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1.
Eur J Gastroenterol Hepatol ; 33(3): 309-311, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-20232271

ABSTRACT

On 12 March 2020, the WHO declared that the coronavirus disease 2019 (COVID-19) constitutes a pandemic. Cases of liver damage or dysfunction (mainly characterized by moderately elevated serum aspartate aminotransferase levels) have been reported among patients with COVID-19. However, it is currently uncertain whether the COVID-19 related liver damage/dysfunction is due mainly to the viral infection by itself or other coexisting conditions, such as the use of potentially hepatotoxic medications and the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, and multiple organ dysfunction. Individuals at high risk for severe COVID-19 are typical of older age and/or present with comorbid conditions such as diabetes, cardiovascular disease, and hypertension. This is also the same profile for those at increased risk for unrecognized underlying liver disease, especially nonalcoholic fatty liver disease. This could make them more susceptible to liver injury from the virus, medications used in supportive management, or hypoxia. So the aim of this review was to illustrate the clinical implications of COVID-19 on the liver in healthy and diseased states as well as the implications of common liver disorders on the outcome of COVID-19.


Subject(s)
COVID-19/virology , Liver Diseases/virology , Liver/virology , SARS-CoV-2/pathogenicity , COVID-19/diagnosis , COVID-19/epidemiology , Host-Pathogen Interactions , Humans , Liver/pathology , Liver Diseases/diagnosis , Liver Diseases/epidemiology , Prognosis , Risk Assessment , Risk Factors
2.
Int J Mol Sci ; 24(11)2023 Jun 01.
Article in English | MEDLINE | ID: covidwho-20243310

ABSTRACT

Galectin-3 (Gal-3), a beta-galactoside-binding lectin, plays a pivotal role in various cellular processes, including immune responses, inflammation, and cancer progression. This comprehensive review aims to elucidate the multifaceted functions of Gal-3, starting with its crucial involvement in viral entry through facilitating viral attachment and catalyzing internalization. Furthermore, Gal-3 assumes significant roles in modulating immune responses, encompassing the activation and recruitment of immune cells, regulation of immune signaling pathways, and orchestration of cellular processes such as apoptosis and autophagy. The impact of Gal-3 extends to the viral life cycle, encompassing critical phases such as replication, assembly, and release. Notably, Gal-3 also contributes to viral pathogenesis, demonstrating involvement in tissue damage, inflammation, and viral persistence and latency elements. A detailed examination of specific viral diseases, including SARS-CoV-2, HIV, and influenza A, underscores the intricate role of Gal-3 in modulating immune responses and facilitating viral adherence and entry. Moreover, the potential of Gal-3 as a biomarker for disease severity, particularly in COVID-19, is considered. Gaining further insight into the mechanisms and roles of Gal-3 in these infections could pave the way for the development of innovative treatment and prevention options for a wide range of viral diseases.


Subject(s)
COVID-19 , Virus Diseases , Humans , Galectin 3/metabolism , SARS-CoV-2/metabolism , Galectins/metabolism , Virus Diseases/metabolism , Inflammation , Host-Pathogen Interactions
3.
PLoS Pathog ; 18(1): e1010171, 2022 01.
Article in English | MEDLINE | ID: covidwho-2327858

ABSTRACT

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , Lung/virology , SARS-CoV-2/physiology , Virus Internalization , Adult , Animals , Antiviral Agents/pharmacology , COVID-19/immunology , COVID-19/pathology , Cells, Cultured , Chlorocebus aethiops , Drug Evaluation, Preclinical , Drugs, Investigational/pharmacology , Drugs, Investigational/therapeutic use , HEK293 Cells , Host-Pathogen Interactions/drug effects , Humans , Inflammation/pathology , Inflammation/therapy , Inflammation/virology , Lung/pathology , SARS-CoV-2/drug effects , Vero Cells , Virus Internalization/drug effects
4.
Adv Protein Chem Struct Biol ; 133: 231-269, 2023.
Article in English | MEDLINE | ID: covidwho-2323960

ABSTRACT

Secretory proteins are playing important role during the host-pathogen interaction to develop the infection or protection into the cell. Pathogens developing infectious disease to human being are taken up by host macrophages or number of immune cells, play an important role in physiological, developmental and immunological function. At the same time, infectious agents are also secreting various proteins to neutralize the resistance caused by host cells and also helping the pathogens to develop the infection. Secretory proteins (secretome) are only developed at the time of host-pathogen interaction, therefore they become very important to develop the targeted and potential therapeutic strategies. Pathogen specific secretory proteins released during interaction with host cell provide opportunity to develop point of care and rapid diagnostic kits. Proteins secreted by pathogens at the time of interaction with host cell have also been found as immunogenic in nature and numbers of vaccines have been developed to control the spread of human infectious diseases. This chapter highlights the importance of secretory proteins in the development of diagnostic and therapeutic strategies to fight against human infectious diseases.


