|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 9
| Issue : 1 | Page : 9 |
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Role of TGF-β Signaling in Coronavirus Disease 2019
Junzhe Chen1, Wenjing Wu2, Wenbiao Wang3, Ying Tang4, Hui- Yao Lan2
1 Department of Nephrology, The Third Affiliated hospital, Southern Medical University, Guangzhou; Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
2 Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
3 Medical Research Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
4 Department of Nephrology, The Third Affiliated hospital, Southern Medical University, Guangzhou, China
| Date of Submission | 06-Feb-2022 |
| Date of Decision | 03-Mar-2022 |
| Date of Acceptance | 10-May-2022 |
| Date of Web Publication | 27-Jul-2022 |
Correspondence Address:
Hui- Yao Lan
Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2773-0387.348713
Coronavirus disease 2019 (COVID-19) has a broad spectrum of clinical manifestations involving the respiratory, cardiovascular, renal, neuropsychiatric, gastrointestinal, and dermatological systems. Some patients with COVID-19 experience acute infection and post-COVID-19 syndrome. There is increasing evidence that TGF-β signaling plays an important role in the pathogenesis of both acute and chronic COVID-19 infection. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein was reported to interact with Smad3, a key downstream mediator of TGF-β signaling, thereby promoting TGF-β1/Smad3 signaling and causing cell death during the acute phase of COVID-19 infection. Because activation of TGF-β/Smad3 signaling has an essential role in multiple organ fibrosis, it is possible that overreactive TGF-β/Smad3 signaling may cause tissue fibrosis in the lung, heart, and kidney after SARS-CoV-2 infection. Thus, not only administration of antiviral drugs and traditional Chinese medicines, but also targeting of TGF-β signaling components, particularly Smad3, with various therapeutic strategies involving OT-101, pirfenidone, and specific Smad3 inhibitors, such as SIS3, may provide novel and specific therapies for COVID-19 patients.
Keywords: Severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019, TGF-β signaling, cell death, fibrosis
How to cite this article:
Chen J, Wu W, Wang W, Tang Y, Lan HY. Role of TGF-β Signaling in Coronavirus Disease 2019. Integr Med Nephrol Androl 2022;9:9 |
| Introduction | |  |
In December 2019, a series of patients with pneumonia of unknown cause, now known as coronavirus disease 2019 (COVID-19), were reported for the first time.[1] The pathogen was a new strain of coronavirus, designated severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). SARS-CoV-2 was identified as an enveloped, non-segmented, positive-sense RNA virus belonging to the β-coronavirus family, together with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV).[2] After the outbreak, SARS-CoV-2 rapidly spread throughout the world. To date, it has caused more than 390 million infections and more than 5.7 million deaths worldwide.[3]
COVID-19 has a broad spectrum of clinical manifestations from asymptomatic disease to death during the acute phase.[4] Most COVID-19 patients (80%) exhibit a mild clinical syndrome, with symptoms such as fever, fatigue, myalgia, and dry cough.[5],[6] However, severe and critically ill patients may progress to acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), multiple organ dysfunction syndrome (MODS) requiring intensive care, and even death. However, the mechanisms through which COVID-19 causes ARDS, AKI, and MODS remain largely unclear and consequently no specific and effective treatments for COVID-19 are currently available.
| Post-COVID-19 Syndrome | | |
Symptoms of myalgia, fatigue, depression, and disordered sleep were observed in SARS-recovered patients during long-term follow-up.[7] Meanwhile, respiratory system- associated symptoms, such as dyspnea, were frequently noted in patients who had recovered from SARS[8] and MERS.[9] As the number of COVID-19 survivors increases, a hidden concern termed post-COVID-19 syndrome is emerging.[10],[11],[12] Long-term follow-up studies are urgently needed to explore the characteristics of post- COVID-19 syndrome. For example, post-COVID-19 syndrome could be a common health problem,[13] and even asymptomatic COVID-19 patients may have post- COVID-19 syndrome.[14],[15] To date, symptoms involving the respiratory, cardiovascular, renal, neuropsychiatric, gastrointestinal, and dermatological systems are known to be present, conferring a heavy burden on health systems.[11],[13] Long-term monitoring and treatment for post-COVID-19 syndrome may be needed.
