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1.
PLoS Biol ; 21(6): e3002097, 2023 06.
Article in English | MEDLINE | ID: covidwho-20243340

ABSTRACT

Identifying host genes essential for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to reveal novel drug targets and further our understanding of Coronavirus Disease 2019 (COVID-19). We previously performed a genome-wide CRISPR/Cas9 screen to identify proviral host factors for highly pathogenic human coronaviruses. Few host factors were required by diverse coronaviruses across multiple cell types, but DYRK1A was one such exception. Although its role in coronavirus infection was previously undescribed, DYRK1A encodes Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A and is known to regulate cell proliferation and neuronal development. Here, we demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the proviral activity of DYRK1A is conserved across species using cells of nonhuman primate and human origin. In summary, we report that DYRK1A is a novel regulator of ACE2 and DPP4 expression that may dictate susceptibility to multiple highly pathogenic human coronaviruses.


Subject(s)
COVID-19 , Virus Internalization , Animals , Humans , Angiotensin-Converting Enzyme 2 , COVID-19/genetics , COVID-19/metabolism , Dipeptidyl Peptidase 4 , Middle East Respiratory Syndrome Coronavirus/genetics , SARS-CoV-2/genetics , Severe acute respiratory syndrome-related coronavirus/genetics
2.
Vaccine ; 41(21): 3337-3346, 2023 05 16.
Article in English | MEDLINE | ID: covidwho-2293136

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks have constituted a public health issue with drastic mortality higher than 34%, necessitating the development of an effective vaccine. During MERS-CoV infection, the trimeric spike protein on the viral envelope is primarily responsible for attachment to host cellular receptor, dipeptidyl peptidase 4 (DPP4). With the goal of generating a protein-based prophylactic, we designed a subunit vaccine comprising the recombinant S1 protein with a trimerization motif (S1-Fd) and examined its immunogenicity and protective immune responses in combination with various adjuvants. We found that sera from immunized wild-type and human DPP4 transgenic mice contained S1-specific antibodies that can neutralize MERS-CoV infection in susceptible cells. Vaccination with S1-Fd protein in combination with a saponin-based QS-21 adjuvant provided long-term humoral as well as cellular immunity in mice. Our findings highlight the significance of the trimeric S1 protein in the development of MERS-CoV vaccines and offer a suitable adjuvant, QS-21, to induce robust and prolonged memory T cell response.


Subject(s)
Coronavirus Infections , Middle East Respiratory Syndrome Coronavirus , Viral Vaccines , Animals , Mice , Humans , Antibodies, Neutralizing , Antibodies, Viral , Dipeptidyl Peptidase 4 , Immunity, Cellular , Mice, Transgenic , Adjuvants, Immunologic , Recombinant Proteins , Vaccines, Subunit , Spike Glycoprotein, Coronavirus
3.
Vet Res ; 54(1): 34, 2023 Apr 13.
Article in English | MEDLINE | ID: covidwho-2302981

ABSTRACT

Porcine enteric viral infections cause high morbidity and mortality in young piglets (<3 weeks). Later, these rates decrease with age. This age-dependent infectivity remains largely unexplored. This study investigated the changes in intestinal morphology, number of mucus-producing cells and expression level of coronavirus receptors in three age groups of pigs. Villus height and crypt depth increased with age from 3 days to 3 months in duodenum and ileum but not in mid-jejunum, where the villus height decreased from 580 µm at 3 days to 430 µm at 3 months. Enterocyte length-to-width ratio increased from 3 days to 3 months in all intestinal regions. The number of mucus-producing cells increased with age in the intestinal villi and crypts. The Brunner's glands of the duodenum contained the highest concentration of mucus-producing cells. The expression of coronavirus receptor APN was highest in the small intestinal villi at all ages. DPP4 expression slightly decreased over time in jejunum and ileum; it was highest in the ileal villi of 3-day-old piglets (70.2% of cells). ACE2 and TMPRSS2 positive cells increased with age in jejunal and ileal crypts and were particularly dominant in the ileal crypts (> 45% of cells). Except for the expression of DPP4 in the jejunum and ileum of young pigs, the expression pattern of the selected coronavirus receptors was very different and not correlated with the age-dependent susceptibility to viral infections. In contrast, the number of mucus-producing cells increased over time and may play an essential role in protecting enteric mucosae against intestinal viruses.


