathogenesis of COVID-19. Aberrant NF-κB activation leads to increased immune cell numbers and more intense cytokine storms, exacerbating extrapulmonary complications and systemic effects (Kesika et al., 2024; Zhou et al., 2024). SARS-CoV-2 nucleoproteins (NPs) promote NF-κB activation by enhancing the association between TAK1 and the IKK complex. Viral RNA undergoes liquid-liquid phase separation (LLPS) with NP to recruit TAK1 and the IKK complex, leading to NF-κB activation. The C-terminal domain (CTD) of SARS-CoV-2 NP plays a critical role in LLPS and NF-κB activation (Wang et al., 2022). This finding also confirms that phosphorylated NF-κB (p-NFκB) is highly expressed in SARS-CoV-2 NP+ cells.
To better understand immune cell dynamics in the GI tract, researchers conducted a spatial neighbor analysis, comparing NP− and NP+ samples. In NP+ tissue clusters, NP+ cells notably surrounded CD8+ T-cells, CD4+ T-cells, CD20+ B-cells, and had spatially exclusive interactions with CD68+ macrophages. Importantly, the interaction between CD68+ macrophages and other immune cells, especially CD4+ T-cells, was significantly reduced in NP+ tissue samples compared to NP− samples. These findings showed extensive clustering of CD68+ immune cells in NP+ tissues and weakened interactions between CD68+ cells and CD4+/CD8+ cells, altering the immune response. This phenomenon has been previously observed in neural and cardiac tissues (Bearse et al., 2021; Colombo et al., 2021). Thus, the aggregation of CD68+ immune cells and their reduced interaction with CD4+/CD8+ cells may be crucial factors leading to GI inflammation.
T-cells play an essential role in the immune system’s response to SARS-CoV-2 infection. Studies have confirmed that activated CD8+ T-cells highly express NKG2A, which is regulated by the IL-6/STAT3 signaling pathway and induces CD8+ T-cell inactivation (Zheng et al., 2020). Activated CD4+ T-cells produce cytokines that further activate other immune cells, particularly CD8+ T-cells (Bhardwaj et al., 2022; Kawasaki et al., 2022). Naïve CD8+ T-c
ells undergo massive clonal expansion upon contact with antigen-presenting cells (APCs) and differentiate into effector T-cells to eliminate viruses (Bhardwaj et al., 2022). The interplay between macrophages and T-cells at the intestinal mucosal interface is crucial for maintaining mucosal immune homeostasis (Mann and Li, 2014). Several studies have demonstrated that patients with severe COVID-19 have increased infiltration of inflammatory monocytes and CD68+ macrophages and a corresponding decrease in anti-inflammatory alveolar macrophages (Wauters et al., 2021; Chen et al., 2022). Similar results were observed in SARS-CoV-2-infected digestive tract tissues. Recent evidence regarding the active role of intestinal epithelial cells (IECs) in the mucosal immune system has shown that they act as nonprofessional APCs, activating subsets of T-cells with regulatory functions. IECs do not express conventional costimulatory molecules like CD80 and CD86 but do express B7 family members, such as ICOS-L and PD-1L (Shao et al., 2005). Under certain conditions, antigens presented by IECs can suppress rather than stimulate the immune response (Nakazawa et al., 2004; Roda et al., 2010). The detailed mechanisms behind this effect should be explored in future studies.
To gain deeper insights into CD68+ macrophages and their interactions with CD4+ and CD8+ cells, RNA-seq analysis of COVID-19 GI tissues and weighted gene co-expression network analysis (WGCNA) were conducted to identify key hub genes. The WGCNA results identified a gene module predominantly associated with macrophages (MEgreen) and another module interacting with macrophages (MEred). Genes in the MEgreen module showed the strongest correlation with macrophage activation and were also linked to GI and hepatic dysfunction. These genes were enriched in processes related to immune response activation, innate immune response activation, signal transduction of immune response activation, and regulation of chemotaxis. Macrophages can secrete chemokines to recruit immune cells or produce proinflammatory cytokines, leading to cytokine storm-associated shock, multiple organ failure, and death in COVID-19 patients. Therefore, WGCNA of GI tissues from COVID-19 patients highlighted the potential critical role of CD68+ macrophages in the abnormal GI function observed in COVID-19 patients.
