Andrew Teo

Exposure to dengue virus (DENV) triggers the development of anti-viral antibodies that may contribute to either protection or disease progression. Antibodies exist in different isotypes and subtypes, with diverse specificities and functions. IgG antibodies are produced during primary and secondary DENV infections, where they play a role central role in mediating protective immunity, and may also contribute to antibody-dependent enhancement in a secondary heterotypic infection. Although IgG antibodies are widely recognised as key mediators of protective immune responses during DENV infection, antibody specificities, types and functions that reliably correlate with protection remain unclear. A better understanding of anti-DENV antibodies and their roles in protection against symptomatic dengue is essential especially in guiding the design of dengue vaccines. In this review, antibody functions and effector mechanisms in DENV infection are discussed, with a focus on naturally acquired immunity and neutralising antibody responses following vaccination. In addition, current knowledge gaps in antibody functions during DENV infection will be highlighted.

Severe dengue can damage the liver through unestablished mechanisms. We investigated the role of myeloperoxidase (MPO), a neutrophil enzyme, in dengue through patients, fatal liver samples, and mouse infection models. Observations from two independent clinical cohorts revealed elevated plasma MPO levels in dengue and, in one cohort, MPO was further linked to liver injury markers during the critical phase of disease, whereas livers from dengue fatal cases revealed MPO build-up in the vicinity of CD177+ activated neutrophils. In mice, dengue led to MPO overexpression, oxidative damage, and broad activation of innate and systemic inflammatory pathways in livers. Blocking MPO activity alleviated these and improved survival in one model and delayed disease progression without preventing death in another. These findings establish MPO as a functional mediator of severe dengue-associated liver injury and inflammation, which warrants further preclinical investigation into its hepatic pathogenic mechanism and its validity as target for therapeutic intervention.

Reliable prognostic biomarkers remain an unmet need in dengue. We evaluated urinary neutrophil gelatinase-associated lipocalin and soluble urokinase plasminogen activator receptor for severe dengue prediction in the febrile phase. Urinary neutrophil gelatinase-associated lipocalin and soluble urokinase plasminogen activator receptor demonstrated areas under the receiver operating curve of 0.88 and 0.79, respectively, in discriminating against severe dengue. The noninvasive sampling offers practical advantages as risk stratification tools.

In the early COVID-19 pandemic, the strain on healthcare facilities highlighted the need for reliable biomarkers to predict progression to severe COVID-19. Neutrophils, the most abundant leukocytes in circulation, are early defenders against pathogens. In a Singaporean adult cohort, early neutrophil mediators were assessed for their suitability as prognostic biomarkers of COVID-19 complications. Plasma levels of myeloperoxidase (MPO), elastase, soluble urokinase plasminogen activator receptor (suPAR), and soluble suppressor of tumorigenicity 2 (sST2) in 35 nonsevere and 14 severe cases were measured twice, 2 to 7 d apart after hospitalization. Nineteen controls were included. The levels of MPO, elastase, suPAR, and sST2 were significantly higher in patients with severe COVID-19 compared with those with mild and healthy controls. At baseline sampling, MPO and suPAR predicted severe COVID-19 and had AUROCs of 0.76 and 0.87, respectively. MPO and suPAR at cut-off values of 26.41 ng/mL and 3.19 ng/mL, respectively showed approximately 71% sensitivity and 81% to 84% specificity to differentiate severe COVID-19. In contrast, elastase and neutrophil counts were less predictive of severe disease. In adult COVID-19, MPO and suPAR may be reliable prognostic biomarkers of severe disease during acute COVID-19. Further validation of these markers in a larger cohort and in other infectious diseases is warranted.

COVID-19 is a respiratory infection caused by the highly transmissible SARS-CoV-2. While most infected patients exhibit mild to moderate symptoms, a minority may develop severe vascular damage, which can be fatal. One example of this damage is disruption to the endothelial glycocalyx (EG) layer. EG alterations have been implicated in microcirculation changes and severe endothelial dysfunction in COVID-19 [1,2]. Current evidence suggests that host-pathogen interactions, such as hyperimmune activation or persistent presence of viral antigens, are associated with EG damage and may potentially bring about continuous endothelial dysfunction even after clinical recovery. Notably, the glycocalyx is also present on the epithelium, but we will focus on the EG and its implication on vascular health in COVID-19. Additionally, we will propose possible mediators that are linked with EG damage and suggest therapeutic agents that could aid EG restoration and protection.

Background: Dengue cases continue to rise and can overwhelm healthcare systems during outbreaks. In dengue, neutrophil mediators, soluble urokinase plasminogen activator receptor (suPAR) and olfactomedin 4, and mast cell mediators, chymase and tryptase, have not been measured longitudinally across the dengue phases. The utility of these proteins as prognostic biomarkers for severe dengue has also not been assessed in an older adult population. Methods: We prospectively enrolled 99 adults with dengue—40 dengue fever, 46 dengue with warning signs and 13 severe dengue, along with 30 controls. Plasma levels of suPAR, olfactomedin 4, chymase and tryptase were measured at the febrile, critical and recovery phases in dengue patients. Results: The suPAR levels were significantly elevated in severe dengue compared to the other dengue severities and controls in the febrile (P < .001), critical (P < .001), and recovery (P = .005) phases. In the febrile phase, suPAR was a prognostic biomarker of severe dengue, with an AUROC of 0.82. Using a cutoff derived from Youden's index (5.4 ng/mL) and an estimated prevalence of severe dengue (16.5%) in our healthcare institution, the sensitivity was 71.4% with a specificity of 87.9% in the febrile phase, and the positive and negative predictive values were 54.7% and 95.8%, respectively. Olfactomedin 4 was elevated in dengue patients but not in proportion to disease severity in the febrile phase (P = .04) There were no significant differences in chymase and tryptase levels between dengue patients and controls. Conclusions: In adult dengue, suPAR may be a reliable prognostic biomarker for severe dengue in the febrile phase.

Background: SARS-CoV-2, the causative agent of COVID-19, is a threat to public health. Evidence suggests increased neutrophil activation and endothelial glycocalyx (EG) damage are independently associated with severe COVID-19. Here, we hypothesised that an increased level of blood neutrophil myeloperoxidase (MPO) is associated with soluble EG breakdown, and inhibiting MPO activity may reduce EG damage. Methods: Analysing a subset of acute and convalescent COVID-19 plasma, 10 from severe and 15 from non-severe COVID-19 cases, and 9 from pre-COVID-19 controls, we determined MPO levels, MPO activity and soluble EG proteins (syndecan-1 and glypican-1) levels by enzyme-linked immunosorbent assay. In vitro primary human aortic endothelial cells were cultured with plasma untreated or treated with specific MPO inhibitors (MPO-IN-28, AZD5904) to determine EG shedding. We then investigated whether inhibiting MPO activity decreased EG degradation. Results: In COVID-19 plasma, MPO levels, MPO activity and levels of soluble EG proteins are significantly raised compared to controls, and concentrations increase in proportion to disease severity. Despite clinical recovery, protein concentrations remain significantly elevated. Interestingly, there is a trend of increasing MPO activity in convalescent plasma in both severe and non-severe groups. MPO levels and MPO activity correlate significantly with soluble EG levels and inhibiting MPO activity leads to reduced syndecan-1 shedding, in vitro. Conclusions: Neutrophil MPO may increase EG shedding in COVID-19, and inhibiting MPO activity may protect against EG degradation. Further research is needed to evaluate the utility of MPO inhibitors as potential therapeutics against severe COVID-19.