Subject(s)
Angiotensin-Converting Enzyme 2 , Receptors, Coronavirus , Animals , Swine , Receptors, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Dipeptidyl Peptidase 4/metabolism , Jejunum , Ileum , Intestinal Mucosa , Aging , Mucus
4.
Exp Neurol ; 363: 114379, 2023 05.
Article in English | MEDLINE | ID: covidwho-2265676

ABSTRACT

COVID-19 causes neurological damage, systemic inflammation, and immune cell abnormalities. COVID-19-induced neurological impairment may be caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which directly infects cells of the central nervous system (CNS) and exerts toxic effects. Furthermore, SARS-CoV-2 mutations occur constantly, and it is not well understood how the infectivity of the virus to cells of the CNS changes as the virus mutates. Few studies have examined whether the infectivity of cells of CNS - neural stem/progenitor cells (NS/PCs), neurons, astrocytes, and microglia - varies among SARS-CoV-2 mutant strains. In this study, therefore, we investigated whether SARS-CoV-2 mutations increase infectivity to CNS cells, including microglia. Since it was essential to demonstrate the infectivity of the virus to CNS cells in vitro using human cells, we generated cortical neurons, astrocytes, and microglia from human induced pluripotent stem cells (hiPSCs). We added pseudotyped lentiviruses of SARS-CoV-2 to each type of cells, and then we examined their infectivity. We prepared three pseudotyped lentiviruses expressing the S protein of the original strain (the first SARS-CoV-2 discovered in the world), the Delta variant, and the Omicron variant on their envelopes and analyzed differences of their ability to infect CNS cells. We also generated brain organoids and investigated the infectivity of each virus. The viruses did not infect cortical neurons, astrocytes, or NS/PCs, but microglia were infected by the original, Delta, and Omicron pseudotyped viruses. In addition, DPP4 and CD147, potential core receptors of SARS-CoV-2, were highly expressed in the infected microglia, while DPP4 expression was deficient in cortical neurons, astrocytes, and NS/PCs. Our results suggest that DPP4, which is also a receptor for Middle East respiratory syndrome-coronavirus (MERS-CoV), may play an essential role in the CNS. Our study is applicable to the validation of the infectivity of viruses that cause various infectious diseases in CNS cells, which are difficult to sample from humans.


Subject(s)
COVID-19 , Induced Pluripotent Stem Cells , Humans , Microglia , SARS-CoV-2 , Dipeptidyl Peptidase 4 , Neurons
5.
Int J Oncol ; 62(3)2023 03.
Article in English | MEDLINE | ID: covidwho-2257647

ABSTRACT

The worldwide COVID­19 pandemic was brought on by a new coronavirus (SARS Cov­2). A marker/receptor called Dipeptidyl peptidase 4/CD26(DPP4/CD26) may be crucial in determining susceptibility to tumors and coronaviruses. However, the regulation of DPP4 in COVID­invaded cancer patients and its role on small molecule compounds remain unclear. The present study used the Human Protein Atlas, Monaco, and Schmiedel databases to analyze the expression of DPP4 in human tissues and immune cells. The association between DPP4 expression and survival in various tumor tissues was compared using GEPIA 2. The DNMIVD database was used to analyze the correlation between DPP4 expression and promoter methylation in various tumors. On the cBioPortal network, the frequency of DPP4 DNA mutations in various cancers was analyzed. The correlation between DPP4 expression and immunomodulators was analyzed by TISIDB database. The inhibitory effects of cordycepin (CD), N6, N6­dimethyladenosine (m62A) and adenosine (AD) on DPP4 in cancer cells were evaluated. DPP4 was mainly expressed in endocrine tissue, followed by gastrointestinal tract, female tissue (mainly in placenta), male tissue (mainly in prostate and seminal vesicle), proximal digestive tract, kidney, bladder, liver, gallbladder and respiratory system. In immune cells, DPP4 mRNA was mainly expressed in T cells, and its expression was upregulated in esophageal carcinoma, kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, stomach adenocarcinoma, thyroid carcinoma and thymoma. However, it was downregulated in breast invasive carcinoma, kidney chromophobe, lung squamous cell carcinoma and skin cutaneous melanoma. Thus, DPP4 is involved in viral invasion in most types of cancer. The expression of DPP4 could be inhibited by CD, m62A and AD in different tumor cells. Moreover, CD significantly inhibited the formation of GFP­positive syncytial cells. In vivo experiments with AD injection further showed that AD significantly inhibited lymphocyte activating factor 3 expression. These drugs may have potential to treat COVID­19 by targeting DPP4. Thus, DPP4 may be medically significant for SARS­CoV­2­infected cancer patients, providing prospective novel targets and concepts for the creation of drugs against COVID­19.


