Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

peer reviewedDespite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain–specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA’s predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies

HIV-1 Envelope Glycoprotein Cell Surface Localization Is Associated with Antibody-Induced Internalization

To minimize immune responses against infected cells, HIV-1 has evolved different mechanisms to limit the surface expression of its envelope glycoproteins (Env). Recent observations suggest that the binding of certain broadly neutralizing antibodies (bNAbs) targeting the ‘closed’ conformation of Env induces its internalization. On the other hand, non-neutralizing antibodies (nNAbs) that preferentially target Env in its ‘open’ conformation, remain bound to Env on the cell surface for longer periods of time. In this study, we attempt to better understand the underlying mechanisms behind the differential rates of antibody-mediated Env internalization. We demonstrate that ‘forcing’ open Env using CD4 mimetics allows for nNAb binding and results in similar rates of Env internalization as those observed upon the bNAb binding. Moreover, we can identify distinct populations of Env that are differentially targeted by Abs that mediate faster rates of internalization, suggesting that the mechanism of antibody-induced Env internalization partially depends on the localization of Env on the cell surface

Understudied Factors Influencing Fc-Mediated Immune Responses against Viral Infections

Antibodies play a crucial role in host defense against viruses, both by preventing infection and by controlling viral replication. Besides their capacity to neutralize viruses, antibodies also exert their antiviral effects by crystallizable fragment (Fc)-mediated effector mechanisms. This involves a bridge between innate and adaptive immune systems, wherein antibodies form immune complexes that drive numerous innate immune effector functions, including antibody-dependent cellular cytotoxicity, antibody-dependent complement-mediated lysis, and antibody-dependent phagocytosis. Here, we review certain mechanisms that modulate these antibody-mediated effector functions against virally infected cells, such as viral glycoprotein shedding, viral glycoprotein internalization, antibody cooperativity, and antibody glycosylation. These mechanisms can either protect viral replication or enhance infected cell clearance. Here we discuss the importance of these understudied factors in modulating Fc-mediated effector functions

Evolution of Anti-RBD IgG Avidity following SARS-CoV-2 Infection

SARS-CoV-2 infection rapidly elicits anti-Spike antibodies whose quantity in plasma gradually declines upon resolution of symptoms. This decline is part of the evolution of an immune response leading to B cell differentiation into short-lived antibody-secreting cells or resting memory B cells. At the same time, the ongoing class switch and antibody maturation processes occurring in germinal centers lead to the selection of B cell clones secreting antibodies with higher affinity for their cognate antigen, thereby improving their functional activity. To determine whether the decline in SARS-CoV-2 antibodies is paralleled with an increase in avidity of the anti-viral antibodies produced, we developed a simple assay to measure the avidity of anti-receptor binding domain (RBD) IgG elicited by SARS-CoV-2 infection. We longitudinally followed a cohort of 29 convalescent donors with blood samples collected between 6- and 32-weeks post-symptoms onset. We observed that, while the level of antibodies declines over time, the anti-RBD avidity progressively increases and correlates with the B cell class switch. Additionally, we observed that anti-RBD avidity increased similarly after SARS-CoV-2 mRNA vaccination and after SARS-CoV-2 infection. Our results suggest that anti-RBD IgG avidity determination could be a surrogate assay for antibody affinity maturation and, thus, suitable for studying humoral responses elicited by natural infection and/or vaccination

SARS-CoV-2 Spike Expression at the Surface of Infected Primary Human Airway Epithelial Cells

Different serological assays were rapidly generated to study humoral responses against the SARS-CoV-2 Spike glycoprotein. Due to the intrinsic difficulty of working with SARS-CoV-2 authentic virus, most serological assays use recombinant forms of the Spike glycoprotein or its receptor binding domain (RBD). Cell-based assays expressing different forms of the Spike, as well as pseudoviral assays, are also widely used. To evaluate whether these assays recapitulate findings generated when the Spike is expressed in its physiological context (at the surface of the infected primary cells), we developed an intracellular staining against the SARS-CoV-2 nucleocapsid (N) to distinguish infected from uninfected cells. Human airway epithelial cells (pAECs) were infected with authentic SARS-CoV-2 D614G or Alpha variants. We observed robust cell-surface expression of the SARS-CoV-2 Spike at the surface of the infected pAECs using the conformational-independent anti-S2 CV3-25 antibody. The infected cells were also readily recognized by plasma from convalescent and vaccinated individuals and correlated with several serological assays. This suggests that the antigenicity of the Spike present at the surface of the infected primary cells is maintained in serological assays involving expression of the native full-length Spike

Prognostic Value of PET Myocardial Perfusion Imaging in Obese Patients

ObjectivesThis study sought to determine and compare the prognostic and incremental value of positron emission tomography (PET) in normal, overweight, and obese patients.BackgroundCardiac rubidium 82 (Rb-82) PET is increasingly being used for myocardial perfusion imaging (MPI). A strength of PET is its accurate attenuation correction, thereby potentially improving its diagnostic accuracy in obese patients. The prognostic value of PET in obese patients has not been well studied.MethodsA total of 7,061 patients who had undergone Rb-82 PET MPI were entered into a multicenter observational registry. All patients underwent pharmacologic Rb-82 PET and were followed for cardiac death and all-cause mortality. Based on body mass index (BMI), patients were categorized as normal (<25 kg/m2), overweight (25 to 29.9 kg/m2), or obese (≥30 kg/m2). Using a 17-segment model and 5-point scoring system, the percentage of abnormal myocardium was calculated for stress and rest patients categorized as normal (0%), mild (0.1% to 9.9%), moderate (10% to 19.9%), and severe (≥20%).ResultsA total of 6,037 patients were followed for cardiac death (median: 2.2 years) and the mean BMI was 30.5 ± 7.4 kg/m2. A total of 169 cardiac deaths were observed. PET MPI demonstrated independent and incremental prognostic value over BMI. Normal PET MPI conferred an excellent prognosis with very low annual cardiac death rates in normal (0.38%), overweight (0.43%), and obese (0.15%) patients. As well, both moderately and severe obese patients with a normal PET MPI had excellent prognosis (0.20% and 0.10%, respectively). The net reclassification improvement of PET was 0.46 (95% confidence interval [CI]: 0.31 to 0.61), and appeared similar in the moderately and severe obese patients which were 0.44 (95% CI: 0.12 to 0.76) and 0.63 (95% CI: 0.27 to 0.98), respectively.ConclusionsRb-82 PET has incremental prognostic value in all patients irrespective of BMI. In the obese population, where other modalities may have reduced diagnostic accuracy, cardiac PET appears to be a promising noninvasive modality with prognostic value

Abstracts of National Conference on Research and Developments in Material Processing, Modelling and Characterization 2020

This book presents the abstracts of the papers presented to the Online National Conference on Research and Developments in Material Processing, Modelling and Characterization 2020 (RDMPMC-2020) held on 26th and 27th August 2020 organized by the Department of Metallurgical and Materials Science in Association with the Department of Production and Industrial Engineering, National Institute of Technology Jamshedpur, Jharkhand, India. Conference Title: National Conference on Research and Developments in Material Processing, Modelling and Characterization 2020Conference Acronym: RDMPMC-2020Conference Date: 26–27 August 2020Conference Location: Online (Virtual Mode)Conference Organizer: Department of Metallurgical and Materials Engineering, National Institute of Technology JamshedpurCo-organizer: Department of Production and Industrial Engineering, National Institute of Technology Jamshedpur, Jharkhand, IndiaConference Sponsor: TEQIP-

Students' participation in collaborative research should be recognised

Letter to the editor