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1.
Cell Rep ; 39(11): 110954, 2022 Jun 14.
Article in English | MEDLINE | ID: covidwho-1866958

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to shutoff of protein synthesis, and nsp1, a central shutoff factor in coronaviruses, inhibits cellular mRNA translation. However, the diverse molecular mechanisms employed by nsp1 as well as its functional importance are unresolved. By overexpressing various nsp1 mutants and generating a SARS-CoV-2 mutant, we show that nsp1, through inhibition of translation and induction of mRNA degradation, targets translated cellular mRNA and is the main driver of host shutoff during infection. The propagation of nsp1 mutant virus is inhibited exclusively in cells with intact interferon (IFN) pathway as well as in vivo, in hamsters, and this attenuation is associated with stronger induction of type I IFN response. Therefore, although nsp1's shutoff activity is broad, it plays an essential role, specifically in counteracting the IFN response. Overall, our results reveal the multifaceted approach nsp1 uses to shut off cellular protein synthesis and uncover nsp1's explicit role in blocking the IFN response.


Subject(s)
COVID-19 , Viral Nonstructural Proteins , Cell Line , Humans , RNA Stability , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism
2.
Sci Transl Med ; : eabm4908, 2022 May 17.
Article in English | MEDLINE | ID: covidwho-1846321

ABSTRACT

The SARS-CoV-2 B.1.621 (Mu) variant emerged in January 2021 and was categorized as a variant of interest by the World Health Organization in August 2021. This designation prompted us to study the sensitivity of this variant to antibody neutralization. In a live virus neutralization assay with serum samples from individuals vaccinated with the Pfizer/BioNTech or Moderna mRNA vaccines, we measured neutralization antibody titers against B.1.621, an early isolate (spike 614D), and a variant of concern (B.1.351, beta variant). We observed reduced neutralizing antibody titers against the B.1.621 variant (3.4 to 7-fold reduction, depending on the serum sample and time after the second vaccination) compared to the early isolate and a similar reduction when compared to B.1.351. Likewise, convalescent serum from hamsters previously infected with an early isolate neutralized B.1.621 to a lower degree. Despite this antibody titer reduction, hamsters could not be efficiently re-challenged with the B.1.621 variant, suggesting the immune response to the first infection is adequate to provide protection against a subsequent infection with the B.1.621 variant.

3.
Open Forum Infect Dis ; 9(5): ofac158, 2022 May.
Article in English | MEDLINE | ID: covidwho-1831309

ABSTRACT

Background: Singing in an indoor space may increase the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a case-control study of karaoke-related coronavirus disease 2019 (COVID-19) outbreaks to reveal the risk factors for SARS-CoV-2 infection among individuals who participate in karaoke. Methods: Cases were defined as people who enjoyed karaoke at a bar and who tested positive for SARS-CoV-2 by reverse-transcription polymerase chain reaction between 16 May and 3 July 2020. Controls were defined as people who enjoyed karaoke at the same bar during the same period as the cases and tested negative. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. ORs of key variables adjusted for each other were also estimated (aOR). Results: We identified 81 cases, the majority of whom were active elderly individuals (median age, 75 years). Six cases died (case fatality ratio, 7%). Among the cases, 68 (84%) were guests, 18 of whom had visited ≧2 karaoke bars. A genome analysis conducted in 30 cases showed 6 types of isolates within 4 single-nucleotide variation difference. The case-control study revealed that singing (aOR, 11.0 [95% CI, 1.2-101.0]), not wearing a mask (aOR, 3.7 [95% CI, 1.2-11.2]), and additional hour spent per visit (aOR, 1.7 [95% CI, 1.1-2.7]) were associated with COVID-19 infection. Conclusions: A karaoke-related COVID-19 outbreak that occurred in 2 different cities was confirmed by the results of genome analysis. Singing in less-ventilated, indoor and crowded environments increases the risk of acquiring SARS-CoV-2 infection. Wearing a mask and staying for only a short time can reduce the risk of infection during karaoke.