Subject(s)
Communicable Diseases , Vaccines , Humans , Host-Pathogen Interactions , Macrophages , Communicable Diseases/diagnosis , Communicable Diseases/therapy
7.
Viruses ; 14(1)2021 12 27.
Article in English | MEDLINE | ID: covidwho-2307471

ABSTRACT

The COVID-19 pandemic has been a public health issue around the world in the last few years. Currently, there is no specific antiviral treatment to fight the disease. Thus, it is essential to highlight possible prognostic predictors that could identify patients with a high risk of developing complications. Within this framework, miRNA biomolecules play a vital role in the genetic regulation of various genes, principally, those related to the pathophysiology of the disease. Here, we review the interaction of host and viral microRNAs with molecular and cellular elements that could potentiate the main pulmonary, cardiac, renal, circulatory, and neuronal complications in COVID-19 patients. miR-26a, miR-29b, miR-21, miR-372, and miR-2392, among others, have been associated with exacerbation of the inflammatory process, increasing the risk of a cytokine storm. In addition, increased expression of miR-15b, -199a, and -491 are related to the prognosis of the disease, and miR-192 and miR-323a were identified as clinical predictors of mortality in patients admitted to the intensive care unit. Finally, we address miR-29, miR-122, miR-155, and miR-200, among others, as possible therapeutic targets. However, more studies are required to confirm these findings.


Subject(s)
COVID-19 Drug Treatment , COVID-19/diagnosis , MicroRNAs/genetics , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , COVID-19/complications , COVID-19/genetics , Drug Delivery Systems , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Inflammation , MicroRNAs/administration & dosage , Prognosis , RNA, Viral/genetics , SARS-CoV-2/drug effects , SARS-CoV-2/genetics
8.
Int J Mol Sci ; 24(4)2023 Feb 17.
Article in English | MEDLINE | ID: covidwho-2287597

ABSTRACT

Plastic pollution is a significant problem worldwide because of the risks it poses to the equilibrium and health of the environment as well as to human beings. Discarded plastic released into the environment can degrade into microplastics (MPs) due to various factors, such as sunlight, seawater flow, and temperature. MP surfaces can act as solid scaffolds for microorganisms, viruses, and various biomolecules (such as LPS, allergens, and antibiotics), depending on the MP characteristics of size/surface area, chemical composition, and surface charge. The immune system has efficient recognition and elimination mechanisms for pathogens, foreign agents, and anomalous molecules, including pattern recognition receptors and phagocytosis. However, associations with MPs can modify the physical, structural, and functional characteristics of microbes and biomolecules, thereby changing their interactions with the host immune system (in particular with innate immune cells) and, most likely, the features of the subsequent innate/inflammatory response. Thus, exploring differences in the immune response to microbial agents that have been modified by interactions with MPs is meaningful in terms of identifying new possible risks to human health posed by anomalous stimulation of immune reactivities.


Subject(s)
Microplastics , Water Pollutants, Chemical , Humans , Plastics , Seawater/chemistry , Host-Pathogen Interactions , Immunity , Water Pollutants, Chemical/analysis , Environmental Monitoring
9.
Int J Mol Sci ; 24(4)2023 Feb 16.
Article in English | MEDLINE | ID: covidwho-2287228

ABSTRACT

Porcine epidemic diarrhea (PED) is an acute and severe atrophic enteritis caused by porcine epidemic diarrhea virus (PEDV) that infects pigs and makes huge economic losses to the global swine industry. Previously, researchers have believed that porcine aminopeptidase-N (pAPN) was the primary receptor for PEDV, but it has been found that PEDV can infect pAPN knockout pigs. Currently, the functional receptor for PEDV remains unspecified. In the present study, we performed virus overlay protein binding assay (VOPBA), found that ATP1A1 was the highest scoring protein in the mass spectrometry results, and confirmed that the CT structural domain of ATP1A1 interacts with PEDV S1. First, we investigated the effect of ATP1A1 on PEDV replication. Inhibition of hosts ATP1A1 protein expression using small interfering RNA (siRNAs) significantly reduced the cells susceptibility to PEDV. The ATP1A1-specific inhibitors Ouabain (a cardiac steroid) and PST2238 (a digitalis toxin derivative), which specifically bind ATP1A1, could block the ATP1A1 protein internalization and degradation, and consequently reduce the infection rate of host cells by PEDV significantly. Additionally, as expected, overexpression of ATP1A1 notably enhanced PEDV infection. Next, we observed that PEDV infection of target cells resulted in upregulation of ATP1A1 at the mRNA and protein levels. Furthermore, we found that the host protein ATP1A1 was involved in PEDV attachment and co-localized with PEDV S1 protein in the early stage of infection. In addition, pretreatment of IPEC-J2 and Vero-E6 cells with ATP1A1 mAb significantly reduced PEDV attachment. Our observations provided a perspective on identifying key factors in PEDV infection, and may provide valuable targets for PEDV infection, PEDV functional receptor, related pathogenesis, and the development of new antiviral drugs.


