Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Biomarker of Systemic Chronic Inflammation.

Systemic chronic inflammation (SCI) is persistent, health-damaging, low-grade inflammation that plays a major role in immunosenescence and in development and progression of many diseases. But currently, there are no recognized standard biomarkers to assess SCI levels alone, and SCI is typically measured by combining biomarkers of acute inflammation and infection, e.g., CRP, IL-6, and TNFα. In this review, we highlight 10 properties and characteristics that are shared by the blood protein soluble urokinase plasminogen activator receptor (suPAR) and SCI, supporting the argument that suPAR is a biomarker of SCI: (1) Expression and release of suPAR is upregulated by immune activation; (2) uPAR and suPAR exert pro-inflammatory functions; (3) suPAR is associated with the amount of circulating immune cells; (4) Blood suPAR levels correlate with the levels of established inflammatory biomarkers; (5) suPAR is minimally affected by acute changes and short-term influences, in contrast to many currently used markers of systemic inflammation; (6) Like SCI, suPAR is non-specifically associated with multiple diseases; (7) suPAR and SCI both predict morbidity and mortality; (8) suPAR and SCI share the same risk factors; (9) suPAR is associated with risk factors and outcomes of inflammation above and beyond other inflammatory biomarkers; (10) The suPAR level can be reduced by anti-inflammatory interventions and treatment of disease. Assessing SCI has the potential to inform risk for morbidity and mortality. Blood suPAR is a newer biomarker which may, in fact, be a biomarker of SCI since it is stably associated with inflammation and immune activation; shares the same risk factors as many age-related diseases; is both elevated by and predicts age-related diseases. There is strong evidence that suPAR is a prognostic marker of adverse events, morbidity, and mortality. It is associated with immune activity and prognosis across diverse conditions, including kidney disease, cardiovascular disease, cancer, diabetes, and inflammatory disorders. Thus, we think it likely represents a common underlying disease-process shared by many diseases; that is, SCI. We review the supporting literature and propose a research agenda that can help test the hypothesis that suPAR indexes SCI, with the potential of becoming the new gold standard for measuring SCI.

Soluble urokinase plasminogen activator receptor (suPAR) as a prognostic marker of mortality in healthy, general and patient populations: protocol for a systematic review and meta-analysis.

INTRODUCTION: Chronic inflammation is increasingly recognised as a major contributor to disease, disability and ultimately death, but measuring the levels of chronic inflammation remains non-canonised, making it difficult to relate chronic inflammation and mortality. Soluble urokinase plasminogen activator receptor (suPAR), an emerging biomarker of chronic inflammation, has been proposed as a prognostic biomarker associated with future incidence of chronic disease and mortality in general as well as patient populations. Proper prognostic biomarkers are important as they can help improve risk stratification in clinical settings and provide guidance in treatment or lifestyle decisions as well as in the design of randomised trials. Here, we wish to summarise the evidence about the overall association of the biomarker suPAR with mortality in healthy, general and patient populations across diseases. METHODS AND ANALYSIS: The search will be conducted using Medline, Embase and Scopus databases from their inception to 03 June 2020 to identify studies investigating 'suPAR' and 'mortality'. Observational studies and control groups from intervention studies written in English or Danish will be included. The 'Quality In Prognosis Studies' tool will be used to assess the risk of bias for the studies included. Unadjusted and adjusted mortality outcome measures (eg, risk ratios, ORs, HRs) with 95% CIs will be extracted for healthy individuals, general and patient populations. The primary outcome is all-cause mortality within any given follow-up. Subgroup analyses will be performed based on time of outcome, cause of death, population type, adjustments for conventional risk factors and inflammation markers. ETHICS AND DISSEMINATION: This systematic review will synthesise evidence on the use of suPAR as a prognostic marker for mortality. The results will be disseminated by publication in a peer-reviewed journal. Data used will be obtained from published studies, and ethics approval is therefore not necessary for this systematic review. TRIAL REGISTRATION NUMBER PROSPERO: CRD42020167401.

Plasmodium falciparum-infected erythrocyte knob density is linked to the PfEMP1 variant expressed.

UNLABELLED: Members of the clonally variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediate adhesion of infected erythrocytes (IEs) to vascular receptors. PfEMP1 expression is normally confined to nanoscale knob protrusions on the IE surface membrane. To investigate the relationship between the densities of these IE surface knobs and the PfEMP1 variant expressed, we used specific antibody panning to generate three sublines of the P. falciparum clone IT4, which expresses the PfEMP1 variants IT4VAR04, IT4VAR32b, and IT4VAR60. The knob density in each subline was then determined by atomic force microscopy (AFM) and scanning electron microscopy (SEM) and compared to PfEMP1 and knob-associated histidine-rich protein (KAHRP) expression. Selection for uniform expression of IT4VAR04 produced little change in knob density, compared to unselected IEs. In contrast, selection for IT4VAR32b expression increased knob density approximately 3-fold, whereas IEs selected for IT4VAR60 expression were essentially knobless. When IT4VAR60(+) IEs were subsequently selected to express IT4VAR04 or IT4VAR32b, they again displayed low and high knob densities, respectively. All sublines expressed KAHRP regardless of the PfEMP1 expressed. Our study documents for the first time that knob density is related to the PfEMP1 variant expressed. This may reflect topological requirements to ensure optimal adhesive properties of the IEs. IMPORTANCE: Infections with Plasmodium falciparum malaria parasites are still responsible for many deaths, especially among children and pregnant women. New interventions are needed to reduce severe illness and deaths caused by this malaria parasite. Thus, a better understanding of the mechanisms behind the pathogenesis is essential. A main reason why Plasmodium falciparum malaria is more severe than disease caused by other malaria species is its ability to express variant antigens on the infected erythrocyte surface. These antigens are presented on membrane protrusions known as knobs. This study set out to investigate the interplay between different variant antigens on the surface of P. falciparum-infected erythrocytes and the density of the knobs on which the antigens are expressed. Such a direct analysis of this relationship has not been reported before but adds to the important understanding of the complexity of malaria antigen presentation.