HLA-Bw4 in association with KIR3DL1 favors natural killer cell-mediated protection against severe COVID-19.

Replicating SARS-CoV-2 has been shown to degrade HLA class I on target cells to evade the cytotoxic T-cell (CTL) response. HLA-I downregulation can be sensed by NK cells to unleash killer cell immunoglobulin-like receptor (KIR)-mediated self-inhibition by the cognate HLA-I ligands. Here, we investigated the impact of HLA and KIR genotypes and HLA-KIR combinations on COVID-19 outcome. We found that the peptide affinities of HLA alleles were not correlated with COVID-19 severity. The predicted poor binders for SARS-CoV-2 peptides belong to HLA-B subtypes that encode KIR ligands, including Bw4 and C1 (introduced by B*46:01), which have a small F pocket and cannot accommodate SARS-CoV-2 CTL epitopes. However, HLA-Bw4 weak binders were beneficial for COVID-19 outcome, and individuals lacking the HLA-Bw4 motif were at higher risk for serious illness from COVID-19. The presence of the HLA-Bw4 and KIR3DL1 combination had a 58.8% lower risk of developing severe COVID-19 (OR = 0.412, 95% CI = 0.187-0.904, p = 0.02). This suggests that HLA-Bw4 alleles that impair their ability to load SARS-CoV-2 peptides will become targets for NK-mediated destruction. Thus, we proposed that the synergistic responsiveness of CTLs and NK cells can efficiently control SARS-CoV-2 infection and replication, and NK-cell-mediated anti-SARS-CoV-2 immune responses being mostly involved in severe infection when the level of ORF8 is high enough to degrade HLA-I. The HLA-Bw4/KIR3DL1 genotype may be particularly important for East Asians undergoing COVID-19 who are enriched in HLA-Bw4-inhibitory KIR interactions and carry a high frequency of HLA-Bw4 alleles that bind poorly to coronavirus peptides.

How Healthy Aging and Contact With Children Are Associated With Satisfaction in Middle-Aged and Older Parents in China: A Mediation Analysis.

Objectives: This study aims to examine the mediation role of satisfaction with children on the association between contact with children (CCT) and healthy aging among middle-aged and older parents in China. Methods: Data from 9,575 parents over 45 years old were obtained from the 2018 China Health and Retirement Longitudinal Survey. A multinomial logistic regression model was applied to measure the association between contact, satisfaction, and healthy aging with potential confounders controlled. We used the Sobel-Goodman Mediation test to analyze the mediation role of satisfaction on the association between types of CCT and healthy aging. Results: Parents with contact with adult children had higher satisfaction with children [for contact weekly (satisfied/unsatisfied): relative risk ratio (RRR) = 2.44, CI = 1.92-3.10] and higher healthy aging [for contact weekly (Q5/Q1): RRR = 1.41, CI = 1.13-1.77]. Satisfaction was strongly related to healthy aging [for satisfied (Q5/Q1): RRR = 3.44, CI = 2.14-5.51], and mediated 19.05% of healthy aging for weekly contact (Sobel test z = 4.338; indirect role = 0.014, CI = 0.011-0.018; direct role = 0.061, CI = 0.029-0.094). Subgroup analysis further revealed that satisfaction with contact played a partial mediating role between monthly contact and healthy aging in female and rural groups. Conclusions: Monthly CCT is more appropriate for older parents. Satisfaction with children in older parents seems to act as a significant and partial mediator of the relationship between contact and healthy aging. The contribution of satisfaction to healthy aging could be important to be considered and promoted in women and rural older parents, independent of CCT.

Rapid Development of SARS-CoV-2 Spike Protein Receptor-Binding Domain Self-Assembled Nanoparticle Vaccine Candidates.

The coronavirus disease pandemic of 2019 (COVID-19) caused by the novel SARS-CoV-2 coronavirus resulted in economic losses and threatened human health worldwide. The pandemic highlights an urgent need for a stable, easily produced, and effective vaccine. SARS-CoV-2 uses the spike protein receptor-binding domain (RBD) to bind its cognate receptor, angiotensin-converting enzyme 2 (ACE2), and initiate membrane fusion. Thus, the RBD is an ideal target for vaccine development. In this study, we designed three different RBD-conjugated nanoparticle vaccine candidates, namely, RBD-Ferritin (24-mer), RBD-mi3 (60-mer), and RBD-I53-50 (120-mer), via covalent conjugation using the SpyTag-SpyCatcher system. When mice were immunized with the RBD-conjugated nanoparticles (NPs) in conjunction with the AddaVax or Sigma Adjuvant System, the resulting antisera exhibited 8- to 120-fold greater neutralizing activity against both a pseudovirus and the authentic virus than those of mice immunized with monomeric RBD. Most importantly, sera from mice immunized with RBD-conjugated NPs more efficiently blocked the binding of RBD to ACE2 in vitro, further corroborating the promising immunization effect. Additionally, the vaccine has distinct advantages in terms of a relatively simple scale-up and flexible assembly. These results illustrate that the SARS-CoV-2 RBD-conjugated nanoparticles developed in this study are a competitive vaccine candidate and that the carrier nanoparticles could be adopted as a universal platform for a future vaccine development.