Increased prevalence of AB group and FY*A red blood cell antigen in Caucasian SARS-CoV-2 convalescent plasma donors (preprint)

Background: The SARS-CoV-2 pandemic has put significant additional pressure on healthcare systems throughout the world. The identification of at-risk population beyond age, pre-existing medical conditions and socioeconomic status has been the subject of only a small part of the global COVID-19 research so far. To this day, the extent to which the red blood cell (RBC) antigens expressed by an individual can be associated with SARS-CoV-2 infection or clearance remains unknown. Methods: The phenotypes for ABO and RhD and the genotypes for 37 red blood cell (RBC) antigens were determined using high throughput platforms in 90 Caucasian convalescent plasma donors. The antigen frequencies were compared to the expected Caucasian frequencies using Z-tests for two-proportion. Results: The AB phenotype and FY*A genotype frequencies were both independently and significantly increased (1.5x, p=0.018 and 2.2x, p=0.028, respectively) in the convalescent cohort (N=90) compared to reference frequencies. The AB phenotype was also significantly overrepresented (3.2x, p=0.028) within the FY*A sub-group (N=23). The O group was underrepresented within the cohort proportionally to the AB increase, although non-significantly (p=0.110). No other significant RBC antigen expression patterns in the convalescent Caucasian population were identified. Conclusion: Altogether, our study reveals ABO and Duffy RBC antigen variation among surviving, non-hospitalized COVID-19 patients turned convalescent plasma donors and contributes to the global advancement in understanding COVID-19 potential risk factors.

Impact of School Reopening on Pandemic Spread: A Case Study using an Agent-Based Model for COVID-19 (preprint)

This article examines the impact of partial/full reopening of school/college campuses on the spread of a pandemic using COVID-19 as a case study. The study uses an agent-based simulation model that replicates community spread in an urban region of U.S.A. via daily social mixing of susceptible and infected individuals. Data representing population demographics, SARS-CoV-2 epidemiology, and social interventions guides the model's behavior, which is calibrated and validated using data reported by the government. The model indicates a modest but significant increase (8.15 %) in the total number of reported cases in the region for a complete (100%) reopening compared to keeping schools and colleges fully virtual. For partial returns of 75% and 50%, the percent increases in the number of reported cases are shown to be small (2.87% and 1.26%, respectively) and statistically insignificant. The AB model also predicts that relaxing the stringency of the school safety protocol for sanitizing, use of mask, social distancing, testing, and quarantining and thus allowing the school transmission coefficient to double may result in a small increase in the number of reported infected cases (2.14%). Hence for pandemic outbreaks from viruses with similar characteristics as for SARS-CoV-2, keeping the schools and colleges open with a modest campus safety protocol and in-person attendance below a certain threshold may be advisable.

Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability (preprint)

ABSTRACT Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, such as cancer, ischemic stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema and sepsis, which often leads to acute lung injury, including acute respiratory distress syndrome. However, after initially stimulating permeability, VEGF subsequently mediates angiogenesis to repair damaged tissue. Consequently, understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics that achieve the delicate balance of inhibiting vascular permeability while preserving tissue repair. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. Specifically, we show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9 generated genomic STAT3 knockout zebrafish. Importantly, STAT3 deficiency does not impair vascular development and function in vivo. We identify intercellular adhesion molecule 1 (ICAM-1) as a STAT3-dependent transcriptional regulator and show VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved anti-microbial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse, and human endothelium. Indeed, pharmacologically targeting STAT3 increases vascular barrier integrity using two additional compounds, atovaquone and C188-9. Collectively, our findings suggest that the VEGF, VEGFR-2, JAK2, and STAT3 signaling cascade regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability in vertebrate models. Key Points Genetic STAT3 deficiency in VEGF-inducible zebrafish and mice reveals that VEGF signals through STAT3 to promote vascular permeability Pyrimethamine, a clinically available agent that inhibits STAT3 activity, reduces VEGF-induced vascular permeability in preclinical models