RESUMEN
1.Severe acute respiratory distress syndrome (ARDS) during SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection, manifests as uncontrolled lung inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies can reduce COVID-19 severity if administered in the early viremic phase, but treatments for later stage immuno-thrombotic syndrome and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases during thrombotic, thrombolytic and immune responses. The myxoma poxvirus-derived Serp-1 protein is a secreted immunomodulatory serpin that targets activated coagulation and complement protease pathways as part of a self-defense strategy to combat viral clearance by the innate immune system. When purified and utilized as an anti-immune therapeutic, Serp-1 is effective as an anti-inflammatory drug in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp-1 (PEGSerp-1) as a therapy for immuno-thrombotic complications during ARDS. Treatment with PEGSerp-1 in two distinct mouse-adapted SARS-CoV-2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved clinical outcomes. PEGSerp-1 significantly reduced M1 macrophage invasion in the lung and heart by modifying urokinase-type plasminogen activator receptor (uPAR) and complement membrane attack complex (MAC). Sequential changes in urokinase-type plasminogen activator receptor (uPAR) and serpin gene expression were observed in lung and heart with PEGSerp-1 treatment. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for treatment of severe viral ARDS with additional potential to reduce late SARS-CoV-2 complications related to immune-thrombotic events that persist during long COVID. SignificanceSevere acute respiratory distress syndrome (ARDS) in SARS-CoV-2 infection manifests as uncontrolled tissue inflammation and systemic thrombosis with high mortality. Anti-viral drugs and monoclonal antibodies reduce COVID-19 severity if administered early, but treatments for later stage immuno-thrombosis are limited. Serine protease inhibitors (SERPINS) regulate thrombotic, thrombolytic and complement pathways. We investigate here systemic treatment with purified poxvirus-derived PEGSerp-1 as a therapeutic for immuno-thrombotic complications in viral ARDS. PEGSerp-1 treatment in two mouse-adapted SARS-CoV-2 models (C57Bl/6 and BALB/c) significantly reduced lung and heart inflammation and improved clinical outcomes, with sequential changes in thrombolytic (uPAR) and complement expression. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for immune-thrombotic complications in severe viral ARDS and has potential benefit for long COVID.
RESUMEN
BackgroundHIV may increase SARS-CoV-2 infection risk and COVID-19 severity generally, but data are limited about its impact on postpartum women and their infants. As such, we characterized SARS-CoV-2 infection among mother-infant pairs in Nairobi, Kenya. MethodsWe conducted a nested study of 53 HIV-uninfected and 51 healthy women living with HIV, as well as their HIV-exposed uninfected (N=41) and HIV-unexposed (N=48) infants, participating in a prospective cohort. SARS-CoV-2 serology was performed on plasma collected between 1 May-31 December 2020 to determine the incidence, risk factors, and symptoms of infection. SARS-CoV-2 RNA PCR and sequencing was also performed on stool samples from seropositive participants. ResultsSARS-CoV-2 seropositivity was found in 38% of the 104 mothers and in 17% of the 89 infants. There was no significant association between SARS-CoV-2 infection and maternal HIV (Hazard Ratio [HR]=1.51, 95% CI: 0.780-2.94) or infant HIV exposure (HR=1.48, 95% CI: 0.537-4.09). Maternal SARS-CoV-2 was associated with a >10-fold increased risk of infant infection (HR=10.3, 95% CI: 2.89-36.8). Twenty percent of participants had symptoms, but no participant experienced severe COVID-19 or death. Seroreversion occurred in [~]30% of mothers and infants. SARS-CoV-2 sequences obtained from stool were related to contemporaneously circulating variants. ConclusionsThese data indicate that postpartum Kenyan women and their infants were at high risk for SARS-CoV-2 infection in 2020, and that antibody responses waned rapidly. However, most cases were asymptomatic and healthy women living with HIV did not have a substantially increased risk of infection or severe COVID-19.
RESUMEN
The COVID-19 pandemic prompted a global integration of wastewater-based epidemiology (WBE) into public health surveillance. Among early pre-COVID practitioners was Greater Tempe (population ~200,000), Arizona, where high-frequency, high-resolution monitoring of opioids began in 2018, leading to unrestricted online data release. Leveraging an existing, neighborhood-level monitoring network, wastewater from eleven contiguous catchment areas was analyzed by RT-qPCR for the SARS-CoV-2 E gene from April 2020 to March 2021 (n=1,556). Wastewater data identified an infection hotspot in a predominantly Hispanic and Native American community, triggering targeted interventions. During the first SARS-CoV-2 wave (June 2020), spikes in virus levels preceded an increase in clinical cases by 8.5{+/-}2.1 days, providing an early-warning capability that later transitioned into a lagging indicator (-2.0{+/-}1.4 days) during the December/January 2020-21 wave of clinical cases. Globally representing the first demonstration of immediate, unrestricted WBE data sharing and featuring long-term, innovative, high-frequency, high-resolution sub-catchment monitoring, this successful case study encourages further applications of WBE to inform public health interventions.
