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1.
Sci Adv ; 9(23): eadg2248, 2023 06 09.
Article in English | MEDLINE | ID: covidwho-20239375

ABSTRACT

Numerous viruses use specialized surface molecules called fusogens to enter host cells. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and are associated with severe neurological symptoms through poorly understood mechanisms. We show that SARS-CoV-2 infection induces fusion between neurons and between neurons and glia in mouse and human brain organoids. We reveal that this is caused by the viral fusogen, as it is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that neuronal fusion is a progressive event, leads to the formation of multicellular syncytia, and causes the spread of large molecules and organelles. Last, using Ca2+ imaging, we show that fusion severely compromises neuronal activity. These results provide mechanistic insights into how SARS-CoV-2 and other viruses affect the nervous system, alter its function, and cause neuropathology.


Subject(s)
COVID-19 , Animals , Humans , Mice , SARS-CoV-2/physiology , Neurons , Brain , Neuroglia
2.
Viruses ; 15(5)2023 05 06.
Article in English | MEDLINE | ID: covidwho-20236421

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has given rise to many new variants with increased transmissibility and the ability to evade vaccine protection. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone that has been recently implicated as an essential host factor for SARS-CoV-2 entry and infection. In this study, we investigated the efficacy of YUM70, a small molecule inhibitor of GRP78, to block SARS-CoV-2 viral entry and infection in vitro and in vivo. Using human lung epithelial cells and pseudoviral particles carrying spike proteins from different SARS-CoV-2 variants, we found that YUM70 was equally effective at blocking viral entry mediated by original and variant spike proteins. Furthermore, YUM70 reduced SARS-CoV-2 infection without impacting cell viability in vitro and suppressed viral protein production following SARS-CoV-2 infection. Additionally, YUM70 rescued the cell viability of multi-cellular human lung and liver 3D organoids transfected with a SARS-CoV-2 replicon. Importantly, YUM70 treatment ameliorated lung damage in transgenic mice infected with SARS-CoV-2, which correlated with reduced weight loss and longer survival. Thus, GRP78 inhibition may be a promising approach to augment existing therapies to block SARS-CoV-2, its variants, and other viruses that utilize GRP78 for entry and infection.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Mice , Humans , SARS-CoV-2/physiology , Endoplasmic Reticulum Chaperone BiP , Virus Internalization , Spike Glycoprotein, Coronavirus , Pandemics , Lung
3.
Front Immunol ; 14: 1185233, 2023.
Article in English | MEDLINE | ID: covidwho-20244458

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a contagious respiratory virus that is the cause of the coronavirus disease 2019 (COVID-19) pandemic which has posed a serious threat to public health. COVID-19 is characterized by a wide spectrum of clinical manifestations, ranging from asymptomatic infection to mild cold-like symptoms, severe pneumonia or even death. Inflammasomes are supramolecular signaling platforms that assemble in response to danger or microbial signals. Upon activation, inflammasomes mediate innate immune defense by favoring the release of proinflammatory cytokines and triggering pyroptotic cell death. Nevertheless, abnormalities in inflammasome functioning can result in a variety of human diseases such as autoimmune disorders and cancer. A growing body of evidence has showed that SARS-CoV-2 infection can induce inflammasome assembly. Dysregulated inflammasome activation and consequent cytokine burst have been associated with COVID-19 severity, alluding to the implication of inflammasomes in COVID-19 pathophysiology. Accordingly, an improved understanding of inflammasome-mediated inflammatory cascades in COVID-19 is essential to uncover the immunological mechanisms of COVID-19 pathology and identify effective therapeutic approaches for this devastating disease. In this review, we summarize the most recent findings on the interplay between SARS-CoV-2 and inflammasomes and the contribution of activated inflammasomes to COVID-19 progression. We dissect the mechanisms involving the inflammasome machinery in COVID-19 immunopathogenesis. In addition, we provide an overview of inflammasome-targeted therapies or antagonists that have potential clinical utility in COVID-19 treatment.