| TGF-β Signaling in COVID-19 Patients | | |
Mammals have three TGF-β isoforms, TGF-β1, TGF-β2, and TGF-β3.[16] TGF-β has also been characterized as latent and active forms. Active TGF-β is released from the latent TGF-β complex after cleavage by proteases like matrix metalloproteinase (MMP) 2 and MMP9.[17],[18] Active TGF-β1 binds to TGF receptor 2 (TGFR2) and subsequently activates TGF receptor 1 (TGFR1) and downstream Smad-dependent (canonical) or Smad- independent (non-canonical) pathways.[16],[19] It has become clear that the TGF-β signaling pathway is a key pathway for regulation of cell apoptosis, proliferation, differentiation, epithelial-mesenchymal transition, and fibrosis.[20]
Similar to patients with SARS[21] and MERS,[22] serum TGF-β levels are significantly elevated in COVID-19 patients and associated with both disease severity and poor clinical outcomes.[23] Indeed, blood TGF-β1 levels are highly elevated at the time of first medical intervention.[24] Blood TGF-β levels are also markedly elevated in severe COVID-19 patients, before decreasing during the convalescence phase.[25] Meanwhile, circulating TGF-β1 levels remain high in post-COVID-19 patients compared with healthy controls.[10] SARS-CoV papain-like protease (PLpro) can significantly increase the TGF-β1 mRNA and protein levels in human promonocytes.[26] A computational analysis of noncoding RNA interactions predicted that the TGF-β signaling pathway is involved in SARS-CoV/CoV-2 infection.[27],[28] A rapid transcriptome analysis of nasopharyngeal swabs confirmed that the TGF-β signaling pathway is significantly upregulated in severe COVID-19 patients.[29] Indeed, SARS-CoV-2 can induce expression of TGF-β family genes in blood monocytes.[30]
TGF-β signaling in COVID-19-associated ARDS and pulmonary fibrosis
SARS-CoV-2 initially infects and replicates in upper respiratory tract epithelial cells, followed by lung epithelial cells, where angiotensin-converting enzyme 2 (ACE2) is highly expressed.[31] Immunohistochemical detection of S protein, N protein,[32],[33] and viral inclusions[34],[35] confirms the presence of SARS-CoV-2 in the lungs of COVID-19 patients. Although most COVID-19 patients manifest a mild respiratory disease, 5%–8% of COVID-19 patients develop ARDS, which is the leading cause of death.[11],[36] There are three major pulmonary pathological changes in COVID-19 patients: 1) reactive epithelial changes and diffuse alveolar damage, 2) microvascular damage, and 3) acute fibrinous and organizing pneumonia and interstitial fibrosis.[37] A report on COVID-19 patients described that 44% have parenchymal injury and 41% have an irregular interface, representing early signs of fibrosis during the acute phase.[38] Radiographic results for COVID-19 patients showed that fibrotic changes are common beyond 7 days after diagnosis,[38] and fibrosis becomes apparent after 3 weeks.[37] A follow-up study on SARS survivors revealed significant impairment of lung function in 23.7% of patients, with 27.8% developing radiographic abnormalities at 12 months after SARS onset.[39] Among children affected by SARS, 32% have radiographic abnormalities, including parenchymal scars, at 12 months after diagnosis.[40] A 15-year follow-up study on SARS survivors revealed that 38% of patients have ground-glass opacity and cord-like consolidation.[8] A study on MERS survivors with a mean follow-up of 43 days also showed that 36% have abnormal radiological findings.[9] Pulmonary fibrosis was identified as one of the sequelae of SARS and MERS.[39] Given that SARS-CoV-2, SARS-CoV-1, and MERS-CoV all belong to the β-coronavirus family, we speculate that pulmonary fibrosis is one of the important features of post-COVID-19 syndrome, because impaired lung function is observed in patients after COVID-19 infection.[41] Lung radiographic abnormalities are common among COVID-19 patients after hospitalization.[42] A 6-month follow-up study on 353 COVID-19 patients with complete chest computed tomographic (CT) imaging showed that more than 45% of patients have GGO, while 16% have irregular lines.[15] Meanwhile, abnormality of CT findings in a follow-up examination is positively associated with disease severity in COVID-19 patients.[15] More than one-third of severe COVID-19 patients develop lung fibrotic- like changes within 6 months after discharge[43]. Compared with the acute phase, 9% of patients have worse radiographic abnormalities during the follow-up period at an average of 54 days.[44] The only option for irreversible lung injury involving pathological end-stage pulmonary fibrosis in COVID-19 patients is lung transplantation.[45] Longer follow-up studies in COVID-19 patients, especially for lung function and radiological findings, are warranted.
