Neutralization assays of SARS-CoV-2 pseudoviruses expressing wild-type, omicron, or a synthetic resistant spike protein in plasma drawn from 47 people over time showed much lower omicron ...neutralization than Wuhan-hu-1 neutralization after two doses of an mRNA vaccine. However, samples from persons vaccinated after recovery from Covid-19 and those who received a booster vaccine had high levels of omicron neutralization.
The number and variability of the neutralizing epitopes targeted by polyclonal antibodies in individuals who are SARS-CoV-2 convalescent and vaccinated are key determinants of neutralization breadth ...and the genetic barrier to viral escape
. Using HIV-1 pseudotypes and plasma selection experiments with vesicular stomatitis virus/SARS-CoV-2 chimaeras
, here we show that multiple neutralizing epitopes, within and outside the receptor-binding domain, are variably targeted by human polyclonal antibodies. Antibody targets coincide with spike sequences that are enriched for diversity in natural SARS-CoV-2 populations. By combining plasma-selected spike substitutions, we generated synthetic 'polymutant' spike protein pseudotypes that resisted polyclonal antibody neutralization to a similar degree as circulating variants of concern. By aggregating variant of concern-associated and antibody-selected spike substitutions into a single polymutant spike protein, we show that 20 naturally occurring mutations in the SARS-CoV-2 spike protein are sufficient to generate pseudotypes with near-complete resistance to the polyclonal neutralizing antibodies generated by individuals who are convalescent or recipients who received an mRNA vaccine. However, plasma from individuals who had been infected and subsequently received mRNA vaccination neutralized pseudotypes bearing this highly resistant SARS-CoV-2 polymutant spike, or diverse sarbecovirus spike proteins. Thus, optimally elicited human polyclonal antibodies against SARS-CoV-2 should be resilient to substantial future SARS-CoV-2 variation and may confer protection against potential future sarbecovirus pandemics.
More than one year after its inception, the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains difficult to control despite ...the availability of several working vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies
. Here we report on a cohort of 63 individuals who have recovered from COVID-19 assessed at 1.3, 6.2 and 12 months after SARS-CoV-2 infection, 41% of whom also received mRNA vaccines
. In the absence of vaccination, antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable between 6 and 12 months after infection. Vaccination increases all components of the humoral response and, as expected, results in serum neutralizing activities against variants of concern similar to or greater than the neutralizing activity against the original Wuhan Hu-1 strain achieved by vaccination of naive individuals
. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in the variants of concern
. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand markedly after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants.
Antibodies elicited by infection accumulate somatic mutations in germinal centers that can increase affinity for cognate antigens. We analyzed 6 independent groups of clonally related severe acute ...respiratory syndrome-coronavirus-2 (SARS-CoV-2) Spike receptor-binding domain (RBD)-specific antibodies from 5 individuals shortly after infection and later in convalescence to determine the impact of maturation over months. In addition to increased affinity and neutralization potency, antibody evolution changed the mutational pathways for the acquisition of viral resistance and restricted neutralization escape options. For some antibodies, maturation imposed a requirement for multiple substitutions to enable escape. For certain antibodies, affinity maturation enabled the neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.
Display omitted
•Maturation over months increases potency of SARS-CoV-2 neutralizing antibodies•Antibody maturation restricts options for viral escape•Maturation of some antibodies enables neutralization of additional sarbecoviruses•Antibody-spike structures reveal changes that improve potency and breadth
SARS-CoV-2 RBD-binding antibodies accumulate mutations over months of convalescence, but how maturation affects antibody properties is unclear. Muecksch et al. analyze 6 groups of clonally related neutralizing antibodies from convalescent donors and reveal that antibody maturation increases affinity, potency, and breadth, and restricts viral escape options. They also identify the structural basis for these improved antibody properties during maturation.
Vaccination will likely be a key component of strategies to curtail or prevent future sarbecovirus pandemics and to reduce the prevalence of infection and disease by future SARS-CoV-2 variants. A ..."pan-sarbecovirus" vaccine, that provides maximum possible mitigation of human disease, should elicit neutralizing antibodies with maximum possible breadth. By positioning multiple different receptor binding domain (RBD) antigens in close proximity on a single immunogen, it is postulated that cross-reactive B cell receptors might be selectively engaged. Heteromultimeric vaccines could therefore elicit individual antibodies that neutralize a broad range of viral species. Here, we use model systems to investigate the ability of multimeric sarbecovirus RBD immunogens to expand cross-reactive B cells and elicit broadly reactive antibodies. Homomultimeric RBD immunogens generated higher serum neutralizing antibody titers than the equivalent monomeric immunogens, while heteromultimeric RBD immunogens generated neutralizing antibodies recognizing each RBD component. Moreover, RBD heterodimers elicited a greater fraction of cross-reactive germinal center B cells and cross-reactive RBD binding antibodies than did homodimers. However, when serum antibodies from RBD heterodimer-immunized mice were depleted using one RBD component, neutralization activity against the homologous viral pseudotype was removed, but neutralization activity against pseudotypes corresponding to the other RBD component was unaffected. Overall, simply combining divergent RBDs in a single immunogen generates largely separate sets of individual RBD-specific neutralizing serum antibodies that are mostly incapable of neutralizing viruses that diverge from the immunogen components.
