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2.
Pathog Immun ; 6(2): 149-152, 2021.
Article in English | MEDLINE | ID: covidwho-1662940

ABSTRACT

On September 10, 2021, a special tribunal established by the French government launched an inquiry into the activities of former health minister Dr. Agnes Buzyn who was charged with "endangering the lives of others". It is surprising to learn of this accusation and inquiry into the actions of a public health official whose response to the epidemic was, to all appearances, exemplary.

3.
JCI Insight ; 7(4)2022 02 22.
Article in English | MEDLINE | ID: covidwho-1637818

ABSTRACT

Why multisystem inflammatory syndrome in children (MIS-C) develops after SARS-CoV-2 infection in a subset of children is unknown. We hypothesized that aberrant virus-specific T cell responses contribute to MIS-C pathogenesis. We quantified SARS-CoV-2-reactive T cells, serologic responses against major viral proteins, and cytokine responses from plasma and peripheral blood mononuclear cells in children with convalescent COVID-19, in children with acute MIS-C, and in healthy controls. Children with MIS-C had significantly lower virus-specific CD4+ and CD8+ T cell responses to major SARS-CoV-2 antigens compared with children convalescing from COVID-19. Furthermore, T cell responses in participants with MIS-C were similar to or lower than those in healthy controls. Serologic responses against spike receptor binding domain (RBD), full-length spike, and nucleocapsid were similar among convalescent COVID-19 and MIS-C, suggesting functional B cell responses. Cytokine profiling demonstrated predominant Th1 polarization of CD4+ T cells from children with convalescent COVID-19 and MIS-C, although cytokine production was reduced in MIS-C. Our findings support a role for constrained induction of anti-SARS-CoV-2-specific T cells in the pathogenesis of MIS-C.


Subject(s)
COVID-19/complications , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , COVID-19/immunology , Child , Child, Preschool , Female , Humans , Male
4.
Sci Immunol ; 6(66): eabf1152, 2021 Dec 03.
Article in English | MEDLINE | ID: covidwho-1583226

ABSTRACT

Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin formulations, including immune-stimulatory complexes (ISCOMs) formed by the self-assembly of saponin and phospholipids in the absence or presence of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). We found that MPLA self-assembles with saponins to form particles physically resembling ISCOMs, which we termed saponin/MPLA nanoparticles (SMNP). Saponin-containing adjuvants exhibited distinctive mechanisms of action, altering lymph flow in a mast cell­dependent manner and promoting antigen entry into draining lymph nodes. SMNP was particularly effective, exhibiting even greater potency than the compositionally related adjuvant AS01B in mice, and primed robust germinal center B cell, TFH, and HIV tier 2 neutralizing antibodies in nonhuman primates. Together, these findings shed new light on mechanisms by which saponin adjuvants act to promote the immune response and suggest that SMNP may be a promising adjuvant in the setting of HIV, SARS-CoV-2, and other pathogens.


Subject(s)
Adaptive Immunity/drug effects , Adjuvants, Immunologic/pharmacology , Lymph/drug effects , Saponins/pharmacology , Toll-Like Receptors/agonists , Animals , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Female , Lymph/physiology , Macaca mulatta , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nanoparticles , Rats , Rats, Wistar
5.
Sci Adv ; 7(50): eabj6538, 2021 Dec 10.
Article in English | MEDLINE | ID: covidwho-1559847

ABSTRACT

There is a need for additional rapidly scalable, low-cost vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to achieve global vaccination. Aluminum hydroxide (alum) adjuvant is the most widely available vaccine adjuvant but elicits modest humoral responses. We hypothesized that phosphate-mediated coanchoring of the receptor binding domain (RBD) of SARS-CoV-2 together with molecular adjuvants on alum particles could potentiate humoral immunity by promoting extended vaccine kinetics and codelivery of vaccine components to lymph nodes. Modification of RBD immunogens with phosphoserine (pSer) peptides enabled efficient alum binding and slowed antigen clearance, leading to notable increases in germinal center responses and neutralizing antibody titers in mice. Adding phosphate-containing CpG or saponin adjuvants to pSer-RBD:alum immunizations synergistically enhanced vaccine immunogenicity in mice and rhesus macaques, inducing neutralizing responses against SARS-CoV-2 variants. Thus, phosphate-mediated coanchoring of RBD and molecular adjuvants to alum is an effective strategy to enhance the efficacy of SARS-CoV-2 subunit vaccines.