It is well known that TGF-β can induce fibroblast proliferation,[46] myofibroblast differentiation,[47],[48] and extracellular matrix (ECM) protein production and deposition.[46],[49] Consequently, TGF-β plays an important role in pulmonary fibrosis. TGF-β was also proven to participate in the early phase of ARDS and to be associated with the development of pulmonary edema.[45] SARS-CoV PLpro was reported to upregulate the mRNA and protein levels of TGF-β1 in lung tissue.[50] SARS-CoV PLpro can also stimulate TGF-β-dependent expression of collagen 1 (Col-1) via non-SMAD pathways in human lung epithelial cells.[51] SARS-CoV nucleocapsid (N) protein was shown to interact with Smad3 to activate the canonical pathway, thereby promoting fibrosis.[52]
In COVID-19 patients, TGF-β expression is increased in the bronchoalveolar lavage (BAL) fluid.[53] A bioinformatics analysis revealed that SARS-CoV-2 infection can increase the mRNA level of TGF-β1, which in turn drives fibrosis in human lung epithelial cells.[54] An immunohistochemical analysis showed that expression of TGF-β1 is significantly increased in lung samples from COVID-19 patients compared with those from H1N1 patients and no lung injury (control) patients.[55] Thus, we predict that TGF-β may be a key mediator of pulmonary fibrosis in COVID-19 patients. As shown in [Figure 1], binding of the SARS-CoV-2 spike (S) protein to ACE2 can directly downregulate ACE2 expression.[56] Because the main function of ACE2 is to convert angiotensin II (Ang II) to Ang 1-7,[57] it is possible that the levels of Ang II are elevated in COVID-19 patients as a result of decreased ACE2, thereby promoting activation of TGF-β/Smad3 signaling via TGF-β-dependent and TGF- β-independent pathways.[58] It is also possible that SARS- CoV-2 infection induces lung infiltration of neutrophils that subsequently release several proteases and active TGF-β.[59] Furthermore, high levels of IL-4/IL-13 can trigger activation of M2 macrophages in the lung tissue of COVID-19 patients.[60] M2 macrophages are known to be a rich source of TGF-β1,[30],[55],[60],[61] which may contribute to TGF-β-mediated lung fibrosis in COVID-19 patients. Importantly, we and other investigators found that the N protein of SARS-CoV-2 can directly interact with Smad3 and promote TGF-β1/Smad3 signaling.[52],[62] Thus, SARS-CoV-2 N protein-induced activation of Smad3 signaling may be a key mechanism for the development of lung fibrosis [Figure 1] and [Figure 2]. | Figure 1: Role of TGF-β signaling in COVID-19. After SARS-CoV-2 enters cells via ACE2, its N protein (CoV-2 N) can activate TGF-β signaling directly by binding and promote Smad3-mediated cell death and fibrosis, which can be exacerbated by increased angiotensin II (Ang II) signaling and local inflammatory responses including production of TGF-β by M2 macrophages and release of active TGF-β via PMN-dependent proteases. PMN, polymorphonuclear neutrophil; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
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 | Figure 2: TGF-β signaling in COVID-19-associated tissue fibrosis. After SARS-CoV-2 enters cells via ACE2, its N protein (CoV-2 N) can activate TGF-β signaling directly by binding and promote Smad3-mediated fibrosis, which can be further enhanced by non-Smad-dependent TGF-β signaling pathways such as the PI3K/AKT signaling pathway. COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ROS, reactive oxygen species; FOXO, forkhead box O; mTOR, mammalian target of rapamycin.
