BPIFB4 Circulating Levels and Its Prognostic Relevance in COVID-19

Abstract

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.

The association of COVID-19 severity and susceptibility and genetic risk factors: A systematic review of the literature

“… ( Baldassarri et al, 2021 ) BPIFB4 LAV-BPIFB4 Italy 171, 64 with COVID-19 Values of BPIFB4 were markedly lower in COVID-19-positive individuals as compared with negative patients.BPIFB4 levels in plasma are negatively correlated with SARS-CoV-2 illness severity. ( Ciaglia et al, 2021 ) Complement 3 Complement 3 (S) European, Mediterranean, and the Middle East Not mentioned C3 was associated with increased COVID-19-related death. ( Delanghe et al, 2021 ) CCR5 rs9845542, rs12639314, rs35951367, rs34418657 Europe 6406 hospitalized COVID-19 patients and 902,088 controls rs9845542, rs12639314, rs35951367 polymorphisms were associated with severe COVID-19 illness and low CCR5 expression ( Cantalupo et al, 2021 ) CCR5 rs333 Czech Republic 416 Δ32 deletion in the CCR5 , most found in Caucasians, could offer protection against COVID-19 illness.…”

Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline

“…Here we present exciting new results on the pleiotropic activity of LAV-BPIFB4, a well-known determinant of healthy aging [ 15 – 19 ] and resiliency to develop cardiovascular disease [ 18 , 21 , 22 ]. We describe for the first time the LAV-BPIFB4 efficacy in contrasting immunosenescence, inflammatory cytokine release, aorta senescence, activation of CD38 + cells, and NAD + decline in a murine model of advanced ageing.…”

“…These observations draw attention to our recent findings showing that LLIs showed to be exempted from the pro-inflammatory status typical of inflammaging because of the peculiar monocyte asset capable to polarize toward the anti-inflammatory M2 macrophages in a BPIFB4-dependent manner [ 15 ]. This finding together with the inverse correlation between BPIFB4 plasmatic level and the degree of COVID-19 severity [ 19 ] really suggest a better tendency to cope with harmful responses during infectious disease or deleterious chronic reactions.…”

“…BPIFB4 is a secreted protein, its levels are increased in serum of long-living individuals [ 15 ], and high BPIFB4 levels classify their health status [ 16 , 17 ]. Furthermore, a prognostic significance in vascular pathology (i.e., atherosclerotic patients) [ 18 ] and recently in COVID-19 severity, has been also conferred to its circulating levels [ 19 ]. Likewise, homozygous LAV carriers have higher circulating BPIFB4 levels and showed a huge increase in endothelial nitric oxisynthase (eNOS) activation in peripheral blood mononuclear cells (PBMCs) [ 16 , 20 ].…”

The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy

“…The longevity-associated variant encoded by a four-SNP haplotype of BPIFB4 (i.e., bactericidal/permeability-increasing fold-containing family B member 4) gene was previously found to be able to enhance health/longevity and cellular homeostasis both in several (in vitro and murine) models of human diseases (COVID-19, Huntington’s disease, heart failure, atherosclerosis, diabetic complications, frailty, etc.) and in frail people [ 32 , 33 , 34 , 35 , 36 ]. High levels of the secreted BPIFB4 protein are found in serum of long-living individuals (LLIs) classifying their healthy status [ 37 ].…”