Role of SARS-CoV-2 -induced cytokines and growth factors in coagulopathy and thromboembolism

Severe COVID-19 patients frequently present thrombotic complications which commonly lead to multiorgan failure and increase the risk of death. Severe SARS-CoV-2 infection induces the cytokine storm and is often associated with coagulation dysfunction. D-dimer, a hallmark of venous thromboembolism (VTE), is observed at a higher level in the majority of hospitalized COVID-19 patients. The precise molecular mechanism of the disproportionate effect of SARS-CoV-2 infection on the coagulation system is largely undefined. SARS-CoV-2 –induced endotheliopathy and, induction of cytokines and growth factors (GFs) most likely play important roles in platelet activation, coagulopathy, and VTE. Generally, viral infections lead to systemic inflammation and induction of numerous cytokines and GFs and many of them are reported to be associated with increased VTE. Most importantly, platelets play key thromboinflammatory roles linking coagulation to immune mediators in a variety of infections including response to viral infection. Since the pathomechanism of coagulopathy and VTE in COVID-19 is largely undefined, herein we highlight the association of dysregulated inflammatory cytokines and GFs with thrombotic complications and coagulopathy in COVID-19.     

Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus-2 and the related coronavirus disease-19 (COVID-19) is a worldwide emerging situation, which was initially reported in December 2019 in Wuhan, China. Currently, more than 7258842 new cases, and more than 411879 deaths have been reported globally. This new highly transmitted coronavirus is responsible for the development of severe acute respiratory distress syndrome. Due to this disorder, a great number of patients are hospitalized in the intensive care unit followed by connection to extracorporeal membrane oxygenation for breath supporting and survival. Severe acute respiratory distress syndrome is mostly accompanied by the secretion of proinflammatory cytokines, including interleukin (IL)-2, IL-6, IL-7, granulocyte colony-stimulating factor (GSCF), interferon-inducible protein 10 (IP10), monocyte chemotactic protein-1 (MCP1), macrophage inflammatory protein 1A (MIP1A), and tumor necrosis factor alpha (TNF-α), an event which is known as “cytokine storm”. Further disease pathology involves a generalized modulation of immune responses, leading to fatal multiorgan failure. Currently, no specific treatment or vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been developed. Mesenchymal stromal cells (MSCs), which are known for their immunosuppressive actions, could be applied as an alternative co-therapy in critically-ill COVID-19 patients. Specifically, MSCs can regulate the immune responses through the conversion of Th1 to Th2, activation of M2 macrophages, and modulation of dendritic cells maturation. These key immunoregulatory properties of MSCs may be exerted either by produced soluble factors or by cell-cell contact interactions. To date, several clinical trials have been registered to assess the safety, efficacy, and therapeutic potential of MSCs in COVID-19. Moreover, MSC treatment may be effective for the reversion of ground-glass opacity of damaged lungs and reduce the tissue fibrosis. Taking into account the multifunctional properties of MSCs, the proposed stem-cell-based therapy may be proven significantly effective in critically-ill COVID-19 patients. The current therapeutic strategy may improve the patient’s overall condition and in parallel may decrease the mortality rate of the current disease.     

Postbiotics as potential promising tools for SARS-CoV-2 disease adjuvant therapy

The SARS-CoV-2 pandemic defines the global health tension of our time. There are several continuous efforts to find a definitive cure in this regard. According to some adverse effects and problems of customary SARS-CoV-2 disease therapies, bioactive compounds, for example probiotics-derived metabolites (postbiotics) have been accomplishing supreme importance by investigators for adjuvant cures in patients with SARS-CoV-2. Postbiotics inhibit angiotensin-converting enzyme 2 activity and stimulate the immune system. They also boost the SARS-CoV-2 disease treatment effectiveness and reduce its adverse effects in SARS-CoV-2 illness patients as a result of antiviral and anti-inflammatory effects. Furthermore, postbiotics having unique features such as high safety, high shelf life and stability to the gastrointestinal tract can be utilized as hopeful instruments for both adjuvant and inhibition strategies in SARS-CoV-2 patients with no earnest unfavourable adverse effects. The concept of postbiotics and their biocompatible characteristics are comprehensively discussed in the present review while highlighting the bilateral relationship between postbiotic biometabolites and respiratory tract infection with a special look at the potential biological role in the inactivation of SARS-CoV-2 and reduction of related inflammatory pathways.     