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Besides the canonical signaling pathway, phosphatidylinositol 3-kinase (PI3K)/AKT (non-canonical) signaling pathways can also participate in lung fibrosis development in COVID-19 patients.[55] Mammalian target of rapamycin (mTOR) and Forkhead box O (FOXO), as the main downstream targets of the PI3K/AKT pathway, may be involved in the expression of profibrotic genes.[63] Meanwhile, TGF-β1-mediated production of reactive oxygen species (ROS) via NOX4 was proven to participate in the pathogenesis of fibrosis.[64] All of these pathways may be associated with the lung fibrosis observed in COVID-19 patients, as shown in [Figure 2].
TGF-β signaling in COVID-19-associated acute heart injury and cardiac fibrosis
Besides the respiratory system, ACE2 receptors are highly expressed in the heart[65]. Electron microscopy and immunohistochemistry analyses have confirmed the presence of SARS-CoV-2 in the heart.[66] The manifestations of cardiovascular system are common in COVID-19 patients,[67] which include arrhythmia,[68],[69] myocardial injury[69],[70],[71],[72] manifested as elevated cardiac troponin I (cTnI), NT- proBNP, creatine kinase, and lactate dehydrogenase (LDH), and heart failure.[1] The levels of cardiac biomarkers are closely correlated with disease severity in COVID-19 patients[73],[74]. Heart failure also accounts for a significant proportion of deaths in COVID-19 patients during the acute phase of infection.[1],[74] Cardiac magnetic resonance (CMR) imaging shows myocardial inflammation in 60% of recently-recovered COVID-19 patients.[75] Pathologically, mild myocardial edema and atypical interstitial fibrosis with infiltration of inflammatory cells are observed.[76]
Tachycardia is the most common complication in SARS patients during the follow-up period.[77] A 12-year follow- up study on SARS patients revealed that 44% exhibit cardiovascular abnormalities.[78] The similarities between SARS-CoV-1 and SARS-CoV-2 suggest that cardiovascular abnormalities should be carefully monitored in COVID-19 patients during the follow-up period. A 2–3-month follow- up study revealed a high rate of diastolic dysfunction (60%) in COVID-19 patients after hospital discharge.[79] Furthermore, the COMEBAC Study Group reported that 12% of COVID-19 patients have impaired left ventricular ejection fraction (<50%) in the follow-up echocardiography assessment.[42] with all of these patients being ICU survivors. CMR imaging reveals the presence of myocardial edema, fibrosis, and impaired right ventricle function in COVID-19 survivors.[80]
The levels of TGF-β, interstitial Col-1, and Col-3 are elevated in the heart of COVID-19 patients compared with control patients.[81] The mRNA level of TGF-β1 is also upregulated in the left ventricular myocardium of COVID-19 patients with left ventricular fibrosis.[24] The possible mechanisms linking TGF-β signaling and cardiac fibrosis in COVID-19 patients may be similar to those for pulmonary fibrosis, as already discussed and shown in [Figure 2].
