Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people.

中文翻译：

---

BPIFB4 循环水平及其在 COVID-19 中的预后相关性

由于衰老相关事件和有害炎症，衰老和合并症使个体面临 COVID-19 严重疾病和死亡的最大风险。长寿个体 (LLI) 不太容易受到炎症的影响，并且对 COVID-19 的抵抗力更强。正如所证明的，LLI 的特征在于高循环水平的 BPIFB4，一种参与对炎症刺激的稳态反应的蛋白质。此外，LLI 显示 BPIFB4 中 4 个错义单核苷酸多态性单倍型（长寿相关变体 [LAV]）的次要等位基因的纯合基因型富集，能够抵消动物模型中疾病的进展。因此，本研究旨在评估 BPIFB4 水平在 COVID-19 患者中的存在和意义，以及 LAV-BPIFB4 在对抗 COVID-19 中的潜在治疗用途。发现 LLI 中的 BPIFB4 血浆浓度显着高于老年健康对照，而在 64 名 COVID-19 患者中显着降低。此外，BPIFB4 值的下降与疾病严重程度相关。根据 LAV-BPIFB4 的免疫调节作用，虽然 SARS-CoV-2 感染细胞的裂解物在体外诱导健康外周血单核细胞的炎症反应，但与重组蛋白 (rh) LAV-BPIFB4 的共同处理导致了保护性和自限反应，最终导致 T 细胞（TCD4+ 和 TCD8+）的 CD69 激活标志物下调和 MCP-1 减少。相反，rhLAV-BPIFB4 诱导了 IL-18 和 IL-1b 水平的快速增加，在病毒感染的早期阶段表现出很大的保护作用。这个证据，