Subject(s)
COVID-19 , Humans , Inflammasomes/metabolism , SARS-CoV-2/physiology , COVID-19 Drug Treatment , Cytokines
4.
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
5.
Curr Opin Allergy Clin Immunol ; 21(1): 8-15, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-2326975

ABSTRACT

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly become a great public health hazard globally. Nasal epithelial cells are an important site for SARS-CoV-2 infection and replication. The purpose of this review is to summarize recent findings on the endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) and the potential impact of SARS-CoV-2 infection. RECENT FINDINGS: Endotypes of CRSwNP are characterized by type 1, type 2 and type 3 inflammation according to patterns of inflammatory cells and the cytokines expressed in nasal tissue. Nasal epithelial cells show the highest expression of angiotensin-converting enzyme 2 (ACE2), the receptor for attachment and entry of SARS-CoV-2 into host cells, among all investigated cells in the respiratory tree. SARS-CoV-2 infection likely leads to increased activation of T-helper-1 (Th1) cell responses. Recent studies further suggest that ACE2 may be upregulated by type 1 and downregulated by type 2 inflammatory cytokines in nasal epithelial cells. SUMMARY: Expression of ACE2 in nasal epithelial cells is influenced by inflammatory endotypes of CRSwNP. Type 1 inflammation in nasal tissue may increase the risk of SARS-CoV-2 infection by upregulating ACE2 expression. However, clinical association between CRSwNP and COVID-19 is still unclear.


Subject(s)
COVID-19/epidemiology , Nasal Polyps/epidemiology , Rhinitis/epidemiology , SARS-CoV-2/physiology , Sinusitis/epidemiology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , COVID-19/virology , Comorbidity , Goblet Cells/immunology , Humans , Inflammation/immunology , Nasal Polyps/immunology , Rhinitis/immunology , Risk Factors , Sinusitis/immunology , Virus Internalization
6.
Sci Rep ; 13(1): 7162, 2023 05 03.
Article in English | MEDLINE | ID: covidwho-2316264

ABSTRACT

Coronavirus disease (COVID-19) has generated interest in the assessment of systemic immune status, but existing knowledge about mucosal immunity is clearly insufficient to understand the full pathogenetic mechanisms of the disease. The aim of this study was to evaluate the long-term effects of novel coronavirus infection on mucosal immunity in the postinfection period among health care workers (HCWs). A total of 180 health care workers with and without a history of COVID-19 who ranged in age from 18 to 65 years were enrolled in this one-stage, cross-sectional study. The study subjects completed the 36-Item Short Form (36) Health Survey (SF-36) and the Fatigue Assessment Scale. Secretory immunoglobulin A (sIgA) and total immunoglobulin G (IgG) levels were quantified in saliva samples, induced sputum samples, and nasopharyngeal and oropharyngeal scrapings by an enzyme-linked immunosorbent assay. Specific anti-SARS-CoV-2 IgG antibodies were quantified in serum samples by chemiluminescence immunoassay. Analysis of the questionnaire data showed that all HCWs with a history of COVID-19 reported health problems that limited their daily activities and negative changes in their emotional health three months after the disease, regardless of its severity. The following shifts were detected in the adaptive arm of the immune response in different mucosal compartments. Among subjects who had severe or moderate-to-severe COVID-19, salivary sIgA levels were significantly higher than those in the control group (p < 0.05 and p < 0.005, respectively). Compared to the subjects in the control group, all subjects with prior COVID-19 had significantly higher levels of total IgG in induced sputum. In the group of patients who had had severe infection, total IgG in saliva was also higher (p < 0.05). A direct statistically significant correlation was also detected between the levels of total IgG in all studied samples and the levels of specific IgG antibodies against SARS-CoV-2 in the serum. A significant correlation was observed between total IgG levels and the parameters of physical and social activities, mental health, and fatigue levels. Our study demonstrated long-term changes in the humoral mucosal immune response, which were most pronounced in health care workers with a history of severe or moderate-to-severe COVID-19, and an association of these changes with certain clinical signs of post-COVID-19 syndrome.