Subject(s)
Adenocarcinoma , COVID-19 , Carcinoma, Hepatocellular , Liver Neoplasms , Melanoma , Pancreatic Neoplasms , Skin Neoplasms , Humans , Male , Female , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , SARS-CoV-2 , Adenosine , Pandemics , Prospective Studies , COVID-19/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Immunity
6.
Cell ; 186(4): 850-863.e16, 2023 02 16.
Article in English | MEDLINE | ID: covidwho-2239711

ABSTRACT

It is unknown whether pangolins, the most trafficked mammals, play a role in the zoonotic transmission of bat coronaviruses. We report the circulation of a novel MERS-like coronavirus in Malayan pangolins, named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV). Among 86 animals, four tested positive by pan-CoV PCR, and seven tested seropositive (11 and 12.8%). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1). This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection, which is enhanced by a furin cleavage site that is absent in all known bat HKU4r-CoVs. The MjHKU4r-CoV-1 spike shows higher binding affinity for hDPP4, and MjHKU4r-CoV-1 has a wider host range than bat HKU4-CoV. MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice. Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.


Subject(s)
Coronavirus Infections , Coronavirus , Dipeptidyl Peptidase 4 , Pangolins , Animals , Humans , Mice , Chiroptera , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Endopeptidases/metabolism , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/metabolism , Peptide Hydrolases/metabolism , Receptors, Virus/metabolism , Virus Internalization , Coronavirus/physiology
7.
Int J Environ Res Public Health ; 20(4)2023 Feb 19.
Article in English | MEDLINE | ID: covidwho-2245410

ABSTRACT

Being diverse and widely distributed globally, bats are a known reservoir of a series of emerging zoonotic viruses. We studied fecal viromes of twenty-six bats captured in 2015 in the Moscow Region and found 13 of 26 (50%) samples to be coronavirus positive. Of P. nathusii (the Nathusius' pipistrelle), 3 of 6 samples were carriers of a novel MERS-related betacoronavirus. We sequenced and assembled the complete genome of this betacoronavirus and named it MOW-BatCoV strain 15-22. Whole genome phylogenetic analysis suggests that MOW-BatCoV/15-22 falls into a distinct subclade closely related to human and camel MERS-CoV. Unexpectedly, the phylogenetic analysis of the novel MOW-BatCoV/15-22 spike gene showed the closest similarity to CoVs from Erinaceus europaeus (European hedgehog). We suppose MOW-BatCoV could have arisen as a result of recombination between ancestral viruses of bats and hedgehogs. Molecular docking analysis of MOW-BatCoV/15-22 spike glycoprotein binding to DPP4 receptors of different mammals predicted the highest binding ability with DPP4 of the Myotis brandtii bat (docking score -320.15) and the E. europaeus (docking score -294.51). Hedgehogs are widely kept as pets and are commonly found in areas of human habitation. As this novel bat-CoV is likely capable of infecting hedgehogs, we suggest hedgehogs can act as intermediate hosts between bats and humans for other bat-CoVs.


