Background We aim to investigate the profile of acute antibody response in COVID-19 patients, and provide proposals for the usage of antibody test in clinical practice.Methods A multi-center cross-section study (285 patients) and a single-center follow-up study (63 patients) were performed to investigate the feature of acute antibody response to SARS-CoV-2. A cohort of 52 COVID-19 suspects and 64 close contacts were enrolled to evaluate the potentiality of the antibody test. ResultsThe positive rate for IgG reached 100% around 20 days after symptoms onset.The median day of seroconversion for both lgG and IgM was 13 days after symptoms onset. Seroconversion of IgM occurred at the same time, or earlier, or later than that of IgG. IgG levels in 100% patients (19/19) entered a platform within 6 days after seroconversion. The criteria of "IgG seroconversion" and "≥ 4-fold increase in the IgG titers in sequential samples" together diagnosed 82.9% (34/41) of the patients.Antibody test aided to confirm 4 patients with COVID-19 from 52 suspects who failed to be confirmed by RT-PCR and 7 patients from 148 close contacts with negative RT-PCR. ConclusionIgM and IgG should be detected simultaneously at the early phase of infection. The serological diagnosis criterion of seroconversion or the "≥ 4-fold increase in the IgG titer" is suitable for a majority of COVID-19 patients. Serologic test is helpful for the diagnosis of SARS-CoV-2 infection in suspects and close contacts.
Cytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.
22Coronavirus disease 2019 is caused by severe acute respiratory 23 syndrome coronavirus 2 (SARS-CoV-2). The spike protein that mediates 24 SARS-CoV-2 entry into host cells, is one of the major targets for vaccines and 25 therapeutics. Thus, insights into the sequence variations of S protein are key to 26 understanding the infection and antigenicity of SARS-CoV-2. Here, we observed a 27 dominant mutational variant at the 614 position of S protein (aspartate to glycine, 28 D614G mutation). Using pseudovirus-based assay, we found that S-D614 and 29 S-G614 protein pseudotyped viruses share a common receptor, human 30 angiotensin-converting enzyme 2 (ACE2), which could be blocked by recombinant 31 ACE2 with the fused Fc region of human IgG1. However, S-D614 and S-G614 32 protein demonstrated functional differences. First, S-G614 protein could be cleaved 33 by serine protease elastase-2 more efficiently. Second, S-G614 pseudovirus 34 infected 293T-ACE2 cells significantly more efficiently than the S-D614 pseudovirus, 35 Moreover, 93% (38/41) sera from convalescent COVID-19 patients could neutralize 36 both S-D614 and S-G614 pseudotyped viruses with comparable efficiencies, but 37 about 7% (3/41) convalescent sera showed decreased neutralizing activity against 38 S-G614 pseudovirus. These findings have important implications for SARS-CoV-2 39 transmission and immune interventions.40 42 43 44 SARS-CoV-2 is a novel coronavirus reported in 2019 that caused the recent 45 outbreak of coronavirus disease-2019 (COVID-19) 1 . By June 17, 2020, the World 46 Health Organization (WHO) reported that 8.06 million people worldwide had been 47 infected with SARS-CoV-2, and 440,290 individuals died of COVID-19. This 48 pandemic had a significant adverse impact on international social and economic 49 activities. The RNA genome of SARS-CoV-2 was rapidly sequenced to facilitate 50 diagnostic testing, molecular epidemiologic source tracking, and development of 51 vaccines and therapeutic strategies 2 . Coronaviruses are enveloped, 52 positive-stranded RNA viruses that contain the largest known RNA genomes to 53 date. The mutation rate for RNA viruses is extremely high, which may contribute to 54 its transmission and virulence. The only significant variation in the SARS-CoV-2 55 spike (S) protein is a non-synonymous D614G (Aspartate (D) to Glycine (G)) 56 mutation 3 . Primary data showed that S-G614 is a more pathogenic strain of 57 SARS-CoV-2 with high transmission efficiency 3 , however whether D614G 58 conversion in S protein affect the viral entry and infectivity in cell model is still 59 unclear. 60 61The S protein of coronavirus, the major determinant of host and tissue tropism, is a 62 major target for vaccines, neutralizing antibodies, and viral entry inhibitors 4,5 . 63Similar to SARS-CoV, the cellular receptor of SARS-CoV-2 is 64 angiotensin-converting enzyme 2 (ACE2); however, the SARS-CoV-2 S protein has 65 a 10-to 20-fold higher affinity for ACE2 than the corresponding S protein of 66 SARS-CoV 6,7 . Coronaviruses use two d...