5.
Open forum infectious diseases ; 2022.
Article in English | EuropePMC | ID: covidwho-1787333

ABSTRACT

Background Singing in an indoor space may increase the risk of SARS-CoV-2 infection. We conducted a case-control study of karaoke-related COVID-19 outbreaks to reveal the risk factors for SARS-CoV-2 infection among individuals who participate in karaoke. Methods Cases were defined as people who enjoyed karaoke at a bar and who tested positive for SARS-CoV-2 by RT-PCR between May 16 and July 3, 2020. Controls were defined as people who enjoyed karaoke at the same bar during the same period as the cases and tested negative. Odds ratio (OR) and confidence interval (CI) were calculated. ORs were adjusted by variables with significantly high odds ratio (aOR). Results We identified 81 cases, the majority of whom were active elderly individuals (median age: 75 years). Six cases died (case fatality ratio: 7%). Among the cases, 68 (84%) were guests, 18 of whom had visited more than two karaoke bars. A genome analysis conducted in 30 cases showed six types of isolates within four single-nucleotide variations difference. The case-control study revealed that singing (aOR 11.0, 95% CI, 1.2-101.0), not wearing a mask (aOR 3.7, 95% CI 1.2-11.2) and time spent per visit (aOR 1.7, 95% CI 1.1-2.7) were associated with COVID-19 infection. Conclusions A karaoke-related COVID-19 outbreak that occurred in two different cities was confirmed by the results of genome analysis. Singing in less-ventilated, indoor and crowded environments increases the risk of acquiring SARS-CoV-2 infection. Wearing a mask and staying for only a short time can reduce the risk of infection during karaoke.

6.
Cell Rep ; 39(3): 110688, 2022 04 19.
Article in English | MEDLINE | ID: covidwho-1763614

ABSTRACT

The emergence of the SARS-CoV-2 Omicron (B.1.1.529) variant with a surprising number of spike mutations raises concerns about reduced sensitivity of this virus to antibody neutralization and subsequent vaccine breakthrough infections. Here, we infect Moderna mRNA-vaccinated or previously infected hamsters with the Omicron BA.1 variant. While the Moderna mRNA vaccine reduces viral loads in the respiratory tissues upon challenge with an early S-614G isolate, the vaccine efficacy is not as pronounced after infection with the Omicron variant. Previous infection with the early SARS-CoV-2 isolate prevents replication after rechallenge with either virus in the lungs of previously infected hamsters, but the Omicron variant replicates efficiently in nasal turbinate tissue. These results experimentally demonstrate in an animal model that the antigenic changes in the Omicron variant are responsible for vaccine breakthrough and re-infection.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Neutralizing , COVID-19/prevention & control , Cricetinae , Disease Models, Animal , Mesocricetus , Vaccination , Vaccines, Synthetic
7.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330133

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 19 (COVID-19) pandemic. Despite its urgency, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis and its ability to antagonize innate immune responses. SARS-CoV-2 leads to shutoff of cellular protein synthesis and over-expression of nsp1, a central shutoff factor in coronaviruses, inhibits cellular gene translation. However, the diverse molecular mechanisms nsp1 employs as well as its functional importance in infection are still unresolved. By overexpressing various nsp1 mutants and generating a SARS-CoV-2 mutant in which nsp1 does not bind ribosomes, we untangle the effects of nsp1. We uncover that nsp1, through inhibition of translation and induction of mRNA degradation, is the main driver of host shutoff during SARS-CoV-2 infection. Furthermore, we find the propagation of nsp1 mutant virus is inhibited specifically in cells with intact interferon (IFN) response as well as in-vivo, in infected hamsters, and this attenuation is associated with stronger induction of type I IFN response. This illustrates that nsp1 shutoff activity has an essential role mainly in counteracting the IFN response. Overall, our results reveal the multifaceted approach nsp1 uses to shut off cellular protein synthesis and uncover the central role it plays in SARS-CoV-2 pathogenesis, explicitly through blockage of the IFN response.