Subject(s)
Chiroptera , Coronavirus Infections , Middle East Respiratory Syndrome Coronavirus , Animals , Humans , Betacoronavirus , Chiroptera/virology , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Hedgehogs/virology , Molecular Docking Simulation , Moscow , Phylogeny , Russia
8.
J Cell Mol Med ; 24(18): 10274-10278, 2020 09.
Article in English | MEDLINE | ID: covidwho-2229606

ABSTRACT

With the outbreak of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the public healthcare systems are facing great challenges. Coronavirus disease 2019 (COVID-19) could develop into severe pneumonia, acute respiratory distress syndrome and multi-organ failure. Remarkably, in addition to the respiratory symptoms, some COVID-19 patients also suffer from cardiovascular injuries. Dipeptidyl peptidase-4 (DPP-4) is a ubiquitous glycoprotein which could act both as a cell membrane-bound protein and a soluble enzymatic protein after cleavage and release into the circulation. Despite angiotensin-converting enzyme 2 (ACE2), the recently recognized receptor of SARS-CoV and SARS-CoV-2, which facilitated their entries into the host, DPP-4 has been identified as the receptor of middle east respiratory syndrome coronavirus (MERS-CoV). In the current review, we discussed the potential roles of DPP-4 in COVID-19 and the possible effects of DPP-4 inhibitors on cardiovascular system in patients with COVID-19.


Subject(s)
COVID-19 Drug Treatment , Cardiovascular Diseases/enzymology , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Cardiovascular Diseases/virology , Host-Pathogen Interactions , Humans , SARS-CoV-2/physiology , Virus Internalization
9.
Front Endocrinol (Lausanne) ; 13: 1096655, 2022.
Article in English | MEDLINE | ID: covidwho-2234615

ABSTRACT

Background: Diabetes has become a serious global public health problem. With the increasing prevalence of type 2 diabetes mellitus (T2DM), the incidence of complications of T2DM is also on the rise. Sitagliptin, as a targeted drug of DPP4, has good therapeutic effect for T2DM. It is well known that sitagliptin can specifically inhibit the activity of DPP4 to promote insulin secretion, inhibit islet ß cell apoptosis and reduce blood glucose levels, while other pharmacological mechanisms are still unclear, such as improving insulin resistance, anti-inflammatory, anti-oxidative stress, and anti-fibrosis. The aim of this study was to explore novel targets and potential signaling pathways of sitagliptin for T2DM. Methods: Firstly, network pharmacology was applied to find the novel target most closely related to DPP4. Semi-flexible molecular docking was performed to confirm the binding ability between sitagliptin and the novel target, and molecular dynamics simulation (MD) was carried to verify the stability of the complex formed by sitagliptin and the novel target. Furthermore, surface-plasmon resonance (SPR) was used to explored the affinity and kinetic characteristics of sitagliptin with the novel target. Finally, the molecular mechanism of sitagliptin for T2DM was predicted by the enrichment analysis of GO function and KEGG pathway. Results: In this study, we found the cell surface receptor-angiotensin-converting enzyme 2 (ACE2) most closely related to DPP4. Then, we confirmed that sitagliptin had strong binding ability with ACE2 from a static perspective, and the stability of sitagliptin-ACE2 complex had better stability and longer binding time than BAR708-ACE2 in simulated aqueous solution within 50 ns. Significantly, we have demonstrated a strong affinity between sitagliptin and ACE2 on SPR biosensor, and their kinetic characteristics were "fast binding/fast dissociation". The guiding significance of clinical administration: low dose can reach saturation, but repeated administration was needed. Finally, there was certain relationship between COVID-19 and T2DM, and ACE2/Ang-(1-7)/Mas receptor (MasR) axis may be the important pathway of sitagliptin targeting ACE2 for T2DM. Conclusion: This study used different methods to prove that ACE2 may be another novel target of sitagliptin for T2DM, which extended the application of ACE2 in improving diabetes mellitus.