This study aimed to evaluate the association between employment status and mental health, considering food insecurity as a mediator of this relation. A cross-sectional population-based study was ...conducted with adults (≥ 18 and < 60 years) during the COVID-19 outbreak in two cities from Southern Brazil. Employment status was categorized into working, not working, and lost job. The mental health outcomes evaluated were depressive symptoms, perceived stress, and sadness. Food insecurity was identified by the short-form version of the Brazilian Food Insecurity Scale. Adjusted analyses using Poisson regression were performed to assess the association between employment status and mental health. Mediation analysis was performed to investigate the direct and indirect effects of employment status on mental health outcomes. In total, 1,492 adults were analyzed. The not working status was associated with 53% and 74% higher odds of perceived stress and of sadness, respectively. Being dismissed during the pandemic increased the odds of depressive symptoms, perceived stress, and sadness by 68%, 123%, and 128%, respectively. Mediation analyses showed that food insecurity was an important mediator of the association between employment status and depressive symptoms and sadness, but not of perceived stress. The complexity of these results highlights economic and nutritional aspects involved in mental health outcomes.
Resumen: El objetivo fue evaluar la asociación entre la situación laboral y la salud mental y el papel de la inseguridad alimentaria como mediador en esta relación. Se realizó un estudio transversal basado en la población con adultos (≥ 18 y < 60 años) durante el brote de COVID-19 en dos ciudades del Sur de Brasil. La situación laboral se clasificó en trabajando, no trabajando y pérdida de empleo. Los resultados de salud mental evaluados fueron síntomas depresivos, percepción de estrés y sensación de tristeza. La inseguridad alimentaria fue identificada por la versión reducida de la Escala Brasileña de Inseguridad Alimentaria. Se realizaron análisis ajustados por regresión de Poisson para evaluar la asociación entre la situación laboral y la salud mental. Se realizó un análisis de mediación para investigar los efectos directos e indirectos de la situación laboral en los resultados de salud mental. En total, se analizaron 1.492 adultos. No trabajar se asoció con un 53% más de probabilidades de percepción de estrés y un 74% más de probabilidades de tristeza. La pérdida del trabajo aumentó las probabilidades de síntomas depresivos, estrés percibido y sentimientos de tristeza en un 68%, 123% y 128%, respectivamente. Los análisis de mediación mostraron que la inseguridad alimentaria era un mediador importante de la asociación entre la situación laboral y los síntomas depresivos y los sentimientos de tristeza, pero no para el estrés percibido. La complejidad de estos resultados destaca los aspectos económicos y nutricionales que intervienen en los resultados de salud mental.
Resumo: O objetivo foi avaliar a associação entre situação de trabalho e saúde mental e o papel da insegurança alimentar como mediadora dessa relação. Um estudo transversal de base populacional foi conduzido com adultos (≥ 18 e < 60 anos) durante o surto de COVID-19 em duas cidades do Sul do Brasil. A situação de trabalho foi categorizada em trabalhando, não trabalhando e perda do emprego. Os desfechos de saúde mental avaliados foram sintomas depressivos, percepção de estresse e sentimento de tristeza. A insegurança alimentar foi identificada pela versão reduzida da Escala Brasileira de Insegurança Alimentar. Análises ajustadas por regressão de Poisson foram realizadas para avaliar a associação entre situação de trabalho e saúde mental. A análise de mediação foi realizada para investigar os efeitos diretos e indiretos da situação de trabalho sobre os desfechos de saúde mental. No total, foram analisados 1.492 adultos. Não trabalhar associou-se a 53% mais chances de percepção de estresse e 74% maiores de tristeza. A perda do emprego aumentou as chances de sintomas depressivos, estresse percebido e sentimento de tristeza em 68%, 123% e 128%, respectivamente. As análises de mediação mostraram que a insegurança alimentar foi um importante mediador da associação entre situação de trabalho e sintomas depressivos e sentimento de tristeza, mas não para o estresse percebido. A complexidade desses resultados destaca aspectos econômicos e nutricionais envolvidos nos desfechos em saúde mental.