8.
Cell Rep ; 38(7): 110394, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1719436

ABSTRACT

The emergence of the SARS-CoV-2 Delta variant (B.1.617.2) raises concerns about potential reduced sensitivity of the virus to antibody neutralization and subsequent vaccine breakthrough infections. Here, we use a live virus neutralization assay with sera from Pfizer- and Moderna-vaccinated individuals to examine neutralizing antibody titers against SARS-CoV-2 and observe a 3.9- and 2.7-fold reduction, respectively, in neutralizing antibody titers against the Delta variant compared with an early isolate bearing only a D614G substitution in its spike protein. We observe similar reduced sensitivity with sera from hamsters that were previously infected with an early isolate of SARS-CoV-2. Despite this reduction in neutralizing antibody titers against the Delta variant, hamsters previously infected (up to 15 months earlier) with an early isolate are protected from infection with the Delta variant, suggesting that the immune response to the first infection is sufficient to provide protection against subsequent infection with the Delta variant.


Subject(s)
Adaptive Immunity , COVID-19/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/transmission , COVID-19/virology , COVID-19 Vaccines/immunology , Cricetinae , Disease Models, Animal , Humans , Reinfection/immunology , Reinfection/transmission , Reinfection/virology , SARS-CoV-2/genetics , Viral Load
9.
Jpn J Infect Dis ; 2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1698801

ABSTRACT

Prominent genomic recombination has been observed between the Delta and Alpha variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolated from clinical specimens in Japan. Interestingly, the recombination variant detected in this study carries a spike protein identical to the one in the domestic Delta variant, thereby suggesting that further risks would not be concerned with infectivity and immune escape. The recombinant has been classified as XC lineage in the PANGOLIN database. It is necessary to intensively study such marked genetic variations and characterize the emerging variants after careful verification of their lineage and clade assignment.

10.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-308391

ABSTRACT

The COVID-19 pandemic continues to wreak havoc as worldwide SARS-CoV-2 infection, hospitalization, and death rates climb unabated. Effective vaccines remain the most promising approach to counter SARS-CoV-2. Yet, while promising results are emerging from COVID-19 vaccine trials, the need for multiple doses and the challenges associated with the widespread distribution and administration of vaccines remain concerns. Here, we engineered the coat protein of the MS2 bacteriophage 1,2 and generated nanoparticles displaying multiple copies of the SARS-CoV-2 spike (S) protein. The use of these nanoparticles as vaccines generated high neutralizing antibody titers and protected Syrian hamsters 3 from a challenge with SARS-CoV-2 after a single immunization with no infectious virus detected in the lungs. This nanoparticle-based vaccine platform thus provides protection after a single immunization and may be broadly applicable for protecting against SARS-CoV-2 and future pathogens with pandemic potential.

11.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-305709

ABSTRACT

Since little is known about viral and host characteristics of breakthrough infections after COVID-19 vaccination, a nationwide investigation of breakthrough cases was initiated in Japan. 130 cases (90%+ received mRNA vaccines) were reported with respiratory specimens in 117 cases and sera in 68 cases. A subset of cases shed infectious virus regardless of symptom presence or viral lineages. Viral lineages for breakthrough infections matched both temporally and spatially with the circulating lineages in Japan with no novel mutations in spike receptor binding domain that may have escaped from vaccine-induced immunity were found. Anti-spike/neutralizing antibodies of breakthrough infections in the acute phase owing to vaccine-induced immunity were significantly higher than those from unvaccinated convalescent individuals but were comparable to vaccinated uninfected individuals, and followed by boosting in the convalescent phase. Symptomatic cases had low anti-spike/neutralizing antibodies in the acute phase with robust boosting in the convalescent phase, suggesting the presence of serological correlate for symptom development in COVID-19 vaccine breakthrough infections.