Subject(s)
Diabetes Mellitus, Type 2 , Sitagliptin Phosphate , Humans , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , Diabetes Mellitus, Type 2/complications , Dipeptidyl Peptidase 4/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Network Pharmacology , Sitagliptin Phosphate/therapeutic use , Surface Plasmon Resonance
12.
J Microbiol Biotechnol ; 30(3): 427-438, 2020 Mar 28.
Article in English | MEDLINE | ID: covidwho-2163802

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) infects the lower respiratory airway of humans, leading to severe acute respiratory failure. Unlike human dipeptidyl peptidase 4 (hDPP4), a receptor for MERS-CoV, mouse DPP4 (mDPP4) failed to support MERS-CoV infection. Consequently, diverse transgenic mouse models expressing hDPP4 have been developed using diverse methods, although some models show no mortality and/or only transient and mild-to-moderate clinical signs following MERS-CoV infection. Additionally, overexpressed hDPP4 is associated with neurological complications and breeding difficulties in some transgenic mice, resulting in impeding further studies. Here, we generated stable hDPP4-transgenic mice that were sufficiently susceptible to MERS-CoV infection. The transgenic mice showed weight loss, decreased pulmonary function, and increased mortality with minimal perturbation of overexpressed hDPP4 after MERS-CoV infection. In addition, we observed histopathological signs indicative of progressive pulmonary fibrosis, including thickened alveolar septa, infiltration of inflammatory monocytes, and macrophage polarization as well as elevated expression of profibrotic molecules and acute inflammatory response in the lung of MERS-CoV-infected hDPP4-transgenic mice. Collectively, we suggest that this hDPP4-transgenic mouse is useful in understanding the pathogenesis of MERS-CoV infection and for antiviral research and vaccine development against the virus.


Subject(s)
Coronavirus Infections/immunology , Dipeptidyl Peptidase 4/immunology , Lung/pathology , Middle East Respiratory Syndrome Coronavirus/immunology , Pulmonary Fibrosis/pathology , Animals , Coronavirus Infections/complications , Dipeptidyl Peptidase 4/genetics , Disease Models, Animal , Female , Humans , Mice , Mice, Transgenic , Pulmonary Fibrosis/etiology
13.
Nature ; 612(7941): 748-757, 2022 12.
Article in English | MEDLINE | ID: covidwho-2151056

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) and several bat coronaviruses use dipeptidyl peptidase-4 (DPP4) as an entry receptor1-4. However, the receptor for NeoCoV-the closest known MERS-CoV relative found in bats-remains unclear5. Here, using a pseudotype virus entry assay, we found that NeoCoV and its close relative, PDF-2180, can efficiently bind to and use specific bat angiotensin-converting enzyme 2 (ACE2) orthologues and, less favourably, human ACE2 as entry receptors through their receptor-binding domains (RBDs) on the spike (S) proteins. Cryo-electron microscopy analysis revealed an RBD-ACE2 binding interface involving protein-glycan interactions, distinct from those of other known ACE2-using coronaviruses. We identified residues 337-342 of human ACE2 as a molecular determinant restricting NeoCoV entry, whereas a NeoCoV S pseudotyped virus containing a T510F RBD mutation efficiently entered cells expressing human ACE2. Although polyclonal SARS-CoV-2 antibodies or MERS-CoV RBD-specific nanobodies did not cross-neutralize NeoCoV or PDF-2180, an ACE2-specific antibody and two broadly neutralizing betacoronavirus antibodies efficiently inhibited these two pseudotyped viruses. We describe MERS-CoV-related viruses that use ACE2 as an entry receptor, underscoring a promiscuity of receptor use and a potential zoonotic threat.


Subject(s)
Angiotensin-Converting Enzyme 2 , Chiroptera , Middle East Respiratory Syndrome Coronavirus , Receptors, Virus , Virus Internalization , Animals , Humans , Angiotensin-Converting Enzyme 2/metabolism , Chiroptera/metabolism , Chiroptera/virology , Cryoelectron Microscopy , Middle East Respiratory Syndrome Coronavirus/classification , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Middle East Respiratory Syndrome Coronavirus/metabolism , Protein Binding , Receptors, Virus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Dipeptidyl Peptidase 4/metabolism , Viral Zoonoses
14.
PLoS Pathog ; 18(9): e1010834, 2022 09.
Article in English | MEDLINE | ID: covidwho-2039449

