Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

/pdf/evolution-of-antibody-immunity-to-sars-cov-2-p62nzrlqet.pdf

Evolution of antibody immunity to SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by five-fold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 4 months after coronavirus disease-2019 (COVID-19) onset, using immunofluorescence, or polymerase chain reaction, revealed persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

/pdf/evolution-of-antibody-immunity-to-sars-cov-2-4lya6o4k1m.pdf

Evolution of Antibody Immunity to SARS-CoV-2

http://www.cell.com/article/S2666634022001672/pdf

Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection

Our understanding of the hepatic consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its resultant coronavirus disease 2019 (COVID-19) has evolved rapidly since the onset of the pandemic. In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury. Furthermore, large international cohorts have been able to characterize the disease course of COVID-19 in patients with pre-existing chronic liver disease. Patients with cirrhosis have particularly high rates of hepatic decompensation and death following SARS-CoV-2 infection and we outline hypotheses to explain these findings, including the possible role of cirrhosis-associated immune dysfunction. This finding contrasts with outcome data in pharmacologically immunosuppressed patients after liver transplantation who seem to have comparatively better outcomes from COVID-19 than those with advanced liver disease. Finally, we discuss the approach to SARS-CoV-2 vaccination in patients with cirrhosis and after liver transplantation and predict how changes in social behaviours and clinical care pathways during the pandemic might lead to increased liver disease incidence and severity.

/pdf/covid-19-and-liver-disease-mechanistic-and-clinical-3khcz0o8tf.pdf

COVID-19 and liver disease: mechanistic and clinical perspectives.

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in an unprecedented setback for global economy and health. SARS-CoV-2 has an exceptionally high level of transmissibility and extremely broad tissue tropism. However, the underlying molecular mechanism responsible for sustaining this degree of virulence remains largely unexplored. In this article, we review the current knowledge and crucial information about how SARS-CoV-2 attaches on the surface of host cells through a variety of receptors, such as ACE2, neuropilin-1, AXL, and antibody–FcγR complexes. We further explain how its spike (S) protein undergoes conformational transition from prefusion to postfusion with the help of proteases like furin, TMPRSS2, and cathepsins. We then review the ongoing experimental studies and clinical trials of antibodies, peptides, or small-molecule compounds with anti-SARS-CoV-2 activity, and discuss how these antiviral therapies targeting host–pathogen interaction could potentially suppress viral attachment, reduce the exposure of fusion peptide to curtail membrane fusion and block the formation of six-helix bundle (6-HB) fusion core. Finally, the specter of rapidly emerging SARS-CoV-2 variants deserves a serious review of broad-spectrum drugs or vaccines for long-term prevention and control of COVID-19 in the future.

/pdf/molecular-mechanism-of-interaction-between-sars-cov-2-and-kqhr17j2cq.pdf

Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy.

BACKGROUND Currently, there is no direct evidence to prove the active replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the intestinal tract and relevant pathological changes in the colon and rectum. We investigated the presence of virions and pathological changes in surgical rectal tissues of a patient with clinically confirmed coronavirus disease 2019 (COVID-19) with rectal adenocarcinoma. METHODS The clinical data were collected during hospitalization and follow-up of this patient. Quantitative reverse transcriptase-polymerasechain reaction (RT-PCR) was performed on the rectal tissue specimens obtained from surgical resection, succus entericus and intestinal mucosa of ileostomy, and rectal mucosa during follow-up after recovery. Ultrathin sections of surgical samples were observed for SARS-CoV-2 virions using electron microscopy. Histopathological examination was performed using hematoxylin-eosin stain. Immunohistochemical analysis and immunofluorescence were carried out on rectal tissues to evaluate the distribution of SARS-CoV-2 antigen and immune cell infiltrations. RESULTS The patient had fever and cough on day 3 postoperatively, was diagnosed with COVID-19 on day 7, and was discharged from the hospital on day 41. RNA of SARS-CoV-2 was detected in surgically resected rectal specimens but not in samples collected 37 days after discharge. Notably, coincident with rectal tissues of surgical specimens testing nucleic acid positive for SARS-CoV-2, typical coronavirus virions in rectal tissue were observed under electron microscopy. Moreover, abundant lymphocytes and macrophages (some were SARS-CoV-2 positive) infiltrating the lamina propria were found with no significant mucosal damage. CONCLUSIONS We first report the direct evidence of active SARS-CoV-2 replication in a patient's rectum during the incubation period, which might explain SARS-CoV-2 fecal-oral transmission.

