Holton, S. E. | bioRxiv Science

bioRxiv2024

Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis

OBJECTIVESWe aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system. DESIGNIn two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH. Eight deceased patients defined as COVID-sHLH underwent genomic sequencing in order to identify variants in immune-related genes. SETTINGTwo tertiary care hospitals in Seattle, Washington (Virginia Mason Medical Center and Harborview Medical Center). PATIENTS186 patients with COVID-19 INTERVENTIONSNone MEASUREMENTS AND MAIN RESULTSNine percent of enrolled COVID-19 subjects met our defined criteria for sHLH. Using broad serum proteomic approaches (O-link and SomaScan), we identified three biomarkers for COVID-19 associated sHLH (soluble PD-L1, TNF-R1, and IL-18BP), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and sTNF-R1). We also identified novel biomarkers and pathways of COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected variants in several genes involved in immune responses in individuals with COVID-sHLH, including in DOCK8 and in TMPRSS15, suggesting that genetic alterations in immune-related genes may contribute to hyperinflammation and fatal outcomes in COVID-19. CONCLUSIONSBiomarkers of COVID-19 associated sHLH, such as soluble PD-L1, and pathways, such as the syntaxin pathway, and variants in immune genes in these individuals, suggest critical roles for the immune response in driving sHLH in the context of COVID-19. Key PointsO_ST_ABSQUESTIONC_ST_ABSTo define biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system. FINDINGSIn two independent cohorts using two different platforms, we identified sPD-L1, IL-18BP, and sTNF-R1 as COVID-sHLH biomarkers. We identified the syntaxin pathway as important in COVID-sHLH and variants in immune-related genes in a subset of deceased COVID-sHLH subjects. MEANINGImmune related proteins and pathways are dysregulated in COVID-sHLH.

immunology↗

bioRxiv2023

A 3D Printed Ventilated Perfused Lung Model Platform to Dissect the Lung's Response to Viral Infection in the Presence of Respiration

In this study, we developed a three-dimensionally (3D) printed lung model that faithfully recapitulates the intricate lung environment. This 3D model incorporated alveolar and vascular components that allow for a comprehensive exploration of lung physiology and responses to infection in vitro. In particular, we investigated the intricate role of ventilation on formation of the alveolar epithelial layer and its response to viral infections. In this regard, we subjected our 3D printed, perfused lung model to a continuous respiratory cycle at the air-liquid interface (ALI) for up to 10 days followed by infection with two viruses: influenza virus (Pr8) and respiratory syncytial virus (RSV), at two different concentrations for 24 or 48 h. The results revealed that ventilation induced increased tight-junction formation with better epithelial barrier function over time, facilitated higher expression of alveolar epithelial specific genes, enabled higher level of infection with an increased progression of viral spread and replication over time, and modulated the production of pro-inflammatory cytokines and chemokines. Our findings represent a critical step forward in advancing our understanding of lung-specific viral responses and respiratory infections in response to ventilation, which sheds light on vital aspects of pulmonary physiology and pathobiology.

bioengineering↗