Previous investigations revealed that the receptor-binding domain of the SARS-CoV-2 spike protein induces overproduction of VEGF in enterocytes through the Ras-Raf-MEK-ERK pathway. This phenomenon acts as a proinflammatory factor in the intestinal inflammatory response and serves as a vascular permeability regulator, causing local vascular leakage and the extravasation of inflammatory cytokines. Analysis showed that genes within the MEgreen module were significantly enriched in both the VEGF and MAPK signaling pathways, reinforcing the idea that the MEgreen module plays a crucial role in the immune response during COVID-19 in the GI tract. Further examination through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of genes in the MEgreen module confirmed the enrichment of pathways related to VEGF and MAPK. The MAPK pathway, a key mediator of inflammation, is activated by various inputs, including the p38 MAP kinase pathway, Ras-Raf-MEK-ERK pathway, c-Jun kinase/stress-activated pathway, and MEK5/ERK5 signaling pathway. Elevated p38 MAPK activity has been associated with adverse outcomes such as platelet aggregation, arterial thrombosis, endothelial cell apoptosis, hypoxia vasoconstriction, and vascular remodeling. Given the potential detrimental effects of COVID-19, targeting the MAPK pathway has been proposed as a viable treatment strategy for alleviating the cellular damage and adverse hyperinflammatory effects associated with this disease. Findings underscore the pivotal role of the MEgreen module in the GI tract immune response during COVID-19, linking it to the dysregulation of VEGF expression and the activation of the MAPK pathway, providing insights into potential therapeutic approaches for addressing COVID-19-related complications.
Overall, the characterization of macrophage activation as a featured immune response in SARS-CoV-2 infection of the GI tract proposes a set of genes that are determinants of COVID-19 progression. Activation of the p38 MAPK pathway might be a key event during GI tract infection in COVID-19 patients. This study provides new insights into the mechanism of the inflammatory response in acute COVID-19 syndrome and highlights potential therapeutic targets for relieving GI symptoms in COVID-19 patients. The detailed examination of these immune responses and the identification of critical genes and pathways offer a roadmap for developing targeted treatments that could mitigate the long-term GI complications of COVID-19, ultimately improving patient outcomes and quality of life.
Thes study……
The enveloped RNA betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the etiological agent responsible for coronavirus disease 2019 (COVID-19). This virus has the capability to induce severe acute respiratory syndrome. However, following the acute phase of COVID-19, patients frequently encounter persistent or evolving symptoms such as fatigue, dyspnea, cognitive impairment, and gastrointestinal (GI) disorders; this condition is referred to as long COVID-19 or post-COVID-19 syndrome (Joshee et al., 2022). Notably, GI symptoms, including nausea, vomiting, abdominal pain, dysgeusia/ageusia, anorexia, lack/loss of appetite, and diarrhea, persist in patients with long COVID-19. The incidence rates of long COVID-19 vary across studies and are potentially influenced by cohort size. The etiology of long COVID-19 remains unclear, and while SARS-CoV-2 primarily affects the respiratory system, evidence suggests the potential involvement of digestive tract infection (Crook et al., 2021).
In the acute phase of COVID-19, high titers of SARS-CoV-2 RNA have been extracted from feces (Guan and Zhong, 2020; Lin et al., 2020; Xiao et al., 2020). Additionally, SARS-CoV-2 efficiently infects and propagates in intestinal epithelial cells in vitro, and the virus is detectable in the stool and intestinal mucosa of some patients long after clearance from the upper respiratory tract (Alvarado et al., 2022). The hypothesis of viral persistence in the GI system is supported by the continuous detection of residual viral antigens in the GI tissues (colon, appendix, ileum) of convalescent patients (Goh et al., 2022). Understanding the precise contribution of the GI tract to the pathobiology of long COVID-19 is beneficial for developing potential therapeutic approaches targeting the GI tract.