ABSTRACT

No vaccines or specific antiviral drugs are authorized against Middle East respiratory syndrome coronavirus (MERS-CoV) despite its high mortality rate and prevalence in dromedary camels. Since 2012, MERS-CoV has been causing sporadic zoonotic infections in humans, which poses a risk of genetic evolution to become a pandemic virus. MERS-CoV genome encodes five accessory proteins, 3, 4a, 4b, 5 and 8b for which limited information is available in the context of infection. This work describes 4b as a virulence factor in vivo, since the deletion mutant of a mouse-adapted MERS-CoV-Δ4b (MERS-CoV-MA-Δ4b) was completely attenuated in a humanized DPP4 knock-in mouse model, resulting in no mortality. Attenuation in the absence of 4b was associated with a significant reduction in lung pathology and chemokine expression levels at 4 and 6 days post-infection, suggesting that 4b contributed to the induction of lung inflammatory pathology. The accumulation of 4b in the nucleus in vivo was not relevant to virulence, since deletion of its nuclear localization signal led to 100% mortality. Interestingly, the presence of 4b protein was found to regulate autophagy in the lungs of mice, leading to upregulation of BECN1, ATG3 and LC3A mRNA. Further analysis in MRC-5 cell line showed that, in the context of infection, MERS-CoV-MA 4b inhibited autophagy, as confirmed by the increase of p62 and the decrease of ULK1 protein levels, either by direct or indirect mechanisms. Together, these results correlated autophagy activation in the absence of 4b with downregulation of a pathogenic inflammatory response, thus contributing to attenuation of MERS-CoV-MA-Δ4b.


Subject(s)
Coronavirus Infections , Middle East Respiratory Syndrome Coronavirus , Animals , Antiviral Agents , Autophagy-Related Protein-1 Homolog , Camelus/genetics , Dipeptidyl Peptidase 4/genetics , Humans , Lung , Mice , Nuclear Localization Signals , RNA, Messenger , Virulence Factors/genetics
15.
J Med Chem ; 65(19): 12562-12593, 2022 10 13.
Article in English | MEDLINE | ID: covidwho-2036741

ABSTRACT

Viral pathologies encompass activation of pro-oxidative pathways and inflammatory burst. Alleviating overproduction of reactive oxygen species and cytokine storm in COVID-19 is essential to counteract the immunogenic damage in endothelium and alveolar membranes. Antioxidants alleviate oxidative stress, cytokine storm, hyperinflammation, and diminish the risk of organ failure. Direct antiviral roles imply: impact on viral spike protein, interference with the ACE2 receptor, inhibition of dipeptidyl peptidase 4, transmembrane protease serine 2 or furin, and impact on of helicase, papain-like protease, 3-chyomotrypsin like protease, and RNA-dependent RNA polymerase. Prooxidative environment favors conformational changes in the receptor binding domain, promoting the affinity of the spike protein for the host receptor. Viral pathologies imply a vicious cycle, oxidative stress promoting inflammatory responses, and vice versa. The same was noticed with respect to the relationship antioxidant impairment-viral replication. Timing, dosage, pro-oxidative activities, mutual influences, and interference with other antioxidants should be carefully regarded. Deficiency is linked to illness severity.


Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Anti-Inflammatory Agents , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Cytokine Release Syndrome , Dipeptidyl Peptidase 4 , Furin , Humans , Papain , RNA-Dependent RNA Polymerase , Reactive Oxygen Species , Serine , Spike Glycoprotein, Coronavirus/metabolism
16.
J Cell Mol Med ; 26(19): 4940-4948, 2022 10.
Article in English | MEDLINE | ID: covidwho-2019413

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the novel coronavirus responsible for worldwide coronavirus disease (COVID-19). We previously observed that Angiotensin-converting enzyme 2 (ACE2) and Dipeptidyl peptidase-4 (DPP4) are significantly overexpressed in naso-oropharyngeal swabs (NPS) of COVID-19 patients, suggesting their putative functional role in the disease progression. ACE2 and DPP4 overexpression in COVID-19 patients may be associated to epigenetic mechanism, such as miRNA differential expression. We investigated if hsa-let7b-5p, reported to target both ACE2 and DPP4 transcripts, could be involved in the regulation of these genes. We verified that the inhibition and overexpression of hsa-let7b-5p matched to a modulation of both ACE2 and DPP4 levels. Then, we observed a statistically significant downregulation (FC = -1.5; p < 0.05) of hsa-let7b-5p in the same COVID-19 and control samples of our previous study. This is the first study that shows hsa-let7b-5p low expression in naso-oropharyngeal swabs of COVID-19 patients and demonstrates a functional role of this miR in regulating ACE2 and DPP4 levels. These data suggest the involvement of hsa-let7b-5p in the regulation of genes necessary for SARS-CoV-2 infections and its putative role as a therapeutic target for COVID-19.