6.
Open Forum Infect Dis ; 8(11): ofab217, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1526175

ABSTRACT

BACKGROUND: Immunocompromised patients show prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal swabs. We report a case of prolonged persistence of viable SARS-CoV-2 associated with clinical relapses of coronavirus disease 2019 (COVID-19) in a patient with mantle cell lymphoma who underwent treatment with rituximab, bendamustine, cytarabine with consequent lymphopenia and hypogammaglobulinemia. METHODS: Nasopharyngeal swabs and blood samples were tested for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR). On 5 positive nasopharyngeal swabs, we performed viral culture and next-generation sequencing. We analyzed the patient's adaptive and innate immunity to characterize T- and NK-cell subsets. RESULTS: SARS-CoV-2 RT-PCR on nasopharyngeal swabs samples remained positive for 268 days. All 5 performed viral cultures were positive, and genomic analysis confirmed a persistent infection with the same strain. Viremia resulted positive in 3 out of 4 COVID-19 clinical relapses and cleared each time after remdesivir treatment. The T- and NK-cell dynamic was different in aviremic and viremic samples, and no SARS-CoV-2-specific antibodies were detected throughout the disease course. CONCLUSIONS: In our patient, SARS-CoV-2 persisted with proven infectivity for >8 months. Viremia was associated with COVID-19 relapses, and remdesivir treatment was effective in viremia clearance and symptom remission, although it was unable to clear the virus from the upper respiratory airways. During the viremic phase, we observed a low frequency of terminal effector CD8+ T lymphocytes in peripheral blood; these are probably recruited in inflammatory tissue for viral eradication. In addition, we found a high level of NK-cell repertoire perturbation with relevant involvement during SARS-CoV-2 viremia.

8.
Cell Rep Med ; 2(6): 100321, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1253745

ABSTRACT

The pathogenesis of severe coronavirus disease 2019 (COVID-19) remains poorly understood. While several studies suggest that immune dysregulation plays a central role, the key mediators of this process are yet to be defined. Here, we demonstrate that plasma from a high proportion (93%) of critically ill COVID-19 patients, but not healthy controls, contains broadly auto-reactive immunoglobulin M (IgM) and less frequently auto-reactive IgG or IgA. Importantly, these auto-IgMs preferentially recognize primary human lung cells in vitro, including pulmonary endothelial and epithelial cells. By using a combination of flow cytometry, analytical proteome microarray technology, and lactose dehydrogenase (LDH)-release cytotoxicity assays, we identify high-affinity, complement-fixing, auto-reactive IgM directed against 260 candidate autoantigens, including numerous molecules preferentially expressed on the cellular membranes of pulmonary, vascular, gastrointestinal, and renal tissues. These findings suggest that broad IgM-mediated autoimmune reactivity may be involved in the pathogenesis of severe COVID-19, thereby identifying a potential target for therapeutic interventions.


Subject(s)
Autoantibodies/immunology , COVID-19/pathology , Immunoglobulin M/immunology , Autoantibodies/blood , COVID-19/immunology , COVID-19/virology , Cell Line , Complement C4/metabolism , Critical Illness , Humans , Immunoglobulin M/blood , Intensive Care Units , Lung/metabolism , Protein Array Analysis , Proteome/analysis , SARS-CoV-2/isolation & purification
9.
Mod Pathol ; 34(9): 1614-1633, 2021 09.
Article in English | MEDLINE | ID: covidwho-1241797