Subject(s)
COVID-19 , Health Personnel , Immunity, Mucosal , Russia , COVID-19/immunology , COVID-19/pathology , COVID-19/physiopathology , Humans , Young Adult , Adult , Middle Aged , Immunoglobulin A/analysis , Respiratory System/immunology , Antibodies, Viral/analysis , Severity of Illness Index , Immunoglobulin G/analysis , SARS-CoV-2/physiology
7.
J Virol ; 97(5): e0199222, 2023 05 31.
Article in English | MEDLINE | ID: covidwho-2319107

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to cell surface receptors and is activated for membrane fusion and cell entry via proteolytic cleavage. Phenomenological data have shown that SARS-CoV-2 can be activated for entry at either the cell surface or in endosomes, but the relative roles in different cell types and mechanisms of entry have been debated. Here, we used single-virus fusion experiments and exogenously controlled proteases to probe activation directly. We found that plasma membrane and an appropriate protease are sufficient to support SARS-CoV-2 pseudovirus fusion. Furthermore, fusion kinetics of SARS-CoV-2 pseudoviruses are indistinguishable no matter which of a broad range of proteases is used to activate the virus. This suggests that the fusion mechanism is insensitive to protease identity or even whether activation occurs before or after receptor binding. These data support a model for opportunistic fusion by SARS-CoV-2 in which the subcellular location of entry likely depends on the differential activity of airway, cellsurface, and endosomal proteases, but all support infection. Inhibition of any single host protease may thus reduce infection in some cells but may be less clinically robust. IMPORTANCE SARS-CoV-2 can use multiple pathways to infect cells, as demonstrated recently when new viral variants switched dominant infection pathways. Here, we used single-virus fusion experiments together with biochemical reconstitution to show that these multiple pathways coexist simultaneously and specifically that the virus can be activated by different proteases in different cellular compartments with mechanistically identical effects. The consequences of this are that the virus is evolutionarily plastic and that therapies targeting viral entry should address multiple pathways at once to achieve optimal clinical effects.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Cell Membrane/metabolism , COVID-19/virology , Peptide Hydrolases/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
8.
Proc Natl Acad Sci U S A ; 119(32): e2205690119, 2022 08 09.
Article in English | MEDLINE | ID: covidwho-2311515

ABSTRACT

The furin cleavage site (FCS), an unusual feature in the SARS-CoV-2 spike protein, has been spotlighted as a factor key to facilitating infection and pathogenesis by increasing spike processing. Similarly, the QTQTN motif directly upstream of the FCS is also an unusual feature for group 2B coronaviruses (CoVs). The QTQTN deletion has consistently been observed in in vitro cultured virus stocks and some clinical isolates. To determine whether the QTQTN motif is critical to SARS-CoV-2 replication and pathogenesis, we generated a mutant deleting the QTQTN motif (ΔQTQTN). Here, we report that the QTQTN deletion attenuates viral replication in respiratory cells in vitro and attenuates disease in vivo. The deletion results in a shortened, more rigid peptide loop that contains the FCS and is less accessible to host proteases, such as TMPRSS2. Thus, the deletion reduced the efficiency of spike processing and attenuates SARS-CoV-2 infection. Importantly, the QTQTN motif also contains residues that are glycosylated, and disruption of its glycosylation also attenuates virus replication in a TMPRSS2-dependent manner. Together, our results reveal that three aspects of the S1/S2 cleavage site-the FCS, loop length, and glycosylation-are required for efficient SARS-CoV-2 replication and pathogenesis.