TGF-β signaling in COVID-19-associated AKI and renal fibrosis
In addition to the respiratory system and heart, ACE2 is highly expressed in proximal tubule and glomerular parietal epithelial cells in the kidney, based on single-cell RNA sequencing.[82] In COVID-19 patients, SARS-CoV-2 S protein and N protein are detectable in renal tubular epithelial cells (TECs) by immunohistochemistry,[83],[84],[85] while SARS- CoV-2 particles can be observed in TECs and podocyte cells by electron microscopy.[37] The renal manifestations of COVID-19 patients in the acute period are diverse, ranging from proteinuria to hematuria.[86],[87] The incidence of AKI is associated with the severity of COVID-19.[88] Kidney CT findings indicated that inflammation and edema occur in the renal parenchyma of COVID-19 patients.[89] The pathological changes in COVID-19 patients include various degrees of acute tubular injury and collapsing glomerulopathy.[83],[84],[85] Our recent study proved that SARS- CoV-2 N protein induces AKI by causing TEC death through a TGF-β/Smad3-dependent G1 cell cycle arrest mechanism [Figure 3].[62] This was confirmed by protection against SARS-CoV-2 N-induced AKI in mice lacking Smad3.[62] TGF-β/Smad signaling may also play a role in AKI via other cell death signaling pathways, such as receptor-interacting protein kinase (RIPK) protein/mixed- lineage kinase domain-like protein (MLKL)-mediated necroptosis,[90],[91] and TGF-β-inducible early response gene 1 (TIEG1), death-associated protein kinase (DAPK), or p53-induced cell apoptosis.[91],[92] Meanwhile, apoptosis- related protein released from mitochondria upon TGF-β stimulation may also increase the activity of caspase 3.[93] Thus, necroptosis and apoptosis may be the mechanisms related to cell death in COVID-19 patients [Figure 3]. | Figure 3: TGF-β signaling in COVID-19-associated cell death. After SARS-CoV-2 enters cells via ACE2, its N protein (CoV-2 N) can activate TGF-β signaling directly by binding and promote Smad3-dependent cell death pathways including p21/p27-mediated G1 cell cycle arrest, RIPK/MLKL-mediated necroptosis, and TIEG1/ DAPK/p53-dependent apoptosis. DAPK, death-associated protein kinase; RIPK, receptor-interacting protein kinase; MLKL, mixed-lineage kinase domain-like protein.
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AKI is also observed in patients with SARS and MERS,[94],[95] but few studies have focused on the long-term renal outcomes. In contrast, the long-term renal outcomes in COVID-19 patients have been investigated. A follow-up study on COVID-19 patients compared with non-infected control patients revealed that COVID-19 patients exhibit a decline in estimated glomerular filtration rate (eGFR) that is associated with kidney disease severity at 6 months after AKI.[96] A 9.6-month follow-up study showed a lower eGFR in a group of mainly non-hospitalized COVID-19 patients compared with age, sex, and education-matched control patients.[14] Huang et al.[15] found that 35% COVID-19 patients have reduced kidney function at 6 months after AKI. A 3-month follow-up study on critically ill COVID-19 patients showed that about 10% of AKI patients with renal recovery at the discharge are diagnosed with new-onset chronic kidney disease (CKD), increasing to 44.8% in AKI patients without renal recovery. Furthermore, 5% of COVID-19 survivors need dialysis at 3 months after discharge.[97] In COVID-19 patients diagnosed with AKI requiring kidney replacement therapy, only 62.2% of patients have full renal recovery after a mean follow-up period of 151 days.[98] Based on these studies, development of CKD appears to occur after COVID-19.
Renal fibrosis is a common pathway for CKD. Jansen et al.[99] reported that tubule interstitial fibrosis in COVID-19 patients increases independently of pre-existing CKD. They also observed activation of TGF-β signaling in renal proximal tubular epithelial cells and podocytes in COVID-19 patients. Furthermore, they found that blocking of TGF-β receptor I using SB431542 can ameliorate the Col-1 expression induced by SARS-CoV-2. On the basis of our own study,[62] we predict that SARS-CoV-2 N protein can interact with Smad3 and thus enhance Smad3-mediated renal fibrosis, which may be a key mechanism for CKD development in patients with COVID-19.
| Potential Treatments for COVID-19 | | |
Antiviral drugs
Remdesivir
Remdesivir (GS-5734), a prodrug for adenosine analogues, has been shown to act as a broad-spectrum antiviral agent against several RNA viruses, including MERS-CoV[100] and Ebola virus.[101] Based on reports that remdesivir can effectively inhibit SARS-CoV-2 in mouse models and in vitro,[102],[103] it has received approval from the FDA for the treatment of SARS-CoV-2 infection and has shown clinical efficacy, particularly in critically ill patients.[104],[105] However, the mode of intravenous injection has limited its clinical use.