Gastrointestinal Manifestations and SARS-CoV-2 Infection
Previous work from various research groups has revealed that GI infection caused by SARS-CoV-2 in COVID-19 patients expands the virus’s infection spectrum and underscores the significance of GI manifestations in COVID-19 patients. This GI infection has also been confirmed in nonhuman primate models (Jin et al., 2020; Xiao et al., 2020; Jiao et al., 2021). Researchers have verified that vascular endothelial growth factor (VEGF) is overproduced by enterocytes, enhancing permeability and promoting inflammation, which are related to disease severity and systemic inflammation (Vahl et al., 1996). Despite their critical role in the host immune response, the cellular and genomic signatures involved in GI inflammation in COVID-19 patients remain understudied.
Single-nucleus RNA sequencing (snRNA-Seq) analyses have shown substantial dysregulation of the immune response in COVID-19 autopsy tissues (Delorey et al., 2021). Multiple studies have demonstrated infiltrated plasma cells and lymphocytes and interstitial edema in the lamina propria in the stomach, duodenum, and rectum of COVID-19 patients (Xiao et al., 2020; Livanos et al., 2021). These pathological changes were confirmed in a nonhuman primate model, emphasizing the importance of inflammatory cytokines as determinants of pathogenesis (Jiao et al., 2021). Increased inflammatory cytokine secretion aberrantly activates monocytes/macrophages and T-cells and increases epithelial cell migration into the bloodstream, accelerating disease progression (Mjösberg and Rao, 2018; Xiao et al., 2020). Dysfunction of intestinal macrophages impairs their role in the regulation of GI homeostasis, inflammatory responses, gut secretion, and gut motility (Yip et al., 2021). Abnormal intraepithelial lymphocytes are less able to promote cell-mediated immune responses by activating other immune cells to control viral spread, which is critical in the defense against both extracellular and intracellular pathogens (Niessl et al., 2021). Therefore, to systematically characterize the GI immune microenvironment of patients and identify key immune gene signatures, it is important to investigate stromal components, understand their significance, and identify effective therapeutic targets to alleviate GI symptoms in COVID-19 patients.
Immune Cell Dynamics in the Gastrointestinal Tract
The current study utilized SARS-CoV-2-infected GI tract tissue from COVID-19 patients. Through imaging mass cytometry, immunostaining, and reanalysis of in-house transcriptome sequencing data, researchers delineated immune cell population variation and identified potential key signaling pathways. Defining the interrelationships between GI mucosa damage and tissue immune cells at distinct immunopathological stages of COVID-19 will help elucidate the mechanisms of GI manifestations to better optimize COVID-19 medical management and mitigation efforts.
Angiotensin-converting enzyme 2 (ACE2) serves as the primary receptor for the cellular entry of SARS-CoV-2 and is widely distributed throughout the entire GI tract. Consequently, the GI system is susceptible to SARS-CoV-2 infection, leading to corresponding clinical symptoms (Elmunzer et al., 2023). Multiple studies have detected viral particles and RNA from SARS-CoV-2 in fecal samples, indicating the presence of the virus in the digestive system (Xiao et al., 2020). Moreover, emerging research has consistently reported a higher incidence of GI disorders, including irritable bowel syndrome, functional diarrhea, and fecal incontinence, in COVID-19 patients. However, the mechanisms underlying the GI functional abnormalities induced by SARS-CoV-2 infection have yet to be systematically elucidated.
