The urgent need for an effective SARS-CoV-2 vaccine has forced development to progress in the absence of well-defined correlates of immunity. While neutralization has been linked to protection ...against other pathogens, whether neutralization alone will be sufficient to drive protection against SARS-CoV-2 in the broader population remains unclear. Therefore, to fully define protective humoral immunity, we dissected the early evolution of the humoral response in 193 hospitalized individuals ranging from moderate to severe. Although robust IgM and IgA responses evolved in both survivors and non-survivors with severe disease, non-survivors showed attenuated IgG responses, accompanied by compromised Fcɣ receptor binding and Fc effector activity, pointing to deficient humoral development rather than disease-enhancing humoral immunity. In contrast, individuals with moderate disease exhibited delayed responses that ultimately matured. These data highlight distinct humoral trajectories associated with resolution of SARS-CoV-2 infection and the need for early functional humoral immunity.
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•IgA and IgM evolve rapidly across all levels of disease severity•Rapid and potent IgG class switching is linked to survival•Moderate disease is associated with a delay but ultimate convergence of IgG•Early S2-cross-reactivity is linked to survival after severe disease
Analyses of the functional humoral trajectories associated with the resolution of SARS-CoV-2 infection find that despite equivalent IgM and IgA immunity to the virus across all levels of disease severity, survival and recovery are linked to early class switching to IgG and the ability to leverage Fcγ receptors targeting the spike protein.
As SARS-CoV-2 infections and death counts continue to rise, it remains unclear why some individuals recover from infection, whereas others rapidly progress and die. Although the immunological ...mechanisms that underlie different clinical trajectories remain poorly defined, pathogen-specific antibodies often point to immunological mechanisms of protection. Here, we profiled SARS-CoV-2-specific humoral responses in a cohort of 22 hospitalized individuals. Despite inter-individual heterogeneity, distinct antibody signatures resolved individuals with different outcomes. Although no differences in SARS-CoV-2-specific IgG levels were observed, spike-specific humoral responses were enriched among convalescent individuals, whereas functional antibody responses to the nucleocapsid were elevated in deceased individuals. Furthermore, this enriched immunodominant spike-specific antibody profile in convalescents was confirmed in a larger validation cohort. These results demonstrate that early antigen-specific and qualitative features of SARS-CoV-2-specific antibodies point to differences in disease trajectory, highlighting the potential importance of functional antigen-specific humoral immunity to guide patient care and vaccine development.
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•Limited early differences were observed in titers and neutralization across groups•Five antibody features could collectively differentiate convalescents and deceased•A shift in the balance of spike versus nucleocapsid immunity separated the groups•Spike-specific phagocytic and complement fixing activity was enriched in convalescents
Although most SARS-CoV-2-infected individuals experience mild disease, a significant fraction of individuals become severely infected. Early biomarkers that predict outcome are urgently needed. Atyeo et al. demonstrate that distinct acute SARS-CoV-2 humoral immune responses exist across severely ill individuals who ultimately convalesce or pass away.
SARS-CoV-2-specific ELISA development Roy, Vicky; Fischinger, Stephanie; Atyeo, Caroline ...
Journal of immunological methods,
09/2020, Letnik:
484-485
Journal Article
Recenzirano
Odprti dostop
Critical to managing the spread of COVID-19 is the ability to diagnose infection and define the acquired immune response across the population. While genomic tests for the novel Several Acute ...Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) detect the presence of viral RNA for a limited time frame, when the virus is shed in the upper respiratory tract, tests able to define exposure and infection beyond this short window of detectable viral replication are urgently needed. Following infection, antibodies are generated within days, providing a durable read-out and archive of exposure and infection. Several antibody tests have emerged to diagnose SARS-CoV-2. Here we report on a qualified quantitative ELISA assay that displays all the necessary characteristics for high-throughput sample analysis. Collectively, this test offers a quantitative opportunity to define both exposure and levels of immunity to SARS-CoV-2.