Paxlovid
Paxlovid, a combination of nirmatrelvir (PF-07321332) and ritonavir, is an effective and safe orally bioavailable antiviral drug. Nirmatrelvir binds to SARS-CoV-2 Mpro[106] (main protease; referred to as 3CL protease), which is critical in the replication stage.[107] Ritonavir is used to enhance the therapeutic concentration of nirmatrelvir[108]. Nirmatrelvir was proven to have excellent anti-SARS-CoV-2 activity both in vitro and in animal models.[109] A randomized, double-blind study (RCT) showed that paxlovid can significantly reduce the risk of hospitalization and death in non-hospitalized adults with COVID-19.[110]
Traditional Chinese medicines (TCMs)
TCMs, which are mainly used to treat diseases based on holism and syndrome differentiation, have long been used for the treatment of infectious diseases and have been shown to play indispensable roles in the prevention and treatment of severe epidemic diseases. Several clinical studies have shown that TCMs play significant roles in the treatment of COVID-19.[111],[113] However, the underlying mechanisms of the effects of TCMs in the treatment of COVID-19 remain unclear.
Lianhua Qingwen capsules were preliminarily confirmed to show efficacy in the management of SARS patients, and have been recommended for the treatment of COVID-19 patients.[114] The antiviral activity of LH against SARS-CoV-2 was examined using Vero E6 cells. LH significantly can inhibit the replication of SARS-CoV-2 and reduce the mRNA levels of pro-inflammatory cytokines, including TNF-α, IL-6, MCP-1/ CCL2, and IP-10/CXCL10, suggesting that LH may inhibit the cytokine storm induced by SARS-CoV-2.[115]
Jinhua Qinggan Granules were developed during the 2009 H1N1 influenza pandemic. Network pharmacology and molecular docking techniques revealed that the mechanism of action may be attributed to some of the active constituents, such as kaempferol, baicalein, and oroxylin A, that can bind to SARS-CoV-2 3CL hydrolase and regulate many signaling pathways, including the TNF, PI3K/Akt, and HIF-1 signaling pathways.[116]
Among the TCMs commonly used to treat epidemic diseases, Gancao (Glycyrrhizae Radix Et Rhizoma) and HuangQin (Scutellariae Radix) are administered with high priority. When LigandFit was used to screen for candidate compounds in TCMs, 27 compounds docked with the 3CL hydrolase target and 48 docked with the ACE2 target. The screened compounds were distributed in 27 kinds of TCMs. Among them, Gancao and HuangQin contain the largest amounts of the identified compounds.[117] Thus, Gancao and HuangQin show potential anti-SARS-COV-2 activity by binding to ACE2 and 3CL hydrolase and regulating target genes related to the immune system, inflammation, cellular processes, and endocrine system.[117]
When network pharmacology-based technologies were employed to analyze the mechanisms of action for Chinese herbs in the treatment of COVID-19, 258 compounds and 53 overlapping genes were identified.[118] The key compounds included quercetin, wogonin, luteolin, and oroxylin A. All of these compounds have close associations with IL-6 and contain binding sites for TGF-β.[118] Quercetin is a naturally-abundant flavonoid that is widely distributed in various herbal medicines, especially in the clearing away heat and dampness herbs. In the supercomputer SUMMIT drug-docking screen and expression profiling experiments involving gene set enrichment analyses, quercetin was listed as one of the promising compounds to inhibit SARS-CoV-2 infection.[119] A computational docking model identified that quercetin can bind to either the isolated viral S protein at its host receptor-binding region or the S protein–human ACE2 receptor interface, thus potentially limiting viral recognition of host cells and/or disrupting host–virus interactions.[120] Kyoto encyclopedia of genes and genomes pathway analysis indicated that quercetin may act via several signaling pathways, including the TNF, HIF-1α, TLR, VEGF, and apoptosis- related signaling pathways to effectively treat COVID-19- induced renal injuries.[121] However, most of the research on the mechanisms of action for TCMs in the treatment of COVID-19 has been based on computer-aided systematic approaches, and thus further in vivo and in vitro validation experiments are needed.