Subject(s)
COVID-19 , MicroRNAs , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , SARS-CoV-2/genetics
17.
Proc Natl Acad Sci U S A ; 119(34): e2117089119, 2022 08 23.
Article in English | MEDLINE | ID: covidwho-1984597

ABSTRACT

The COVID-19 pandemic has incurred tremendous costs worldwide and is still threatening public health in the "new normal." The association between neutralizing antibody levels and metabolic alterations in convalescent patients with COVID-19 is still poorly understood. In the present work, we conducted absolutely quantitative profiling to compare the plasma cytokines and metabolome of ordinary convalescent patients with antibodies (CA), convalescents with rapidly faded antibodies (CO), and healthy subjects. As a result, we identified that cytokines such as M-CSF and IL-12p40 and plasma metabolites such as glycylproline (gly-pro) and long-chain acylcarnitines could be associated with antibody fading in COVID-19 convalescent patients. Following feature selection, we built machine-learning-based classification models using 17 features (six cytokines and 11 metabolites). Overall accuracies of more than 90% were attained in at least six machine-learning models. Of note, the dipeptide gly-pro, a product of enzymatic peptide cleavage catalyzed by dipeptidyl peptidase 4 (DPP4), strongly accumulated in CO individuals compared with the CA group. Furthermore, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination experiments in healthy mice demonstrated that supplementation of gly-pro down-regulates SARS-CoV-2-specific receptor-binding domain antibody levels and suppresses immune responses, whereas the DPP4 inhibitor sitagliptin can counteract the inhibitory effects of gly-pro upon SARS-CoV-2 vaccination. Our findings not only reveal the important role of gly-pro in the immune responses to SARS-CoV-2 infection but also indicate a possible mechanism underlying the beneficial outcomes of treatment with DPP4 inhibitors in convalescent COVID-19 patients, shedding light on therapeutic and vaccination strategies against COVID-19.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Drug Treatment , COVID-19 , Convalescence , Cytokines , Dipeptides , Dipeptidyl-Peptidase IV Inhibitors , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibody Formation , COVID-19/blood , COVID-19/immunology , Cytokines/blood , Dipeptides/blood , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Machine Learning , Metabolome , Mice , SARS-CoV-2 , Vaccination
18.
Nature ; 609(7928): 785-792, 2022 09.
Article in English | MEDLINE | ID: covidwho-1972633

ABSTRACT

Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs. 1,2) (SARS-CoV-2), Middle East respiratory syndrome coronavirus3 (MERS-CoV) and SARS-CoV-1 (ref. 4), vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture5-7 and in patient tissues8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that caspase-6, a cysteine-aspartic protease of the apoptosis cascade, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid proteins, generating fragments that serve as interferon antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss in golden Syrian hamsters infected with SARS-CoV-2 and improves the survival of mice expressing human DPP4 that are infected with mouse-adapted MERS-CoV. Our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.


Subject(s)
Aspartic Acid , Caspase 6 , Coronavirus Infections , Coronavirus , Cysteine , Host-Pathogen Interactions , Virus Replication , Animals , Apoptosis , Aspartic Acid/metabolism , Caspase 6/metabolism , Coronavirus/growth & development , Coronavirus/pathogenicity , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus Nucleocapsid Proteins/metabolism , Cricetinae , Cysteine/metabolism , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Humans , Interferons/antagonists & inhibitors , Interferons/immunology , Lung/pathology , Mesocricetus , Mice , Middle East Respiratory Syndrome Coronavirus , Severe acute respiratory syndrome-related coronavirus , SARS-CoV-2 , Survival Rate , Weight Loss
19.
Proc Biol Sci ; 289(1979): 20220193, 2022 07 27.
Article in English | MEDLINE | ID: covidwho-1961305