Subject(s)
COVID-19 , Furin , Proteolysis , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Amino Acid Motifs/genetics , Animals , COVID-19/virology , Chlorocebus aethiops , Furin/chemistry , Humans , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Sequence Deletion , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vero Cells , Virus Replication/genetics
9.
Health Promot Pract ; 22(2): 152-155, 2021 03.
Article in English | MEDLINE | ID: covidwho-2292983

ABSTRACT

To limit the spread of coronavirus disease 2019 (COVID-19), the Centers for Disease Control and Prevention issued recommendations that individuals wear face masks in public. Despite these recommendations, the individual decision to adhere and wear a mask may not be a simple decision. In this article, we examine the decision to wear a mask from a social-ecological perspective. Through critical analysis of societal, interpersonal and community, and intrapersonal influences, it is clear that the decision to wear a mask is multifaceted and influenced by constructs including public health recommendations and government mandates, racism and cultural norms, geography, household income, age, and personal attitudes. Understanding the multifactorial influences on mask wearing during COVID-19 is crucial for informing the creation and distribution of inclusive public health messaging regarding mask wearing now in the midst of an unprecedented health crisis, and in future unforeseen public health emergencies.


Subject(s)
COVID-19/prevention & control , Masks , COVID-19/epidemiology , COVID-19/transmission , Communicable Disease Control , Humans , Mandatory Programs , SARS-CoV-2/physiology , Social Environment , United States/epidemiology
10.
Sci Signal ; 16(782): eabq1366, 2023 04 25.
Article in English | MEDLINE | ID: covidwho-2298370

ABSTRACT

Macrophages are key cellular contributors to the pathogenesis of COVID-19, the disease caused by the virus SARS-CoV-2. The SARS-CoV-2 entry receptor ACE2 is present only on a subset of macrophages at sites of SARS-CoV-2 infection in humans. Here, we investigated whether SARS-CoV-2 can enter macrophages, replicate, and release new viral progeny; whether macrophages need to sense a replicating virus to drive cytokine release; and, if so, whether ACE2 is involved in these mechanisms. We found that SARS-CoV-2 could enter, but did not replicate within, ACE2-deficient human primary macrophages and did not induce proinflammatory cytokine expression. By contrast, ACE2 overexpression in human THP-1-derived macrophages permitted SARS-CoV-2 entry, processing and replication, and virion release. ACE2-overexpressing THP-1 macrophages sensed active viral replication and triggered proinflammatory, antiviral programs mediated by the kinase TBK-1 that limited prolonged viral replication and release. These findings help elucidate the role of ACE2 and its absence in macrophage responses to SARS-CoV-2 infection.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/genetics , Cytokines , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Macrophages/metabolism , Virion/metabolism
11.
J Virol ; 97(4): e0014423, 2023 04 27.
Article in English | MEDLINE | ID: covidwho-2297692

ABSTRACT

2019 coronavirus disease (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to respiratory illness, COVID-19 patients exhibit neurological symptoms lasting from weeks to months (long COVID). It is unclear whether these neurological manifestations are due to an infection of brain cells. We found that a small fraction of human induced pluripotent stem cell (iPSC)-derived neurons, but not astrocytes, were naturally susceptible to SARS-CoV-2. Based on the inhibitory effect of blocking antibodies, the infection seemed to depend on the receptor angiotensin-converting enzyme 2 (ACE2), despite very low levels of its expression in neurons. The presence of double-stranded RNA in the cytoplasm (the hallmark of viral replication), abundant synthesis of viral late genes localized throughout infected cells, and an increase in the level of viral RNA in the culture medium (viral release) within the first 48 h of infection suggested that the infection was productive. Productive entry of SARS-CoV-2 requires the fusion of the viral and cellular membranes, which results in the delivery of the viral genome into the cytoplasm of the target cell. The fusion is triggered by proteolytic cleavage of the viral surface spike protein, which can occur at the plasma membrane or from endosomes or lysosomes. We found that SARS-CoV-2 infection of human neurons was insensitive to nafamostat and camostat, which inhibit cellular serine proteases, including transmembrane serine protease 2 (TMPRSS2). Inhibition of cathepsin L also did not significantly block infection. In contrast, the neuronal infection was blocked by apilimod, an inhibitor of phosphatidyl-inositol 5 kinase (PIK5K), which regulates early to late endosome maturation. IMPORTANCE COVID-19 is a disease caused by the coronavirus SARS-CoV-2. Millions of patients display neurological symptoms, including headache, impairment of memory, seizures, and encephalopathy, as well as anatomical abnormalities, such as changes in brain morphology. SARS-CoV-2 infection of the human brain has been documented, but it is unclear whether the observed neurological symptoms are linked to direct brain infection. The mechanism of virus entry into neurons has also not been characterized. Here, we investigated SARS-CoV-2 infection by using a human iPSC-derived neural cell model and found that a small fraction of cortical-like neurons was naturally susceptible to infection. The productive infection was ACE2 dependent and TMPRSS2 independent. We also found that the virus used the late endosomal and lysosomal pathway for cell entry and that the infection could be blocked by apilimod, an inhibitor of cellular PIK5K.