Potential treatments for post-COVID-19 syndrome
Trabedersen/AP 12009 (OT-101)
OT-101 is an antisense oligodeoxynucleotide designed to target the mRNA of human TGF-β2.[122] It has been clinically evaluated in patients with advanced solid tumors in a phase I/II study.[123] OT-101 was proven to effectively inhibit tumor growth and metastasis[123],[124]. It also has the ability to overcome chemoresistance.[122] Uckun et al.[125] found that OT-101 suppresses viral replication of SARS-CoV-2 through inhibition of TGF-β, and also prevents the progression of mild ARDS and helps the recovery in COVID-19 patients.
Pirfenidone
Pirfenidone, an orally antifibrotic drug, inhibits conversion of pro-TGF-β to latent TGF-β by blocking furin.[126] Pirfenidone can attenuate TGF-β1-induced expression of fibronectin and α-SMA in human lung fibroblasts,[127] and inhibit the upregulation of Col-I mRNA in a concentration-dependent manner.[128] In a mouse model of bleomycin-induced pulmonary fibrosis, pirfenidone was shown to attenuate the development of fibrosis.[129]
Pirfenidone can reduce the decline in forced vital capacity (FCV) in pulmonary fibrosis patients.[130] It has been approved by the FDA for the treatment of idiopathic pulmonary fibrosis patients since 2014. Based on these findings, pirfenidone may be a safe anti-fibrotic drug to prevent pulmonary fibrosis in SARS-CoV-2 patients by blocking activation of TGF-β. The efficacy and safety of pirfenidone (NCT04282902) in SARS-CoV-2 infection is under investigation.
Smad3 inhibitors
Because Smad3 is a key mediator of TGF-β signaling related to AKI and fibrosis[16] and SARS-CoV-1/2 N protein can bind to Smad3 and promote Smad3 signaling,[52],[62] the development of specific Smad3 inhibitors could be a novel therapeutic strategy for COVID-19-associated AKI and organ fibrosis. This hypothesis was tested in a recent study on SARS-CoV-2 N protein-induced AKI in mice, in which treatment with the Smad3 inhibitor SIS3 was shown to inhibit AKI induced by kidney-specific overexpression of SARS- CoV-2 protein.[62]
| Conclusions | | |
The mechanisms underlying COVID-19-associated acute and chronic lung, cardiovascular, and renal injuries remain largely unclear and consequently there are no specific and effective treatment strategies for COVID-19 patients. Based on long-term follow-up studies, post-COVID-19 symptoms remain of concern. Therefore, further studies on COVID-19 survivors with post-COVID-19 symptoms are urgently needed. Because the TGF-β signaling pathway is one of the key pathways involved in the acute and chronic phases of COVID-19, understanding the role and molecular mechanisms of TGF-β signaling in COVID-19 may be the first step toward the development of targeted therapies for patients with COVID-19.
Financial support and sponsorship
This work was supported by the Research Grants Council of Hong Kong (14117418, 14104019, and 14101121), Lui Che Woo Institute of Innovative Medicine (CARE Program), Hong Kong Scholar Program (XJ2019052), National Natural Science Foundation of China (82070709 and 82100723), and Guangdong-Hong Kong-Macao-Joint Labs Program from Guangdong Science and Technology (2019B121205005).
Conflicts of interest
Hui-Yao Lan is a Co-Editor-in-Chief of the journal. The article was subject to the journal’s standard procedures, and peer review was handled independently of this editor and his research groups.
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