Background Coronavirus disease 2019 (COVID-19) is a global pandemic with no licensed vaccine or specific antiviral agents for therapy. Little is known about the longitudinal dynamics of SARS-CoV-2-specific neutralizing antibodies (NAbs) in COVID-19 patients. Methods Blood samples (n=173) were collected from 30 COVID-19 patients over a 3-month period after symptom onset and analyzed for SARS-CoV-2-specific NAbs, using the lentiviral pseudotype assay, coincident with the levels of IgG and proinflammatory cytokines. Results SARS-CoV-2-specific NAb titers were low for the first 7–10 d after symptom onset and increased after 2–3 weeks. The median peak time for NAbs was 33 d (IQR 24–59 d) after symptom onset. NAb titers in 93·3% (28/30) of the patients declined gradually over the 3-month study period, with a median decrease of 34·8% (IQR 19·6–42·4%). NAb titers increased over time in parallel with the rise in IgG antibody levels, correlating well at week 3 (r = 0·41, p & 0·05). The NAb titers also demonstrated a significant positive correlation with levels of plasma proinflammatory cytokines, including SCF, TRAIL, and M-CSF. Conclusions These data provide useful information regarding dynamic changes in NAbs in COVID-19 patients during the acute and convalescent phases.
SARS-CoV-2, a novel ß-coronavirus, cause severe pneumonia and has spread throughout the globe rapidly. The disease associated with SARS-CoV-2 infection is named COVID-19. To date, real-time RT-PCR is the only test able to confirm this infection. However, the accuracy of RT-PCR depends on several factors; variations in these factors might significantly lower the sensitivity of detection. Here, we developed a peptide-based luminescent immunoassay that detected immunoglobulin G (IgG) and IgM. The assay cut-off value was determined by evaluating the sera from healthy and infected patients for pathogens other than SARS-CoV-2. To evaluate assay performance, we detected IgG and IgM in the sera from confirmed patients. The positive rate of IgG and IgM was 71.4% and 57.2%, respectively. Therefore, combining our immunoassay with real-time RT-PCR might enhance the diagnostic accuracy of COVID-19.
Hepadnavirus covalently closed circular (ccc) DNA is the bona fide viral transcription template, which plays a pivotal role in viral infection and persistence. Upon infection, the non-replicative cccDNA is converted from the incoming and de novo synthesized viral genomic relaxed circular (rc) DNA, presumably through employment of the host cell’s DNA repair mechanisms in the nucleus. The conversion of rcDNA into cccDNA requires preparation of the extremities at the nick/gap regions of rcDNA for strand ligation. After screening 107 cellular DNA repair genes, we herein report that the cellular DNA ligase (LIG) 1 and 3 play a critical role in cccDNA formation. Ligase inhibitors or functional knock down/out of LIG1/3 significantly reduced cccDNA production in an in vitro cccDNA formation assay, and in cccDNA-producing cells without direct effect on viral core DNA replication. In addition, transcomplementation of LIG1/3 in the corresponding knock-out or knock-down cells was able to restore cccDNA formation. Furthermore, LIG4, a component in non-homologous end joining DNA repair apparatus, was found to be responsible for cccDNA formation from the viral double stranded linear (dsl) DNA, but not rcDNA. In conclusion, we demonstrate that hepadnaviruses utilize the whole spectrum of host DNA ligases for cccDNA formation, which sheds light on a coherent molecular pathway of cccDNA biosynthesis, as well as the development of novel antiviral strategies for treatment of hepatitis B.
Background Coronavirus disease 2019 (COVID-19) is a global pandemic with no licensed vaccine or specific antiviral agents for therapy. Little is known about the longitudinal dynamics of SARS-CoV-2-specific neutralizing antibodies (NAbs) in COVID-19 patients. Methods Blood samples (n=173) were collected from 30 COVID-19 patients over a 3-month period after symptom onset and analyzed for SARS-CoV-2-specific NAbs, using the lentiviral pseudotype assay, coincident with the levels of IgG and proinflammatory cytokines. Results SARS-CoV-2-specific NAb titers were low for the first 7-10 d after symtom onset and increased after 2-3 weeks. The median peak time for NAbs was 33 d (IQR 24-59 d) after symptom onset. NAb titers in 93.3% (28/30) of the patients declined gradually over the 3-month study period, with a median decrease of 34.8% (IQR 19.6-42.4%). NAb titers increased over time in parallel with the rise in IgG antibody levels, correlating well at week 3 (r = 0.41, p < 0.05). The NAb titers also demonstrated a significant positive correlation with levels of plasma proinflammatory cytokines, including SCF, TRAIL, and M-CSF. Conclusions These data provide useful information regarding dynamic changes in NAbs in COVID-19 patients during the acute and convalescent phases.
SIRT3 is a host factor epigenetically restricting HBV cccDNA transcription by acting cooperatively with histone methyltransferase; these data provide a rationale for the use of SIRT3 activators in the prevention or treatment of HBV infection. (Hepatology 2018).
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