/pdf/direct-evidence-of-active-sars-cov-2-replication-in-the-33v0he0s41.pdf

Direct evidence of active SARS-CoV-2 replication in the intestine.

We report our diagnosis of a rare case of primary angiomatoid fibrous histiocytoma in the mandible of a 42-year-old male using next-generation sequencing to detect disease-specific EWSR1-ATF1 fusion.After the initial cone beam computerized tomography scan and reconstruction, we performed immunohistochemical staining and fluorescence in situ hybridization analysis on tissue samples to detect EWSR1 gene rearrangement. For the final diagnosis, we performed next-generation sequencing to detect disease-specific EWSR1-ATF1 fusion.FISH analysis showed approximately 55% of tumor cells with mostly isolated red signals, as well as several split red-green signals, indicating the presence of EWSR1 gene rearrangement. Next-generation sequencing analysis identified an EWSR1 exon9-ATF1 exon4 fusion, a diagnostic biomarker of angiomatoid fibrous histiocytoma (AFH). Based on the findings, we diagnosed primary AFH derived from the mandible.Next-generation sequencing is a powerful methodology for detecting disease-specific EWSR1-ATF1 fusion and diagnosing primary angiomatoid fibrous histiocytoma. 

Primary angiomatoid fibrous histiocytoma of the mandible with EWSR1-ATF1 fusion in an adult patient: case report and review of literature.

The immune system plays a significant role in controlling oral squamous cell carcinoma (OSCC) initiation and progression. Natural killer (NK) cells actively participate in antitumor immunity but become dysfunctional or exhausted in the tumor microenvironment. To explore the mechanisms of NK cell dysfunction in OSCC, we characterized the expression and function of AT‐rich interaction domain 2 (ARID2) in NK cells in a murine OSCC model. ARID2 was downregulated in tongue NK cells compared with splenic NK cells. Notably, ARID2 was significantly decreased in NK cells with an exhausted phenotype and weakened antitumor function. ARID2 knockdown resulted in the upregulation of programmed cell death protein 1 (PD‐1) and downregulation of interferon‐gamma (IFN‐γ), tumor necrosis factor (TNF), granzyme B and perforin in NK cells. As a result, ARID2 knockdown impaired NK cell cytotoxicity. Besides, ARID2 overexpression suppressed the expression of PD‐1 and lymphocyte‐activation gene 3, and promoted the expression of IFN‐γ, TNF, granzyme B and perforin in NK cells which were adoptively transferred into OSCC‐bearing mice. Taken together, our study implies that the OSCC microenvironment triggers ARID2 downregulation in intratumoral NK cells. In turn, ARID2 downregulation results in PD‐1 upregulation on NK cells and subsequently impairs NK cell cytotoxicity. Therefore, we uncovered a novel mechanism of NK cell dysfunction in OSCC.

Downregulation of AT‐rich interaction domain 2 underlies natural killer cell dysfunction in oral squamous cell carcinoma

The immune responses play significant roles in the onset, progression, and outcome of oral squamous cell carcinoma (OSCC). CD4+ regulatory T cells (Tregs) significantly impact tumor immunity. However, their role in OSCC development remains elusive.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/iid3.746

Interleukin‐23 receptor defines T helper 1‐like regulatory T cells in oral squamous cell carcinoma

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Direct evidence of active SARS-CoV-2 replication in the intestine.

Primary angiomatoid fibrous histiocytoma of the mandible with EWSR1-ATF1 fusion in an adult patient: case report and review of literature.

Downregulation of AT‐rich interaction domain 2 underlies natural killer cell dysfunction in oral squamous cell carcinoma

Interleukin‐23 receptor defines T helper 1‐like regulatory T cells in oral squamous cell carcinoma