Subject(s)
Coronavirus Infections , Host-Pathogen Interactions , Porcine epidemic diarrhea virus , Sodium-Potassium-Exchanging ATPase , Swine Diseases , Animals , CD13 Antigens/metabolism , Chlorocebus aethiops , Porcine epidemic diarrhea virus/physiology , Receptors, Virus/metabolism , RNA, Double-Stranded , RNA, Small Interfering , Swine , Swine Diseases/metabolism , Vero Cells , Virus Attachment , Coronavirus Infections/metabolism , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Sodium-Potassium-Exchanging ATPase/metabolism
11.
Adv Exp Med Biol ; 1406: 19-39, 2023.
Article in English | MEDLINE | ID: covidwho-2257734

ABSTRACT

The core of biomedical science is the use of laboratory techniques to support the diagnosis and treatment of disease in clinical settings. Despite tremendous advancement in our understanding of medicine in recent years, we are still far from having a complete understanding of human physiology in homeostasis, let alone the pathology of disease states. Indeed medical advances over the last two hundred years would not have been possible without the invention of and continuous development of visualisation techniques available to research scientists and clinicians. As we have all learned from the recent COVID pandemic, despite advances in modern medicine we still have much to learn regarding infection biology. Indeed antimicrobial resistant (AMR) bacteria are a global threat to human health, meaning research into bacterial pathogenesis is vital. In this chapter, we will briefly describe the nature of microbes and host immune responses before delving into some of the visualisation techniques utilised in the field of biomedical research with a focus on host-pathogen interactions. We will give a brief overview of commonly used techniques from gold standard staining methods, in situ hybridisation, microscopy, western blotting, microbial characterisation, to cutting-edge image flow cytometry and mass spectrometry. Specifically, we will focus on techniques utilised to visualise interactions between the host, our own bodies, and invading organisms including bacteria. We will touch on in vitro and ex vivo modelling methodology with examples utilised to delineate pathogenicity in disease. A better understanding of bacterial biology, immunology and how these fields interact (host-pathogen communications) in biomedical research is integral to developing novel therapeutic approaches which circumvent the need for antibiotics, an important issue as we enter a post-antibiotic era.


Subject(s)
COVID-19 , Humans , Bacteria , Host-Pathogen Interactions , Anti-Bacterial Agents
12.
PLoS Biol ; 21(1): e3001693, 2023 01.
Article in English | MEDLINE | ID: covidwho-2266404

ABSTRACT

RNA recombination in positive-strand RNA viruses is a molecular-genetic process, which permits the greatest evolution of the genome and may be essential to stabilizing the genome from the deleterious consequences of accumulated mutations. Enteroviruses represent a useful system to elucidate the details of this process. On the biochemical level, it is known that RNA recombination is catalyzed by the viral RNA-dependent RNA polymerase using a template-switching mechanism. For this mechanism to function in cells, the recombining genomes must be located in the same subcellular compartment. How a viral genome is trafficked to the site of genome replication and recombination, which is membrane associated and isolated from the cytoplasm, is not known. We hypothesized that genome translation was essential for colocalization of genomes for recombination. We show that complete inactivation of internal ribosome entry site (IRES)-mediated translation of a donor enteroviral genome enhanced recombination instead of impairing it. Recombination did not occur by a nonreplicative mechanism. Rather, sufficient translation of the nonstructural region of the genome occurred to support subsequent steps required for recombination. The noncanonical translation initiation factors, eIF2A and eIF2D, were required for IRES-independent translation. Our results support an eIF2A/eIF2D-dependent mechanism under conditions in which the eIF2-dependent mechanism is inactive. Detection of an IRES-independent mechanism for translation of the enterovirus genome provides an explanation for a variety of debated observations, including nonreplicative recombination and persistence of enteroviral RNA lacking an IRES. The existence of an eIF2A/eIF2D-dependent mechanism in enteroviruses predicts the existence of similar mechanisms in other viruses.