Previous research has demonstrated that SARS-CoV-2 GI infection stimulates the production of cytokines, such as VEGF, which might contribute to systemic inflammation and be associated with disease progression (Wu et al., 2021; Zeng et al., 2022). The landscape of immune cells, such as those in the stomach, duodenum, and rectum, present in COVID-19 patients is unclear. Thus, this study comprehensively explored GI tract-infiltrating immune cells in SARS-CoV-2 N protein-positive patient tissues (NP+ tissues) via IMC. A conspicuously expanded CD68+ macrophage population was found in these NP+ tissues. Specifically, a gene module related to CD68+ macrophages resulted in immune cell infiltration and activation. In COVID-19 patients, abnormal activation of macrophages expressing M1/M2 polarization markers (CD68, CD80, CD163, and CD206) in the lung is associated with the production of cytokines, including IL-6, IL-10, and TNF-α, as indicated by previous studies (Lian et al., 2022). Similarly, in the neural tissues of patients with severe COVID-19, the presence of CD68+ activated microglia and CD8+ cytotoxic T lymphocytes exacerbates the severity of neuroinflammation (Ruz-Caracuel et al., 2022). An examination of the infiltration of cardiac tissues also demonstrated significant infiltration of CD3+ and CD8+ cytotoxic lymphocytes, accompanied by the presence of CD68+ macrophages (Maiese et al., 2021). Thus, CD68+ cells, which are proinflammatory cells, were identified in IMC results and are likely to be crucial cells contributing to GI inflammation and functional abnormalities.
The NF-κB Pathway and Its Implications
In COVID-19, heightened inflammation in the GI tract, the body’s largest immune organ, is likely to contribute to disease progression, making it a key predictor of disease severity and morbidity. The NF-κB pathway is responsive to stress stimuli such as cytokines, pathogenic infection, and environmental stress, activating downstream effectors such as transcription factors to enhance the production of proinflammatory cytokines (Cuadrado and Nebreda, 2010). Additionally, evidence suggests that NF-κB plays a pivotal role in the pathogenesis of COVID-19. Aberrant NF-κB activation leads to increased numbers of immune cells and more intense cytokine storms, exacerbating extrapulmonary complications and systemic effects (Kesika et al., 2024; Zhou et al., 2024). SARS-CoV-2 NPs have been reported to promote the activation of the NF-κB signaling pathway by enhancing the association between TAK1 and the IKK complex. With viral RNA, the NP undergoes liquid-liquid phase separation (LLPS) to recruit TAK1 and the IKK complex, leading to the promotion of NF-κB activation. The CTD of the SARS-CoV-2 NP plays a critical role in its LLPS and NF-κB activation (Wang et al., 2022). Therefore, this finding also confirms that p-NFκB can be highly expressed in SARS-CoV-2 NP+ cells.
To better understand the immune cell dynamics in the GI tract, a spatial neighbor analysis was conducted, comparing NP− and NP+ samples. Within the NP+ tissue cell clusters, NP+ cells notably surrounded CD8+ T-cells, CD4+ T-cells, CD20+ B-cells, and spatially exclusive interactions to CD68+ macrophages. Importantly, the interaction between CD68+ macrophages and cells with multiple phenotypes, especially CD4+ T-cells, was significantly decreased in NP+ tissue samples relative to NP− tissue samples. These findings demonstrated extensive clustering of CD68+ immune cells in the NP+ group and weakened interactions between CD68+ cells and CD4+/CD8+ cells, altering the immunoreaction, as previously reported at neural and cardiac sites (Bearse et al., 2021; Colombo et al., 2021). Thus, the aggregation of CD68+ immune cells and their attenuated interaction with CD4+/CD8+ cells may be crucial factors leading to GI inflammation.