Subject(s)
COVID-19 , Induced Pluripotent Stem Cells , SARS-CoV-2 , Humans , Angiotensin-Converting Enzyme 2 , COVID-19/physiopathology , Endosomes/metabolism , Endosomes/virology , Induced Pluripotent Stem Cells/metabolism , Neurons/metabolism , Neurons/virology , Post-Acute COVID-19 Syndrome/physiopathology , Post-Acute COVID-19 Syndrome/virology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Phosphotransferases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Astrocytes/virology , Cells, Cultured
12.
J Cell Biol ; 222(7)2023 07 03.
Article in English | MEDLINE | ID: covidwho-2305708

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiologic agent for the global COVID-19 pandemic, triggers the formation of endoplasmic reticulum (ER)-derived replication organelles, including double-membrane vesicles (DMVs), in the host cell to support viral replication. Here, we clarify how SARS-CoV-2 hijacks host factors to construct the DMVs. We show that the ER morphogenic proteins reticulon-3 (RTN3) and RTN4 help drive DMV formation, enabling viral replication, which leads to productive infection. Different SARS-CoV-2 variants, including the delta variant, use the RTN-dependent pathway to promote infection. Mechanistically, our results reveal that the membrane-embedded reticulon homology domain (RHD) of the RTNs is sufficient to functionally support viral replication and physically engage NSP3 and NSP4, two viral non-structural membrane proteins known to induce DMV formation. Our findings thus identify the ER morphogenic RTN3 and RTN4 membrane proteins as host factors that help promote the biogenesis of SARS-CoV-2-induced DMVs, which can act as viral replication platforms.


Subject(s)
Endoplasmic Reticulum , Membrane Proteins , Organelles , SARS-CoV-2 , Humans , COVID-19/virology , Endoplasmic Reticulum/virology , Membrane Proteins/metabolism , Pandemics , SARS-CoV-2/physiology , Virus Replication , Organelles/virology , Viral Nonstructural Proteins/metabolism
13.
Animal Model Exp Med ; 6(1): 51-56, 2023 02.
Article in English | MEDLINE | ID: covidwho-2288696

ABSTRACT

BACKGROUND: New Omicron subvariants are emerging rapidly from BA.1 to BA.4 and BA.5. Their pathogenicity has changed from that of wild-type (WH-09) and Omicron variants have over time become globally dominant. The spike proteins of BA.4 and BA.5 that serve as the target for vaccine-induced neutralizing antibodies have also changed compared to the previous subvariants, which is likely to cause immune escape and the reduction of the protective effect of the vaccine. Our study addresses the above issues and provides a basis for formulating relevant prevention and control strategies. METHODS: We collected cellular supernatant and cell lysates and measured the viral titers, viral RNA loads, and E subgenomic RNA (E sgRNA) loads in different Omicron subvariants grown in Vero E6 cells, using WH-09 and Delta variants as a reference. Additionally, we evaluated the in vitro neutralizing activity of different Omicron subvariants and compared it to the WH-09 and Delta variants using macaque sera with different types of immunity. RESULTS: As the SARS-CoV-2 evolved into Omicron BA.1, the replication ability in vitro began to decrease. Then with the emergence of new subvariants, the replication ability gradually recovered and became stable in the BA.4 and BA.5 subvariants. In WH-09-inactivated vaccine sera, geometric mean titers of neutralization antibodies against different Omicron subvariants declined by 3.7~15.4-fold compared to those against WH-09. In Delta-inactivated vaccine sera, geometric mean titers of neutralization antibodies against Omicron subvariants declined by 3.1~7.4-fold compared to those against Delta. CONCLUSION: According to the findings of this research, the replication efficiency of all Omicron subvariants declined compared with WH-09 and Delta variants, and was lower in BA.1 than in other Omicron subvariants. After two doses of inactivated (WH-09 or Delta) vaccine, cross-neutralizing activities against various Omicron subvariants were seen despite a decline in neutralizing titers.