Assessment of global asymptomatic SARS-CoV-2 infection and management practices from China

With ongoing research, it was found that asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was widespread in coronavirus disease 2019 (COVID-19) populations. Studies have confirmed asymptomatic patients with COVID-19 have potential infectivity, and most of the transmission occurred before symptoms appear. Asymptomatic infection rates varied widely in different countries and regions. Identifying the asymptomatic infected persons and cutting off the infection source is an effective way to prevent the spread of this disease. However, asymptomatic patients have hidden clinical symptoms, and screening based only on the clinical symptoms of COVID-19 can easily lead to a missed diagnosis. Therefore, determining asymptomatic infection patients by SARS-CoV-2 nucleic acid testing is the gold standard. A series of prevention and control measures adopted by the Chinese government, especially the “Four Early” policy, have achieved outstanding achievements, which are worth learning from by other countries.     

Characteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan,China

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is continuously and rapidly circulating at present. Asymptomatic patients have been proven to be contagious and thus pose a significant infection control challenge. Here we describe the characteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan, Shandong province, China. A total of 47 patients with confirmed COVID-19 were recruited. Among them, 11 patients were categorized as asymptomatic cases. We found that the asymptomatic patients in Jinan were relatively young and were mainly clustered cases. The laboratory indicators and lung lesion on chest CT were mild. No special factors were found accounting for the presence or absence of symptoms. The presence of asymptomatic patients increased the difficulty of screening. It is necessary to strengthen the identification of such patients in the future.     

Natural killer cell exhaustion in SARS-CoV-2 infection

At the end of 2019, an outbreak of a severe respiratory disease occurred in Wuhan China, and an increase in cases of unknown pneumonia was alerted. In January 2020, a new coronavirus named SARS-CoV-2 was identified as the cause. The virus spreads primarily through the respiratory tract, and lymphopenia and cytokine storms have been observed in severely ill patients. This suggests the existence of an immune dysregulation as an accompanying event during a serious illness caused by this virus. Natural killer (NK) cells are innate immune responders, critical for virus shedding and immunomodulation. Despite its importance in viral infections, the contribution of NK cells in the fight against SARS-CoV-2 has yet to be deciphered. Different studies in patients with COVID-19 suggest a significant reduction in the number and function of NK cells due to their exhaustion. In this review, we summarize the current understanding of how NK cells respond to SARS-CoV-2 infection.     

Receptor-binding domain of SARS-CoV-2 spike protein efficiently inhibits SARS-CoV-2 infection and attachment to mouse lung

COVID-19, caused by a novel coronavirus, SARS-CoV-2, poses a serious global threat. It was first reported in 2019 in China and has now dramatically spread across the world. It is crucial to develop therapeutics to mitigate severe disease and viral spread. The receptor-binding domains (RBDs) in the spike protein of SARS-CoV and MERS-CoV have shown anti-viral activity in previous reports suggesting that this domain has high potential for development as therapeutics. To evaluate the potential antiviral activity of recombinant SARS-CoV-2 RBD proteins, we determined the RBD residues of SARS-CoV-2 using a homology search with RBD of SARS-CoV. For efficient expression and purification, the signal peptide of spike protein was identified and used to generate constructs expressing recombinant RBD proteins. Highly purified RBD protein fused with the Fc domain of human IgG showed potent anti-viral efficacy, which was better than that of a protein fused with a histidine tag. Intranasally pre-administrated RBD protein also inhibited the attachment of SARS-COV-2 to mouse lungs. These findings indicate that RBD protein could be used for the prevention and treatment of SARS-CoV-2 infection.     

Capivasertib restricts SARS-CoV-2 cellular entry: a potential clinical application for COVID-19

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to more than 150 million infections and about 3.1 million deaths up to date. Currently, drugs screened are urgently aiming to block the infection of SARS-CoV-2. Here, we explored the interaction networks of kinase and COVID-19 crosstalk, and identified phosphoinositide 3-kinase (PI3K)/AKT pathway as the most important kinase signal pathway involving COVID-19. Further, we found a PI3K/AKT signal pathway inhibitor capivasertib restricted the entry of SARS-CoV-2 into cells under non-cytotoxic concentrations. Lastly, the signal axis PI3K/AKT/FYVE finger-containing phosphoinositide kinase (PIKfyve)/PtdIns(3,5)P2 was revealed to play a key role during the cellular entry of viruses including SARS-CoV-2, possibly providing potential antiviral targets. Altogether, our study suggests that the PI3K/AKT kinase inhibitor drugs may be a promising anti-SARS-CoV-2 strategy for clinical application, especially for managing cancer patients with COVID-19 in the pandemic era.     