Subject(s)
Enterovirus Infections , Enterovirus , Humans , Enterovirus/physiology , Enterovirus Infections/virology , Internal Ribosome Entry Sites , Peptide Initiation Factors/genetics , Protein Biosynthesis , RNA, Viral/genetics , RNA, Viral/metabolism , Host-Pathogen Interactions
13.
Adv Exp Med Biol ; 1406: 41-57, 2023.
Article in English | MEDLINE | ID: covidwho-2276611

ABSTRACT

INTRODUCTION: In addition to affecting the upper respiratory tract, severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2) can target kidneys resulting in disease impact. There is a lack of effective treatment for SARs-CoV and SARS-CoV-2, and so one approach could be to consider to lower the probable risk and onset of disease amongst immunocompromised and immunosuppressed individuals and patients. Angiotensin Converting Enzyme 2 (ACE2) has a promising impact including acting against SARs-CoV and SARS-CoV-2 symptoms. Current literature states that ACE2 is expressed across several physiological systems, including the lungs, cardiovascular, gut, kidneys, and central nervous, and across endothelia. AIMS: This chapter seeks to investigate causes and potential mechanisms during SARS infection (CoV-2), renal interaction, and the effects of acute kidney Injury (AKI). OBJECTIVES: This chapter will provide an overview of microscopy and visualization of host-pathogen communication and principles of ACE2 in the context of immunology and impact on renal pathophysiology. DESIGN: This chapter focuses to provide basic principles of ACE2 and the analysis and effect of immunology and pathological components important in relation to SARs infection. DISCUSSION: There has been a surge in literature surrounding mechanisms attributing to SARS-CoV and SARS-CoV-2 action on immune response to pathogens. There is an advantage to implementing ACE2 treatment to improve immune response against infection. CONCLUSION: ACE2 may provide appropriate strategies for the management of symptoms that relate to SARS-CoV and SARS-CoV-2 in most immunocompromised or immunosuppressed patients. Visualization of ACE2 action can be achieved through microscopy to understand host-pathogen communication.


Subject(s)
COVID-19 , Kidney Diseases , Severe acute respiratory syndrome-related coronavirus , Humans , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Peptidyl-Dipeptidase A , Microscopy , Host-Pathogen Interactions
14.
Front Immunol ; 13: 1066733, 2022.
Article in English | MEDLINE | ID: covidwho-2288033

ABSTRACT

COVID-19 often manifests with different outcomes in different patients, highlighting the complexity of the host-pathogen interactions involved in manifestations of the disease at the molecular and cellular levels. In this paper, we propose a set of postulates and a framework for systematically understanding complex molecular host-pathogen interaction networks. Specifically, we first propose four host-pathogen interaction (HPI) postulates as the basis for understanding molecular and cellular host-pathogen interactions and their relations to disease outcomes. These four postulates cover the evolutionary dispositions involved in HPIs, the dynamic nature of HPI outcomes, roles that HPI components may occupy leading to such outcomes, and HPI checkpoints that are critical for specific disease outcomes. Based on these postulates, an HPI Postulate and Ontology (HPIPO) framework is proposed to apply interoperable ontologies to systematically model and represent various granular details and knowledge within the scope of the HPI postulates, in a way that will support AI-ready data standardization, sharing, integration, and analysis. As a demonstration, the HPI postulates and the HPIPO framework were applied to study COVID-19 with the Coronavirus Infectious Disease Ontology (CIDO), leading to a novel approach to rational design of drug/vaccine cocktails aimed at interrupting processes occurring at critical host-coronavirus interaction checkpoints. Furthermore, the host-coronavirus protein-protein interactions (PPIs) relevant to COVID-19 were predicted and evaluated based on prior knowledge of curated PPIs and domain-domain interactions, and how such studies can be further explored with the HPI postulates and the HPIPO framework is discussed.