Subject(s)
Antibodies, Neutralizing , COVID-19 , SARS-CoV-2 , Virus Replication , Animals , COVID-19/virology , Macaca , SARS-CoV-2/physiology , Subgenomic RNA
14.
J Virol ; 97(4): e0036523, 2023 04 27.
Article in English | MEDLINE | ID: covidwho-2249386

ABSTRACT

When humans experience a new, devastating viral infection such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), significant challenges arise. How should individuals as well as societies respond to the situation? One of the primary questions concerns the origin of the SARS-CoV-2 virus that infected and was transmitted efficiently among humans, resulting in a pandemic. At first glance, the question appears straightforward to answer. However, the origin of SARS-CoV-2 has been the topic of substantial debate primarily because we do not have access to some relevant data. At least two major hypotheses have been suggested: a natural origin through zoonosis followed by sustained human-to-human spread or the introduction of a natural virus into humans from a laboratory source. Here, we summarize the scientific evidence that informs this debate to provide our fellow scientists and the public with the tools to join the discussion in a constructive and informed manner. Our goal is to dissect the evidence to make it more accessible to those interested in this important problem. The engagement of a broad representation of scientists is critical to ensure that the public and policy-makers can draw on relevant expertise in navigating this controversy.


Subject(s)
COVID-19 , Pandemics , SARS-CoV-2 , Humans , COVID-19/epidemiology , COVID-19/transmission , COVID-19/virology , Laboratories/standards , Research/standards , SARS-CoV-2/classification , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Scientific Experimental Error , Viral Zoonoses/transmission , Viral Zoonoses/virology , Chiroptera/virology , Animals, Wild/virology
15.
J Chem Phys ; 158(11): 114107, 2023 Mar 21.
Article in English | MEDLINE | ID: covidwho-2257419

ABSTRACT

Surfactants are commonly used as disinfection agents in personal care products against bacteria and viruses, including SARS-CoV-2. However, there is a lack of understanding of the molecular mechanisms of the inactivation of viruses by surfactants. Here, we employ coarse grain (CG) and all-atom (AA) molecular dynamics simulations to investigate the interaction between general families of surfactants and the SARS-CoV-2 virus. To this end, we considered a CG model of a full virion. Overall, we found that surfactants have only a small impact on the virus envelope, being inserted into the envelope without dissolving it or generating pores, at the conditions considered here. However, we found that surfactants may induce a deep impact on the spike protein of the virus (responsible for its infectivity), easily covering it and inducing its collapse over the envelope surface of the virus. AA simulations confirmed that both negatively and positively charged surfactants are able to extensively adsorb over the spike protein and get inserted into the virus envelope. Our results suggest that the best strategy for the design of surfactants as virucidal agents will be to focus on those strongly interacting with the spike protein.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/physiology , Molecular Dynamics Simulation , Spike Glycoprotein, Coronavirus/metabolism , Protein Binding
16.
Hamostaseologie ; 43(1): 67-74, 2023 Feb.
Article in English | MEDLINE | ID: covidwho-2280230