Structure-based vaccine design depends on extensive structural analyses of antigen–antibody complexes.Single-particle electron cryomicroscopy (cryoEM) can circumvent some of the problems of x-ray ...crystallography as a pipeline for obtaining the required structures. We have examined the potential of single-particle cryoEM for determining the structure of influenza-virus hemagglutinin (HA):single-chain variable-domain fragment complexes, by studying a complex we failed to crystallize in pursuing an extended project on the human immune response to influenza vaccines.The result shows that a combination of cryoEM and molecular modeling can yield details of the antigen-antibody interface, although small variation in the twist of the rod-likeHA trimer limited the overall resolution to about 4.5Å.Comparison of principal 3D classes suggests ways to modify the HA trimer to overcome this limitation. A closely related antibody from the same donor did yield crystals when bound with the same HA, giving us an independent validation of the cryoEM results.The two structures also augment our understanding of receptor-binding site recognition by antibodies that neutralize a wide range of influenza-virus variants.
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•Single-particle cryoEM of antigen–antibody complexes•Influenza virus HA bound with single-chain Fv•cryoEM and molecular modeling yield details of the antigen:antibody interface.•HA receptor-binding site recognition by broadly neutralizing antibodies
Most studies of plant–animal mutualistic networks have come from a temporally static perspective. This approach has revealed general patterns in network structure, but limits our ability to ...understand the ecological and evolutionary processes that shape these networks and to predict the consequences of natural and human‐driven disturbance on species interactions. We review the growing literature on temporal dynamics of plant–animal mutualistic networks including pollination, seed dispersal and ant defence mutualisms. We then discuss potential mechanisms underlying such variation in interactions, ranging from behavioural and physiological processes at the finest temporal scales to ecological and evolutionary processes at the broadest. We find that at the finest temporal scales (days, weeks, months) mutualistic interactions are highly dynamic, with considerable variation in network structure. At intermediate scales (years, decades), networks still exhibit high levels of temporal variation, but such variation appears to influence network properties only weakly. At the broadest temporal scales (many decades, centuries and beyond), continued shifts in interactions appear to reshape network structure, leading to dramatic community changes, including loss of species and function. Our review highlights the importance of considering the temporal dimension for understanding the ecology and evolution of complex webs of mutualistic interactions.
We review the growing literature on the temporal dynamics of plant–animal mutualistic networks, discuss potential mechanisms underlying such change and identify the research frontiers in the study of the temporal dynamics of mutualistic networks. Our synthesis highlights the importance of considering the temporal dimension for understanding the ecology and evolution of complex webs of mutualistic interactions.
Long-chain fatty acid (LCFA) oxidation has been shown to play an important role in interleukin-4 (IL-4)-mediated macrophage polarization (M(IL-4)). However, many of these conclusions are based on the ...inhibition of carnitine palmitoyltransferase-1 with high concentrations of etomoxir that far exceed what is required to inhibit enzyme activity (EC90 < 3 μM). We employ genetic and pharmacologic models to demonstrate that LCFA oxidation is largely dispensable for IL-4-driven polarization. Unexpectedly, high concentrations of etomoxir retained the ability to disrupt M(IL-4) polarization in the absence of Cpt1a or Cpt2 expression. Although excess etomoxir inhibits the adenine nucleotide translocase, oxidative phosphorylation is surprisingly dispensable for M(IL-4). Instead, the block in polarization was traced to depletion of intracellular free coenzyme A (CoA), likely resulting from conversion of the pro-drug etomoxir into active etomoxiryl CoA. These studies help explain the effect(s) of excess etomoxir on immune cells and reveal an unappreciated role for CoA metabolism in macrophage polarization.
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•Alternative macrophage activation by IL-4 does not require fatty acid oxidation•Etomoxir concentrations ≥10 μM inhibit the adenine nucleotide translocase•OXPHOS is dispensable for many markers of IL-4-activated macrophages (M(IL-4))•200 μM etomoxir blocks M(IL-4) by perturbing intracellular coenzyme A homeostasis
The CPT-1 inhibitor etomoxir has been used to suggest long-chain fatty acid (LCFA) oxidation is necessary for alternative macrophage activation. Divakaruni and colleagues now show that LCFA oxidation is dispensable. They demonstrate multiple off-target effects of etomoxir and show that depletion of coenzyme A by etomoxir blocks M(IL-4) differentiation.
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