The parent geological materials and formation factors influence the chemical, physical, and mineralogical properties and composition of the soil. Therefore, the aims of this study were to determine ...the chemical and some physical and mineralogical properties of the soil useful for agricultural practice; to determine the natural contents of the semitotal metals in soils of the state of Rio Grande do Sul (Brazil); and to suggest use of the quality reference values (QRVs) in accordance with Resolution 420/2009 of the National Commission for the Environment (Conama). To determine some soil properties useful for agricultural, 254 surface soil samples from areas without known human influence (native grasslands or forests) were analyzed according to the methodology used by the soil testing laboratories of the state of Rio Grande do Sul. In addition, the semitotal heavy metal (Cd, Co, Cr, Cu, Ni, Pb, V, and Zn) contents of the soil were determined by the Usepa 3050B method and Hg was determined through an adaptation of the Usepa 7471 method. The results were studied in five soil groups from the state of Rio Grande do Sul according to soil parent materials: (1) basalt (volcanic rocks) of the Plateau region, (2) crystalline rocks (granite, schists, etc.) of the Southern Shield, (3) pelitic rocks (siltstones, mudstones, etc.) of the Peripheral Depression, (4) sandstones (sedimentary) of the Central Plains, and (5) sediments (unconsolidated) of the Coastal Plains. The properties for agricultural use of these soils were compared using the criteria adopted by the current fertilizer recommendations for the state. Multivariate analysis was used to study metals contents. Average values of available P contents were low in all soil groups; however, average values were high in several soil groups for available K. Averages of total acidity and cation exchange capacity were higher in Group 1 soils. The average values of extractable Zn, Cu, and S were high in all soils. Averages of Fe oxides were higher in the soils formed over basalt than in the other soils. Average metal (Cd, Co, Cr, Cu, Ni, Pb, V, and Zn) contents were higher in Group 1 soils than in the other soil groups (2 to 5). For Hg, however, average values were similar for all soil groups. The Spearman correlation coefficients were positive and highest among the metals (except for Cd and Hg) and the clay, Fed, and extractable Cu soil properties. Another high positive correlation coefficient was found between semitotal Cu and Zn contents and organic carbon. The QRVs for Cd, Co, Cr, Cu, Hg, Ni, Pb, V, and Zn, determined according to Conama Resolution 420/2009, followed the same trend as the average metals contents.
Individuals who receive a third mRNA vaccine dose show enhanced protection against severe COVID-19, but little is known about the impact of breakthrough infections on memory responses. Here, we ...examine the memory antibodies that develop after a third or fourth antigenic exposure by Delta or Omicron BA.1 infection, respectively. A third exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a third mRNA vaccine dose. A fourth antigenic exposure with Omicron BA.1 infection increased variant-specific plasma antibody and memory B cell responses. However, the fourth exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a third mRNA vaccine dose. In conclusion, a third antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a fourth antigenic exposure with Omicron BA.1 are limited to increased strain-specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.
Abstract
Candida albicans cell wall glycoproteins, and in particular their mannose-rich glycans, are important for maintaining cellular integrity as well as host recognition, adhesion, and ...immunomodulation. The asparagine (N)-linked mannose outer chain of these glycoproteins is produced by Golgi mannosyltransferases (MTases). The outer chain is composed of a linear backbone of ∼50 α1,6-linked mannoses, which acts as a scaffold for addition of ∼150 or more mannoses in other linkages. Here, we describe the characterization of C. albicans OCH1, MNN9, VAN1, ANP1, MNN10, and MNN11, which encode the conserved Golgi MTases that sequentially catalyze the α1,6 mannose outer chain backbone. Candida albicans och1Δ/Δ, mnn9Δ/Δ, and van1Δ/Δ mutants block the earliest steps of backbone synthesis and like their Saccharomyces cerevisiae counterparts, have severe cell wall and growth phenotypes. Unexpectedly, and in stark contrast to S. cerevisiae, loss of Anp1, Mnn10, or Mnn11, which together synthesize most of the backbone, have no obvious deleterious phenotypes. These mutants were unaffected in cell morphology, growth, drug sensitivities, hyphal formation, and macrophage recognition. Analyses of secreted glycosylation reporters demonstrated that anp1Δ/Δ, mnn10Δ/Δ, and mnn11Δ/Δ strains accumulate glycoproteins with severely truncated N-glycan chains. This hypo-mannosylation did not elicit increased chitin deposition in the cell wall, which in other yeast and fungi is a key compensatory response to cell wall integrity breaches. Thus, C. albicans has evolved an alternate mechanism to adapt to cell wall weakness when N-linked mannan levels are reduced.
The use of genetically modified (GM) plants has increased in recent decades, but there are uncertainties about their effects on soil microbial communities. Aiming to quantify root colonization and ...characterize arbuscular mycorrhizal fungi (AMF) communities associated with roots and rhizosphere soil of different maize genotypes, a field trial was carried out in Southern Brazil with three maize genotypes as follows: a GM hybrid (DKB 240 VTPRO), its non-modified isoline (DKB 240), and a landrace (Pixurum). Soil samples were collected to evaluate the occurrence of AMF during the growth of corn genotypes at sowing and V3 (vegetative), R1 (flowering), and R3 (grain formation) stages of the crop. The occurrence of AMF was determined by the morphological identification of spores, and by analyzing AMF community composition in soil and roots of maize, using PCR-DGGE. The GM genotype of maize promoted lower mycorrhizal colonization in the vegetative stage and had lower sporulation at grain development than the conventional hybrid and the landrace maize. Twenty AMF morphotypes were identified and 13 were associated with all maize genotypes. The genera
Acaulospora
,
Glomus
, and
Dentiscutata
had the largest numbers of species. There were no differences in AMF community composition due to maize genotypes or genetic modification, but crop phenological stages affected AMF communities associated with maize roots.
PDF