ABSTRACT

COVID-19 convalescent plasma (CCP) has been explored as one of the treatment options for COVID-19. Results of many cohort studies and clinical trials have been recently published. At first glance, the results of the CCP studies appear to be inconsistent. However, it became clear that CCP is not beneficial if CCP with low anti-SARS-CoV-2 antibody concentrations is used, if it is administered late in advanced disease stages, and to patients who already mounted an antibody response against SARS-CoV-2 at the time of CCP transfusion. On the other hand, CCP may prevent progression to severe COVID-19 when very high-titer CCP is given early in vulnerable patients. Immune escape of new variants is a challenge for passive immunotherapy. While new variants of concern developed resistance to most clinically used monoclonal antibodies very rapidly, immune plasma from individuals immunized by both a natural SARS-CoV-2 infection and SARS-CoV-2 vaccination retained neutralizing activity against variants. This review briefly summarizes the evidence on CCP treatment to date and identifies further research needs. Ongoing research on passive immunotherapy is not only relevant for improving care for vulnerable patients in the ongoing SARS-CoV-2 pandemic, but even more as a model for passive immunotherapy in case of future pandemics with a newly evolving pathogen. Compared to other drugs, which must be newly developed in a pandemic (e.g., monoclonal antibodies, antiviral drugs), convalescent plasma is rapidly available, inexpensive to produce, and can be adaptive to viral evolution by selection of contemporary convalescent donors.


Subject(s)
COVID-19 , Humans , SARS-CoV-2/physiology , COVID-19 Vaccines , COVID-19 Serotherapy , Antibodies, Monoclonal
17.
EMBO Rep ; 24(4): e56979, 2023 04 05.
Article in English | MEDLINE | ID: covidwho-2253688

ABSTRACT

Entry of SARS-CoV-2 into human respiratory cells, mediated by the spike protein, is absolutely dependent on the cellular receptor ACE2 (angiotensin-converting enzyme-2). This makes ACE2 an attractive target for therapeutic intervention in COVID-19. In this issue, Zuo et al. discover that vitamin C, an essential nutrient and common dietary supplement, can target ACE2 for ubiquitin-dependent degradation, resulting in the inhibition of SARS-CoV-2 infection (Zuo et al, 2023). The study identifies novel mechanisms of cellular ACE2 regulation and may inform the design of therapeutics targeting SARS-2 and related coronaviruses.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2 , Protein Binding
18.
Epidemiol Prev ; 44(5-6): 330-332, 2020.
Article in Italian | MEDLINE | ID: covidwho-2240354

ABSTRACT

Systematic reviews have shown a prevalence close to 20% of gastrointestinal symptoms in COVID-19 positive patients, with nearly 40% of patients shedding viral RNA in their faeces, even if it may not be infectious, possibly because of inactivation by colonic fluid.According to current evidence, this virus is primarily transmitted by respiratory droplets and contact routes, including contaminated surfaces. The virus is quite stable on stainless steel, being detected up to 48-72 hours after application. Therefore, some individuals can be infected touching common contaminated surfaces, such as bathroom taps. Taps can be underestimated critical points in the transmission chain of the infection. Indeed, just by turning the knob, people leave germs on it, especially after coughing over their hands, sneezing, and/or blowing their nose. After handwashing with soap, user take back their germs when turning the knob. Paradoxically, the following user collects the germs back on his/her fingers by implementing a preventive measure, maybe before putting food into the mouth or wearing contact lenses.The Italian National Institute of Health recommends to clean and disinfect high-touched surfaces, but it is unrealistic and inefficient to do so after each tap use. As an alternative, new toilets should install long elbow-levers - or at least short levers - provided that people are educated to close them with the forearm or the side of the hand. This is already a standard measure in hospitals, but it is particularly important also in high-risk communities, such as retirement homes and prisons. It would be important also in schools, in workplaces, and even in families, contributing to the prevention both of orofaecal and respiratory infections.In the meantime, people should be educated to close existing knobs with disposable paper towel wipes or with toilet paper sheets.