T-cells are essential for the immune system’s reaction to SARS-CoV-2 infection. Studies have confirmed that the subsequently produced CD8+ T-cells highly express NKG2A, regulated by the IL-6/STAT3 signaling pathway, inducing CD8+ T-cell inactivation (Zheng et al., 2020). It has also been shown that activated CD4+ T-cells produce cytokines that further induce the activation of other immune cells, especially CD8+ T-cells (Bhardwaj et al., 2022; Kawasaki et al., 2022). Naïve CD8+ T-cells undergo massive clonal expansion as they contact APCs and differentiate into effector T-cells to kill viruses (Bhardwaj et al., 2022). The interplay between macrophages and T-cells at the intestinal mucosal interface plays a key role in maintaining mucosal immune homeostasis (Mann and Li, 2014). Several studies have demonstrated that patients with severe COVID-19 have increased inflammatory monocyte and CD68+ macrophage infiltration and a corresponding decrease in anti-inflammatory alveolar macrophages (Wauters et al., 2021; Chen et al., 2022). Similar results were observed in SARS-CoV-2-infected digestive tract tissues in this study. Recent evidence regarding the active role of intestinal epithelial cells (IECs) within the mucosal immune system has revealed that they act as nonprofessional APCs, activating subsets of T-cells with regulatory functions. IECs do not express costimulatory molecules such as conventional CD80 and CD86 but do express B7 family members, such as ICOS-L and PD-1L (Shao et al., 2005). Hence, under certain conditions, antigens presented by IECs suppress rather than increase the immune response (Nakazawa et al., 2004; Roda et al., 2010). The detailed mechanisms underlying this effect should be investigated in future studies.
RNA-Seq Analysis and Key Findings
To gain a deeper understanding of CD68+ macrophages and their interactions with CD4+ and CD8+ cells, RNA-seq analysis of COVID-19 GI tissues and WGCNA was conducted to identify key hub genes. Based on the WGCNA results, a gene module predominantly associated with macrophages (MEgreen) and another module interacting with macrophages (MEred) were identified. The genes in the MEgreen module exhibited the strongest correlation with macrophage activation and were also associated with GI and hepatic dysfunction. Additionally, genes in this module were enriched in processes related to immune response activation, innate immune response activation, signal transduction of immune response activation, and regulation of chemotaxis. Macrophages can secrete chemokines to recruit immune cells or produce proinflammatory cytokines, resulting in cytokine storm-associated shock, multiple organ failure, and death in COVID-19 patients. Therefore, WGCNA of GI tissues from COVID-19 patients further highlighted the potential crucial role of CD68+ macrophages in the abnormal GI function observed in COVID-19 patients.
Previous investigations discovered that the receptor-binding domain of the SARS-CoV-2 spike protein induces the overproduction of VEGF in enterocytes through the Ras-Raf-MEK-ERK pathway. This phenomenon acts as a proinflammatory factor participating in the intestinal inflammatory response and serves as a vascular permeability regulator, inducing local vascular leakage and the extravasation of inflammatory cytokines. Analysis revealed that genes within the MEgreen module were significantly enriched in both the VEGF and MAPK signaling pathways, reinforcing the idea that the MEgreen module plays a crucial role in the immune response during COVID-19 in the GI tract. Further examination through GO and KEGG analyses of genes within the MEgreen module confirmed the enrichment of pathways related to VEGF and MAPK. The MAPK pathway, a key mediator of inflammation, is activated by various inputs, including the p38 MAP kinase pathway, Ras-Raf-MEK-ERK pathway, c-Jun kinase/stress-activated pathway, and MEK5/ERK5 signaling pathway. Elevated p38 MAPK activity has been associated with adverse outcomes such as platelet aggregation, arterial thrombosis, endothelial cell apoptosis, hypoxia vasoconstriction, and vascular remodeling. Given the potential detrimental effects of COVID-19, targeting the MAPK pathway has been proposed as a viable treatment strategy for alleviating the cellular damage and adverse hyperinflammatory effects associated with this disease. Thus, findings underscore the pivotal role of the MEgreen module in the GI tract immune response during COVID-19, linking it to the dysregulation of VEGF expression and the activation of the MAPK pathway, providing insights into potential therapeutic approaches for addressing COVID-19-related complications.
The characterization of macrophage activation as a featured immune response in SARS-CoV-2 infection of the GI tract has proposed a set of genes that are determinants of COVID-19 progression. Activation of the p38 MAPK pathway might be a key event during GI tract infection in patients with COVID-19. Therefore, the study provides new insight into the mechanism of the inflammatory response in acute COVID-19 syndrome and highlights potential therapeutic targets for the relief of GI symptoms in COVID-19 patient.
resource : https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1375354/full
