Specialized interferon action in COVID-19.

The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications.

Strategic Surrogates or Sad Sinners: U.S. Taxation of Bartering in Digital Services

The COVID‐19 pandemic caused both a surge in technology use and a deterioration in government finances. At the same time, big tech companies are under scrutiny by lawmakers for tax avoidance, antitrust issues, and other concerns. These realities call for governments to reassess tax policy toward tech companies and for tech companies to reassess legal strategy toward taxes. State and federal governments' tax bases are eroding because of the noncash, barter nature of modern transactions. When a taxpayer uses “free” digital services such as e‐mail, social media, or search engines, she pays via access to her personal data or attention. From a legal and policy standpoint, these barter transactions should be taxed just as if cash had changed hands, but because it is not practicable to identify, value, and tax the data and time of each user, they have escaped taxation, giving many tech companies an unintended tax advantage. To address this unfairness, this article proposes a surrogate tax, through which the tech company acts as a proxy to pay the tax that is technically the liability of its users. In contrast to Digital Services Taxes (DSTs), which have been the main focus of policy makers and the extant literature, surrogate taxes adhere closely to standards of good tax policy, providing an administrable means of capturing untaxed digital barter while advancing fairness across the industry's business models. From a legal strategy standpoint, this article argues that tech companies themselves should support surrogate taxes, to avoid facing more onerous, “sin”‐like taxes, such as DSTs.

The COVIDome Explorer researcher portal.

COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. To expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients, including matched analysis of the whole-blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate herein the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide.

Seroconversion stages COVID19 into distinct pathophysiological states.

COVID19 is a heterogeneous medical condition involving diverse underlying pathophysiological processes including hyperinflammation, endothelial damage, thrombotic microangiopathy, and end-organ damage. Limited knowledge about the molecular mechanisms driving these processes and lack of staging biomarkers hamper the ability to stratify patients for targeted therapeutics. We report here the results of a cross-sectional multi-omics analysis of hospitalized COVID19 patients revealing that seroconversion status associates with distinct underlying pathophysiological states. Low antibody titers associate with hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, and depletion of lymphocytes, neutrophils, and platelets. Upon seroconversion, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased D-dimer, and hypoalbuminemia. We propose that seroconversion status could potentially be used as a biosignature to stratify patients for therapeutic intervention and to inform analysis of clinical trial results in heterogenous patient populations.