12.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-318387

ABSTRACT

Potently neutralizing SARS-CoV-2 antibodies often target the receptor binding site (RBS) of spike protein but the variability of RBS epitopes hampers broad neutralization of different clades of coronaviruses and emerging drifted viruses. Here, we identified a human RBS antibody that potently neutralizes SARS-CoV and SARS-CoV-2 variants that belong to clade 1 SARS-related coronavirus. X-ray crystallography revealed coordinated recognition by the heavy chain to conserved sites and the light chain to RBS, allowing for the mimicry of ACE2 binding mode. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, and the activity was further enhanced by IgG3 switching. Eventually, the coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Furthermore, therapeutic treatment in a hamster model provided protection at low dosage. The structural basis for broadly neutralizing activity informs the design of broad spectrum of therapeutics and vaccines.Funding: This work was supported by Japan Agency for Medical Research and Development grant JP19fk0108111 (TH, YT), JP20fk0108298 (TK, TH, KM, YT), JP20am0101093 (KM), JP20ae0101047 (KM), JP20fk0108251 (HS), and JP20am0101124 (YK), by Ministry of Education, Culture, Sports, Science and Technology grant JPMXS0420100119 (KM) and 20H05773 (TH), by The Naito Foundation (TH), and by Joint Usage/Research Center program of Institute for Frontier Life and Medical Sciences, Kyoto University (KM).Conflict of Interest: AS is an employee of Shionogi & Co., Ltd. MO is a CEO, employee, and shareholder of Trans Chromosomics, Inc. These authors acknowledge a potential conflict of interest and attest that the work contained in this report is free of any bias that might be associated with the commercial goals of the company. TO, YA, MO, TH, KM, and YT declare that an intellectual property application has been filed using the data presented in this paper. The other authors declare that they have no competing interests.Ethical Approval: Animal procedures were approved by the Animal Ethics Committee of the National Institute of Infectious Diseases, Japan, and performed in accordance with the guidelines of the Institutional Animal Care and Use Committee. In vitro escape mutation screening experiments for SARSCoV-2 were performed at the Biosafety Level-3 facility of the Research Center for ZoonosisControl, Hokkaido University, and the National Institute of Infectious Diseases following the institutional guidelines.

13.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-317798

ABSTRACT

The SARS-CoV-2 lineage B.1.1.28 has been evolving in Brazil since February 2020 giving origin to multiple local clades including the new Variant of Concern (VOC) designated P.1 or 501Y.V3. The recent emergence of sub-lineages with convergent mutations in the spike (S) protein raises concern about the potential impact on viral infectivity and immune escape. We describe here the first three confirmed SARS-CoV-2 reinfections cases with the new VOC P.1 in residents of the Amazonas state, Brazil. Three female patients, 29, 40, and 50-year-old, were RT-PCR confirmed for SARS-CoV-2 on two occasions, with at least 92 days apart. Next-generation sequencing and phylogenetic analysis were conducted to precisely access the SARS-CoV-2 lineages of each infection event. SARS-CoV-2 genomic analysis confirmed three cases of reinfections caused by the VOC P.1 in patients that were primo-infected by distinct viral lineages 3–9 months earlier. Case 1 (29-year-old) was positive on March 24, 2020 (lineage B.1.195) and then on December 30, 2020 (lineage P.1);case 2 (50-year-old) was positive on October 19, 2020 (lineage B.1.1.33) and on January 19, 2021 (lineage P.1);case 3 (40-year-old) was positive on April 22, 2020 (lineage B.1.195) and on January 29, 2021 (lineage P.1). The three patients displayed low mean Ct values (< 22) at nasopharyngeal samples and reported less severe illness during reinfection. The present study provides the first evidence of the new VOC P.1 causing multiple reinfections during the second epidemic peak in the Amazonas state. Our findings suggest that reinfected individuals may have been infectious. Although immune responses induced by natural infections do not necessarily prevent subsequent infections by the VOC P.1, they may still protect from severe disease.

14.
mBio ; : e0304421, 2022 Feb 01.
Article in English | MEDLINE | ID: covidwho-1662302

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide since December 2019, causing coronavirus disease 2019 (COVID-19). Although vaccines for this virus have been developed rapidly, repurposing drugs approved to treat other diseases remains an invaluable treatment strategy. Here, we evaluated the inhibitory effects of drugs on SARS-CoV-2 replication in a hamster infection model and in in vitro assays. Favipiravir significantly suppressed virus replication in hamster lungs. Remdesivir inhibited virus replication in vitro, but was not effective in the hamster model. However, GS-441524, a metabolite of remdesivir, effectively suppressed virus replication in hamsters. Co-administration of favipiravir and GS-441524 more efficiently reduced virus load in hamster lungs than did single administration of either drug for both the prophylactic and therapeutic regimens; prophylactic co-administration also efficiently inhibited lung inflammation in the infected animals. Furthermore, pretreatment of hamsters with favipiravir and GS-441524 effectively protected them from virus transmission via respiratory droplets upon exposure to infected hamsters. Repurposing and co-administration of antiviral drugs may help combat COVID-19. IMPORTANCE During a pandemic, repurposing drugs that are approved for other diseases is a quick and realistic treatment option. In this study, we found that co-administration of favipiravir and the remdesivir metabolite GS-441524 more effectively blocked SARS-CoV-2 replication in the lungs of Syrian hamsters than either favipiravir or GS-441524 alone as part of a prophylactic or therapeutic regimen. Prophylactic co-administration also reduced the severity of lung inflammation. Moreover, co-administration of these drugs to naive hamsters efficiently protected them from airborne transmission of the virus from infected animals. Since both drugs are nucleotide analogs that interfere with the RNA-dependent RNA polymerases of many RNA viruses, these findings may also help encourage co-administration of antivirals to combat future pandemics.