ABSTRACT

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) pandemic has had devastating effects on global health and worldwide economy. Despite an initial reluctance to perform autopsies due to concerns for aerosolization of viral particles, a large number of autopsy studies published since May 2020 have shed light on the pathophysiology of Coronavirus disease 2019 (COVID-19). This review summarizes the histopathologic findings and clinicopathologic correlations from autopsies and biopsies performed in patients with COVID-19. PubMed and Medline (EBSCO and Ovid) were queried from June 4, 2020 to September 30, 2020 and histopathologic data from autopsy and biopsy studies were collected based on 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 58 studies reporting 662 patients were included. Demographic data, comorbidities at presentation, histopathologic findings, and virus detection strategies by organ system were collected. Diffuse alveolar damage, thromboembolism, and nonspecific shock injury in multiple organs were the main findings in this review. The pathologic findings emerging from autopsy and biopsy studies reviewed herein suggest that in addition to a direct viral effect in some organs, a unifying pathogenic mechanism for COVID-19 is ARDS with its known and characteristic inflammatory response, cytokine release, fever, inflammation, and generalized endothelial disturbance. This study supports the notion that autopsy studies are of utmost importance to our understanding of disease features and treatment effect to increase our knowledge of COVID-19 pathophysiology and contribute to more effective treatment strategies.


Subject(s)
COVID-19/pathology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Humans , SARS-CoV-2
10.
Cell ; 184(2): 460-475.e21, 2021 01 21.
Article in English | MEDLINE | ID: covidwho-917237

ABSTRACT

SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Azetidines/administration & dosage , COVID-19/drug therapy , COVID-19/immunology , Macaca mulatta , Neutrophil Infiltration/drug effects , Purines/administration & dosage , Pyrazoles/administration & dosage , Sulfonamides/administration & dosage , Animals , COVID-19/physiopathology , Cell Death/drug effects , Cell Degranulation/drug effects , Disease Models, Animal , Inflammation/drug therapy , Inflammation/genetics , Inflammation/immunology , Janus Kinases/antagonists & inhibitors , Lung/drug effects , Lung/immunology , Lung/pathology , Lymphocyte Activation/drug effects , Macrophages, Alveolar/immunology , SARS-CoV-2/physiology , Severity of Illness Index , T-Lymphocytes/immunology , Virus Replication/drug effects
11.
Clin Chem Lab Med ; 58(9): 1573-1577, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-618960

ABSTRACT

Objectives: A milder clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been anecdotally reported over the latest phase of COVID-19 pandemic in Italy. Several factors may contribute to this observation, including the effect of lockdown, social distancing, lower humidity, lower air pollution, and potential changes in the intrinsic pathogenicity of the virus. In this regard, the clinical severity of COVID-19 could be attenuated by mutations in SARS-CoV-2 genome that decrease its virulence, as well as by lower virus inocula. Methods: In this pilot study, we compared the reverse transcription polymerase chain reaction (RT-PCR) amplification profile of 100 nasopharyngeal swabs consecutively collected in April, during the peak of SARS-CoV-2 epidemic, to that of 100 swabs collected using the same procedure in May. Results: The mean Ct value of positive samples collected in May was significantly higher than that of samples collected in the previous period (ORF 1a/b gene: 31.85 ± 0.32 vs. 28.37 ± 0.5, p<0.001; E gene: 33.76 ± 0.38 vs. 29.79 ± 0.63, p<0.001), suggesting a lower viral load at the time of sampling. No significant differences were observed between male and females in the two periods, whilst higher viral loads were found in (i) patients over 60-years old, and (ii) patients that experienced severe COVID-19 during the early stages of the pandemic. Conclusions: This pilot study prompts further investigation on the correlation between SARS-CoV-2 load and different clinical manifestation of COVID-19 during different phases of the pandemic. Laboratories should consider reporting quantitative viral load data in the molecular diagnosis of SARS-CoV-2 infection.


Subject(s)
Betacoronavirus , Coronavirus Infections/virology , Nasopharynx/virology , Pneumonia, Viral/virology , Viral Load , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19 , COVID-19 Testing , Child , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Female , Hospitals, University , Humans , Italy , Male , Middle Aged , Pandemics , Pilot Projects , Pneumonia, Viral/diagnosis , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Young Adult
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