ABSTRACT

Pandemics originating from non-human animals highlight the need to understand how natural hosts have evolved in response to emerging human pathogens and which groups may be susceptible to infection and/or potential reservoirs to mitigate public health and conservation concerns. Multiple zoonotic coronaviruses, such as severe acute respiratory syndrome-associated coronavirus (SARS-CoV), SARS-CoV-2 and Middle Eastern respiratory syndrome-associated coronavirus (MERS-CoV), are hypothesized to have evolved in bats. We investigate angiotensin-converting enzyme 2 (ACE2), the host protein bound by SARS-CoV and SARS-CoV-2, and dipeptidyl-peptidase 4 (DPP4 or CD26), the host protein bound by MERS-CoV, in the largest bat datasets to date. Both the ACE2 and DPP4 genes are under strong selection pressure in bats, more so than in other mammals, and in residues that contact viruses. Additionally, mammalian groups vary in their similarity to humans in residues that contact SARS-CoV, SARS-CoV-2 and MERS-CoV, and increased similarity to humans in binding residues is broadly predictive of susceptibility to SARS-CoV-2. This work augments our understanding of the relationship between coronaviruses and mammals, particularly bats, provides taxonomically diverse data for studies of how host proteins are bound by coronaviruses and can inform surveillance, conservation and public health efforts.


Subject(s)
Chiroptera , Middle East Respiratory Syndrome Coronavirus , Receptors, Coronavirus , SARS-CoV-2 , Severe acute respiratory syndrome-related coronavirus , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Chiroptera/genetics , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Humans , Middle East Respiratory Syndrome Coronavirus/metabolism , Severe acute respiratory syndrome-related coronavirus/metabolism , SARS-CoV-2/metabolism
20.
Int J Mol Sci ; 23(13)2022 Jun 29.
Article in English | MEDLINE | ID: covidwho-1917516

ABSTRACT

People with diabetes are more likely to have severe COVID-19 compared to the general population. Moreover, diabetes and COVID-19 demonstrate a certain parallelism in the mechanisms and organ damage. In this work, we applied bioinformatics analysis of associative molecular networks to identify key molecules and pathophysiological processes that determine SARS-CoV-2-induced disorders in patients with diabetes. Using text-mining-based approaches and ANDSystem as a bioinformatics tool, we reconstructed and matched networks related to hyperglycemia, diabetic complications, insulin resistance, and beta cell dysfunction with networks of SARS-CoV-2-targeted proteins. The latter included SARS-CoV-2 entry receptors (ACE2 and DPP4), SARS-CoV-2 entry associated proteases (TMPRSS2, CTSB, and CTSL), and 332 human intracellular proteins interacting with SARS-CoV-2. A number of genes/proteins targeted by SARS-CoV-2 (ACE2, BRD2, COMT, CTSB, CTSL, DNMT1, DPP4, ERP44, F2RL1, GDF15, GPX1, HDAC2, HMOX1, HYOU1, IDE, LOX, NUTF2, PCNT, PLAT, RAB10, RHOA, SCARB1, and SELENOS) were found in the networks of vascular diabetic complications and insulin resistance. According to the Gene Ontology enrichment analysis, the defined molecules are involved in the response to hypoxia, reactive oxygen species metabolism, immune and inflammatory response, regulation of angiogenesis, platelet degranulation, and other processes. The results expand the understanding of the molecular basis of diabetes and COVID-19 comorbidity.


Subject(s)
COVID-19 , Diabetes Complications , Diabetes Mellitus , Hyperglycemia , Insulin Resistance , Angiotensin-Converting Enzyme 2 , COVID-19/genetics , Comorbidity , Diabetes Complications/genetics , Diabetes Mellitus/epidemiology , Diabetes Mellitus/genetics , Dipeptidyl Peptidase 4/genetics , Gene Regulatory Networks , Humans , Hyperglycemia/complications , Hyperglycemia/genetics , SARS-CoV-2/genetics
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