15.
Cell reports ; 2022.
Article in English | EuropePMC | ID: covidwho-1661117

ABSTRACT

As SARS-CoV-2 variants accumulate mutations, there is a risk of ineffective neutralizing antibodies against new variants and potential re-infection. Halfmann et al. report that, in the hamster model, previous infection with an early prototypical SARS-CoV-2 isolate prevents re-infection of the Delta variant and its transmission to naïve hamsters.

16.
Sci Adv ; 8(1): eabh3827, 2022 Jan 07.
Article in English | MEDLINE | ID: covidwho-1612934

ABSTRACT

One safety concern during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine development has been the vaccine-associated enhanced disease, which is characterized by eosinophilic immunopathology and T helper cell type 2 (TH2)­biased immune responses with insufficient neutralizing antibodies. In this study, we established a lethal animal model using BALB/c mice and a mouse-passaged isolate (QHmusX) from a European lineage of SARS-CoV-2. The QHmusX strain induced acute respiratory illness, associated with diffuse alveolar damage and pulmonary edema, in TH2-prone adult BALB/c mice, but not in young mice or TH1-prone C57BL/6 mice. We also showed that immunization of adult BALB/c mice with recombinant spike protein without appropriate adjuvant caused eosinophilic immunopathology with TH2-shifted immune response and insufficient neutralizing antibodies after QHmusX infection. This lethal mouse model is useful for evaluating vaccine-associated enhanced respiratory disease during SARS-CoV-2 infection and may provide new insights into the disease pathogenesis of SARS-CoV-2.

17.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295960

ABSTRACT

Three COVID-19 waves in Japan have been characterized by the presence of distinct PANGO lineages (B.1.1. 162, B.1.1.284, and B.1.1.214). Recently, in addition to the B.1.1.7 lineage, which shows 25% abundance, an R.1 lineage carrying the E484K mutation in the spike protein was found to show up to 40% predominance.

18.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293389

ABSTRACT

The rapid spread of the SARS-CoV-2 Variant of Concern (VOC) Gamma during late 2020 and early 2021 in Brazilian settings with high seroprevalence raised some concern about the potential role of reinfections in driving the epidemic. Very few cases of reinfection associated with the VOC Gamma, however, have been reported. Here we describe 25 cases of SARS-CoV-2 reinfection confirmed by real-time RT-PCR twice within months apart in Brazil. SARS-CoV-2 genomic analysis confirmed that individuals were primo-infected between March and December 2020 with distinct viral lineages, including B.1.1, B.1.1.28, B.1.1.33, B.1.195 and P.2, and then reinfected with the VOC Gamma between 3 to 12 months after primo-infection. The overall mean cycle threshold (Ct) value of the first (25.7) and second (24.5) episodes were roughly similar for the whole group and 14 individuals displayed mean Ct values < 25.0 at reinfection. Sera of 14 patients tested by plaque reduction neutralization test after reinfection displayed detectable neutralizing antibodies against Gamma and other SARS-CoV-2 variants (B.1.33, B.1.1.28 and Delta). All individuals have milder or no symptoms after reinfection and none required hospitalization. The present study demonstrates that the VOC Gamma was associated with reinfections during the second Brazilian epidemic wave in 2021 and raised concern about the potential infectiousness of reinfected subjects. Although individuals here analyzed failed to mount a long-term sterilizing immunity, they developed a high anti-Gamma neutralizing antibody response after reinfection that may provide some protection against severe disease.