The SARS-CoV-2 induced targeted amino acid profiling in patients at hospitalized and convalescent stage

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has induced an ongoing global health crisis. Here we utilized a combination of targeted amino acids (AAs) and clinical biochemical profiling to analyze the plasma of coronavirus disease 2019 (COVID-19) subjects at the hospitalization stage and 1-month post-infection convalescent stage, respectively, to investigate the systematic injury during COVID-19 disease progress. We found the virus-induced inflammatory status and reduced liver synthesis capacity in hospitalized patients, which manifested with increased branched-chain AAs (BCAAs), aromatic AAs (AAAs), one-carbon related metabolites, and decreased methionine. Most of these disturbances during infection recover except for the increased levels of medium-chain acylcarnitines (ACs) in the convalescent subjects, implying the existence of incomplete fatty acids oxidation during recovery periods. Our results suggested that the imbalance of the AA profiling in COVID-19 patients. The majority of disturbed AAs recovered in 1 month. The incomplete fatty acid oxidation products suggested it might take longer time for convalescent patients to get complete recovery.     

Secretory phospholipase A2 in SARS-CoV-2 infection and multisystem inflammatory syndrome in children (MIS-C)

Secretory phospholipase 2 (sPLA2) acts as a mediator between proximal and distal events of the inflammatory cascade. Its role in SARS-CoV-2 infection is unknown, but could contribute to COVID-19 inflammasome activation and cellular damage. We present the first report of plasma sPLA2 levels in adults and children with COVID-19 compared with controls. Currently asymptomatic adults with a history of recent COVID-19 infection (≥4 weeks before) identified by SARS-CoV-2 IgG antibodies had sPLA2 levels similar to those who were seronegative (9 ± 6 vs.17 ± 28 ng/mL, P = 0.26). In contrast, children hospitalized with severe COVID-19 had significantly elevated sPLA2 compared with those with mild or asymptomatic SARS-CoV-2 infection (269 ± 137 vs. 2 ± 3 ng/mL, P = 0.01). Among children hospitalized with multisystem inflammatory syndrome in children (MIS-C), all had severe disease requiring pediatric intensive care unit (PICU) admission. sPLA2 levels were significantly higher in those with acute illness <10 days versus convalescent disease ≥10 days (540 ± 510 vs. 2 ± 1, P = 0.04). Thus, sPLA2 levels correlated with COVID-19 severity and acute MIS-C in children, implicating a role in inflammasome activation and disease pathogenesis. sPLA2 may be a useful biomarker to stratify risk and guide patient management for children with acute COVID-19 and MIS-C. Therapeutic compounds targeting sPLA2 and inflammasome activation warrant consideration.     

SARS-CoV-2 infection induces beta cell transdifferentiation

1. Download : Download high-res image (212KB)
2. Download : Download full-size image

     

SARS-CoV-2 infection: The role of cytokines in COVID-19 disease

COVID-19 disease, caused by infection with SARS-CoV-2, is related to a series of physiopathological mechanisms that mobilize a wide variety of biomolecules, mainly immunological in nature. In the most severe cases, the prognosis can be markedly worsened by the hyperproduction of mainly proinflammatory cytokines, such as IL-1, IL-6, IL-12, IFN-γ, and TNF-α, preferentially targeting lung tissue. This study reviews published data on alterations in the expression of different cytokines in patients with COVID-19 who require admission to an intensive care unit. Data on the implication of cytokines in this disease and their effect on outcomes will support the design of more effective approaches to the management of COVID-19.     

SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities

The current coronavirus disease 2019 (COVID-19) pandemic has presented unprecedented challenges to global health. Although the majority of COVID-19 patients exhibit mild-to-no symptoms, many patients develop severe disease and need immediate hospitalization, with most severe infections associated with a dysregulated immune response attributed to a cytokine storm. Epidemiological studies suggest that overall COVID-19 severity and morbidity correlate with underlying comorbidities, including diabetes, obesity, cardiovascular diseases, and immunosuppressive conditions. Patients with such comorbidities exhibit elevated levels of reactive oxygen species (ROS) and oxidative stress caused by an increased accumulation of angiotensin II and by activation of the NADPH oxidase pathway. Moreover, accumulating evidence suggests that oxidative stress coupled with the cytokine storm contribute to COVID-19 pathogenesis and immunopathogenesis by causing endotheliitis and endothelial cell dysfunction and by activating the blood clotting cascade that results in blood coagulation and microvascular thrombosis. In this review, we survey the mechanisms of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces oxidative stress and the consequences of this stress on patient health. We further shed light on aspects of the host immunity that are crucial to prevent the disease during the early phase of infection. A better understanding of the disease pathophysiology as well as preventive measures aimed at lowering ROS levels may pave the way to mitigate SARS-CoV-2-induced complications and decrease mortality.     

Immune response and potential therapeutic strategies for the SARS-CoV-2 associated with the COVID-19 pandemic

Following onset of the first recorded case of Coronavirus disease 2019 (COVID-19) in December 2019, more than 269 million cases and over 5.3 million deaths have been confirmed worldwide. COVID-19 is a highly infectious pneumonia, caused by a novel virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, it poses a severe threat to human health across the globe, a trend that is likely to persist in the foreseeable future. This paper reviews SARS-CoV-2 immunity, the latest development of anti-SARS-CoV-2 drugs as well as exploring in detail, immune escape induced by SARS-CoV-2. We expect that the findings will provide a basis for COVID-19 prevention and treatment.     

Heparanase 2 Interacts with Heparan Sulfate with High Affinity and Inhibits Heparanase Activity

Heparanase activity is highly implicated in cell dissemination associated with tumor metastasis, angiogenesis, and inflammation. Heparanase expression is induced in many hematological and solid tumors, associated with poor prognosis. Heparanase homolog, termed heparanase 2 (Hpa2), was cloned based on sequence homology. Detailed characterization of Hpa2 at the biochemical, cellular, and clinical levels has not been so far reported, and its role in normal physiology and pathological disorders is obscure. We provide evidence that unlike heparanase, Hpa2 is not subjected to proteolytic processing and exhibits no enzymatic activity typical of heparanase. Notably, the full-length Hpa2c protein inhibits heparanase enzymatic activity, likely due to its high affinity to heparin and heparan sulfate and its ability to associate physically with heparanase. Hpa2 expression was markedly elevated in head and neck carcinoma patients, correlating with prolonged time to disease recurrence (follow-up to failure; p = 0.006) and inversely correlating with tumor cell dissemination to regional lymph nodes (N-stage; p = 0.03). Hpa2 appears to restrain tumor metastasis, likely by attenuating heparanase enzymatic activity, conferring a favorable outcome of head and neck cancer patients.     

Previous infection with SARS-CoV-2 impacts embryo morphokinetics but not clinical outcomes in a time-lapse imaging system

The goal for the present study was to investigate whether previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may compromise embryo morphokinetics and implantation. For that, a historical cohort study was performed in a private university-affiliated in vitro fertilization center. The study included 1628 embryos from 88 patients undergoing intracytoplasmic sperm injection (ICSI) cycles. Patients were age-matched in a 1:3 ratio to either a coronavirus disease (COVID) group, including patients with a positive SARS-CoV-2 immunoglobulin test (n = 22 patients, 386 embryos), or a control group, including patients with a negative SARS-CoV-2 immunoglobulin test (n = 66, 1242 embryos). The effect of previous infection with SARS-CoV-2 on morphokinetic events and ICSI outcomes was evaluated. Embryos derived from patients in the COVID group presented longer time to pronuclei appearance and fading, time to form two, three, four and five cells, and time to blastulation. The durations of the third cell cycle and to time to complete synchronous divisions were also significantly increased in the COVID group compared with the control group, whereas known implantation diagnosis score Day 5 ranked significantly lower in the COVID group. No differences were observed between the COVID and control groups on clinical outcomes. In conclusion, patients planning parenthood, who have recovered from COVID-19 infection, must be aware of a possible effect of the infection on embryo development potential.