Subject(s)
Bathroom Equipment/virology , COVID-19/prevention & control , Fomites/virology , Hand Hygiene , Health Education , SARS-CoV-2/physiology , COVID-19/transmission , Equipment Contamination , Equipment Design , Feces/virology , Female , Humans , Italy , Male , SARS-CoV-2/isolation & purification , Touch
19.
J Virol ; 97(2): e0161122, 2023 02 28.
Article in English | MEDLINE | ID: covidwho-2246230

ABSTRACT

Identification of bona fide functional receptors and elucidation of the mechanism of receptor-mediated virus entry are important to reveal targets for developing therapeutics against rabies virus (RABV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our previous studies suggest that metabotropic glutamate receptor subtype 2 (mGluR2) functions as an entry receptor for RABV in vitro, and is an important internalization factor for SARS-CoV-2 in vitro and in vivo. Here, we demonstrate that mGluR2 facilitates RABV internalization in vitro and infection in vivo. We found that transferrin receptor 1 (TfR1) interacts with mGluR2 and internalizes with mGluR2 and RABV in the same clathrin-coated pit. Knockdown of TfR1 blocks agonist-triggered internalization of mGluR2. Importantly, TfR1 also interacts with the SARS-CoV-2 spike protein and is important for SARS-CoV-2 internalization. Our findings identify a novel axis (mGluR2-TfR1 axis) used by RABV and SARS-CoV-2 for entry, and reveal TfR1 as a potential target for therapeutics against RABV and SARS-CoV-2. IMPORTANCE We previously found that metabotropic glutamate receptor subtype 2 (mGluR2) is an entry receptor for RABV in vitro, and an important internalization factor for SARS-CoV-2 in vitro and in vivo. However, whether mGluR2 is required for RABV infection in vivo was unknown. In addition, how mGluR2 mediates the internalization of RABV and SARS-CoV-2 needed to be resolved. Here, we found that mGluR2 gene knockout mice survived a lethal challenge with RABV. To our knowledge, mGluR2 is the first host factor to be definitively shown to play an important role in RABV street virus infection in vivo. We further found that transferrin receptor protein 1 (TfR1) directly interacts and cooperates with mGluR2 to regulate the endocytosis of RABV and SARS-CoV-2. Our study identifies a novel axis (mGluR2-TfR1 axis) used by RABV and SARS-CoV-2 for entry and opens a new door for the development of therapeutics against RABV and SARS-CoV-2.


Subject(s)
COVID-19 , Rabies virus , Receptors, Metabotropic Glutamate , Receptors, Transferrin , SARS-CoV-2 , Virus Internalization , Animals , Humans , Mice , Rabies/metabolism , Rabies virus/physiology , Receptors, Metabotropic Glutamate/metabolism , Receptors, Transferrin/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism
20.
Rev Med Virol ; 33(2): e2430, 2023 03.
Article in English | MEDLINE | ID: covidwho-2243953

ABSTRACT

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). In less than three years, an estimated 600 million infections with SARS-CoV-2 occurred worldwide, resulting in a pandemic with tremendous impact especially on economic and health sectors. Initially considered a respiratory disease, COVID-19, along with its long-term sequelae (long-COVID) rather is a systemic disease. Neurological symptoms like dementia or encephalopathy were reported early during the pandemic as concomitants of the acute phase and as characteristics of long-COVID. An excessive inflammatory immune response is hypothesized to play a major role in this context. However, direct infection of neural cells may also contribute to the neurological aspects of (long)-COVID-19. To mainly explore such direct effects of SARS-CoV-2 on the central nervous system, human brain organoids provide a useful platform. Infecting these three-dimensional tissue cultures allows the study of viral neurotropism as well as of virus-induced effects on single cells or even the complex cellular network within the organoid. In this review, we summarize the experimental studies that used SARS-CoV-2-infected human brain organoids to unravel the complex nature of (long)-COVID-19-related neurological manifestations.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/physiology , Post-Acute COVID-19 Syndrome , Central Nervous System , Brain , Organoids
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