19.
Front Microbiol ; 12: 749149, 2021.
Article in English | MEDLINE | ID: covidwho-1518505

ABSTRACT

The coronavirus disease 2019 (COVID-19) has caused a serious disease burden and poses a tremendous public health challenge worldwide. Here, we report a comprehensive epidemiological and genomic analysis of SARS-CoV-2 from 63 patients in Niigata City, a medium-sized Japanese city, during the early phase of the pandemic, between February and May 2020. Among the 63 patients, 32 (51%) were female, with a mean (±standard deviation) age of 47.9 ± 22.3 years. Fever (65%, 41/63), malaise (51%, 32/63), and cough (35%, 22/63) were the most common clinical symptoms. The median C t value after the onset of symptoms lowered within 9 days at 20.9 cycles (interquartile range, 17-26 cycles), but after 10 days, the median C t value exceeded 30 cycles (p < 0.001). Of the 63 cases, 27 were distributed in the first epidemic wave and 33 in the second, and between the two waves, three cases from abroad were identified. The first wave was epidemiologically characterized by a single cluster related to indoor sports activity spread in closed settings, which included mixing indoors with families, relatives, and colleagues. The second wave showed more epidemiologically diversified events, with most index cases not related to each other. Almost all secondary cases were infected by droplets or aerosols from closed indoor settings, but at least two cases in the first wave were suspected to be contact infections. Results of the genomic analysis identified two possible clusters in Niigata City, the first of which was attributed to clade S (19B by Nexstrain clade) with a monophyletic group derived from the Wuhan prototype strain but that of the second wave was polyphyletic suggesting multiple introductions, and the clade was changed to GR (20B), which mainly spread in Europe in early 2020. These findings depict characteristics of SARS-CoV-2 transmission in the early stages in local community settings during February to May 2020 in Japan, and this integrated approach of epidemiological and genomic analysis may provide valuable information for public health policy decision-making for successful containment of chains of infection.

20.
mBio ; 12(5): e0198721, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1494967

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the detrimental effects of antibodies. Antibody-dependent enhancement (ADE) of infection is one of the biggest concerns in terms of not only the antibody reaction to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon reinfection with the virus but also the reaction to COVID-19 vaccines. In this study, we evaluated ADE of infection by using COVID-19 convalescent-phase plasma and BHK cells expressing human Fcγ receptors (FcγRs). We found that FcγRIIA and FcγRIIIA mediated modest ADE of infection against SARS-CoV-2. Although ADE of infection was observed in monocyte-derived macrophages infected with SARS-CoV-2, including its variants, proinflammatory cytokine/chemokine expression was not upregulated in macrophages. SARS-CoV-2 infection thus produces antibodies that elicit ADE of infection, but these antibodies do not contribute to excess cytokine production by macrophages. IMPORTANCE Viruses infect cells mainly via specific receptors at the cell surface. Antibody-dependent enhancement (ADE) of infection is an alternative mechanism of infection for viruses to infect immune cells that is mediated by antibodies and IgG receptors (FcγRs). Because ADE of infection contributes to the pathogenesis of some viruses, such as dengue virus and feline coronavirus, it is important to evaluate the precise mechanism of ADE and its contribution to the pathogenesis of SARS-CoV-2. Here, using convalescent-phase plasma from COVID-19 patients, we found that two types of FcγRs, FcγRIIA and FcγRIIIA, mediate ADE of SARS-CoV-2 infection. Although ADE of infection was observed for SARS-CoV-2 and its recent variants, proinflammatory cytokine production in monocyte-derived macrophages was not upregulated. These observations suggest that SARS-CoV-2 infection produces antibodies that elicit ADE of infection, but these antibodies may not be involved in aberrant cytokine release by macrophages during SARS-CoV-2 infection.


Subject(s)
Cytokines/metabolism , Macrophages/metabolism , Receptors, IgG/metabolism , SARS-CoV-2/pathogenicity , Animals , Antibody-Dependent Enhancement/physiology , Cell Line , Cricetinae , Humans , Real-Time Polymerase Chain Reaction , Receptors, IgG/genetics
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