Subject(s)
COVID-19 , Humans , Host-Pathogen Interactions
15.
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
17.
Nucleic Acids Res ; 50(D1): D497-D508, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-2232151

ABSTRACT

Almost twenty years after its initial release, the Eukaryotic Linear Motif (ELM) resource remains an invaluable source of information for the study of motif-mediated protein-protein interactions. ELM provides a comprehensive, regularly updated and well-organised repository of manually curated, experimentally validated short linear motifs (SLiMs). An increasing number of SLiM-mediated interactions are discovered each year and keeping the resource up-to-date continues to be a great challenge. In the current update, 30 novel motif classes have been added and five existing classes have undergone major revisions. The update includes 411 new motif instances mostly focused on cell-cycle regulation, control of the actin cytoskeleton, membrane remodelling and vesicle trafficking pathways, liquid-liquid phase separation and integrin signalling. Many of the newly annotated motif-mediated interactions are targets of pathogenic motif mimicry by viral, bacterial or eukaryotic pathogens, providing invaluable insights into the molecular mechanisms underlying infectious diseases. The current ELM release includes 317 motif classes incorporating 3934 individual motif instances manually curated from 3867 scientific publications. ELM is available at: http://elm.eu.org.


Subject(s)
Communicable Diseases/genetics , Databases, Protein , Host-Pathogen Interactions/genetics , Protein Interaction Domains and Motifs , Software , Actin Cytoskeleton/chemistry , Actin Cytoskeleton/metabolism , Animals , Binding Sites , Cell Cycle/genetics , Cell Membrane/chemistry , Cell Membrane/metabolism , Communicable Diseases/metabolism , Communicable Diseases/virology , Cyclins/chemistry , Cyclins/genetics , Cyclins/metabolism , Eukaryotic Cells/cytology , Eukaryotic Cells/metabolism , Eukaryotic Cells/virology , Gene Expression Regulation , Humans , Integrins/chemistry , Integrins/genetics , Integrins/metabolism , Mice , Molecular Sequence Annotation , Protein Binding , Rats , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Signal Transduction , Transport Vesicles/chemistry , Transport Vesicles/metabolism , Viruses/genetics , Viruses/metabolism
19.
J Immunol ; 210(3): 335-347, 2023 02 01.
Article in English | MEDLINE | ID: covidwho-2201460

ABSTRACT

Melanoma differentiation-associated gene 5 (MDA5), a member of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), has pivotal roles in innate immune responses against many positive-stranded RNA viruses, including picornavirus and coronavirus. Upon engagement with dsRNA derived from viral infection, MDA5 initiates coordinated signal transduction leading to type I IFN induction to restrict viral replication. In this study, we describe a targeted cleavage events of MDA5 by the 3C protease from Theilovirus. Upon ectopic expression of theilovirus 3C protease from Saffold virus or Theiler's murine encephalomyelitis virus but not encephalomyocarditis virus, fragments of cleaved MDA5 were observed in a dose-dependent manner. When enzymatically inactive Theilovirus 3C protease was expressed, MDA5 cleavage was completely abrogated. Mass spectrometric analysis identified two cleavage sites at the C terminus of MDA5, cleaving off one of the RNA-binding domains. The same cleavage pattern was observed during Theilovirus infection. The cleavage of MDA5 by Theilovirus protease impaired ATP hydrolysis, RNA binding, and filament assembly on RNA, resulting in dysfunction of MDA5 as an innate immune RNA sensor for IFN induction. Furthermore, the cleavage-resistant MDA5 mutant against the 3C protease showed an enhanced IFN response during Saffold virus infection, indicating that Theilovirus has a strategy to circumvent the antiviral immune response by cleaving MDA5 using 3C protease. In summary, these data suggest MDA5 cleavage by 3C protease as a novel immune evasive strategy of Theilovirus.


Subject(s)
Interferon-Induced Helicase, IFIH1 , RNA, Double-Stranded , Theilovirus , Animals , Mice , Cysteine Endopeptidases/genetics , Host-Pathogen Interactions , Immunity, Innate , Interferon Type I/metabolism , Interferon-Induced Helicase, IFIH1/genetics , Interferon-Induced Helicase, IFIH1/metabolism , Peptide Hydrolases/metabolism , RNA, Double-Stranded/immunology , RNA, Double-Stranded/metabolism
20.
Nat Commun ; 13(1): 7907, 2022 12 23.
Article in English | MEDLINE | ID: covidwho-2185829

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung epithelium. Mechanistically, MT1-MMP directly cleaves memACE2 at M706-S to release solACE218-706 that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE218-706 enables SARS-CoV-2 infection in both non-permissive cells and naturally insusceptible C57BL/6 mice. Inhibition of MT1-MMP activities suppresses solACE2-directed entry of SARS-CoV-2 in human organoids and aged mice. Both solACE2 and circulating MT1-MMP are positively correlated in plasma of aged mice and humans. Our findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Host-Pathogen Interactions , Matrix Metalloproteinase 14 , SARS-CoV-2 , Animals , Humans , Mice , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/virology , Mice, Inbred C57BL , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism
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