While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19.

The role of kisspeptin in stimulating hypothalamic GnRH is undisputed. However, the role of kisspeptin signaling in testicular function is less clear. The testes are essential for male reproduction through their functions of spermatogenesis and steroidogenesis. Our review focused on the current literature investigating the distribution, regulation and effects of kisspeptin and its receptor (KISS1/KISS1R) within the testes of species studied to date. There is substantial evidence of localised KISS1/KISS1R expression and peptide distribution in the testes. However, variability is observed in the testicular cell types expressing KISS1/KISS1R. Evidence is presented for modulation of steroidogenesis and sperm function by kisspeptin signaling. However, the physiological importance of such effects, and whether these are paracrine or endocrine manifestations, remain unclear.

The mechanisms that underpin COVID-19 disease severity, and determine the outcome of infection, are only beginning to be unraveled. The host inflammatory response contributes to lung injury, but circulating mediators levels fall below those in classical cytokine storms. We analyzed serial plasma samples from 619 patients hospitalized with COVID-19 recruited through the prospective multicenter ISARIC clinical characterization protocol U.K. study and 39 milder community cases not requiring hospitalization. Elevated levels of numerous mediators including angiopoietin-2, CXCL10, and GM-CSF were seen at recruitment in patients who later died. Markers of endothelial injury (angiopoietin-2 and von-Willebrand factor A2) were detected early in some patients, while inflammatory cytokines and markers of lung injury persisted for several weeks in fatal COVID-19 despite decreasing antiviral cytokine levels. Overall, markers of myeloid or endothelial cell activation were associated with severe, progressive, and fatal disease indicating a central role for innate immune activation and vascular inflammation in COVID-19.

The T cell receptor (TCR) recognizes self or foreign antigens presented by major histocompatibility complex (MHC) molecules. Engagement of the TCR triggers the formation of multi-molecular signalosomes that lead to the generation of second messengers and subsequent activation of multiple distal signaling cascades, such as the Ca +2-calcineurin-NFAT, RasGRP1-Ras-Erk1/2, PKCθ-IKK-NFκB, and TSC1/2-mTOR pathways. These signaling cascades control many aspects of T cell biology. Mechanisms have been evolved to fine-tune TCR signaling to maintain T cell homeostasis and self-tolerance, and to properly mount effective responses to microbial infection. Defects or deregulation of TCR signaling has been implicated in the pathogenesis of multiple human diseases.

Abbreviations: APC, antigen presenting cell; CCR5, C-C chemokine receptor type 5; CD28SA, CD28 superagonist; CK2, casein kinase 2; CTLA-4, cytotoxic T-Lymphocyte Antigen 4; IFNg, interferon gamma; IL-2, interleukin 2; LAG-3, Lymphocyte-activation gene 3; LFA-1, lymphocyte function-associated antigen 1; MFI, mean fluorescence intensity; PBMC, peripheral blood mononuclear cells; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; PTEN, phosphatase and tensin homolog; S-phase, synthesis phase; TCR, T cell receptor; T EMs , effector memory T cells; TIM-3, T cell immunoglobulin mucin 3The CD28 superagonist (CD28SA) TGN1412 was administered to humans as an agent that can selectively activate and expand regulatory T cells but resulted in uncontrolled T cell activation accompanied by cytokine storm. The molecular mechanisms that underlie this uncontrolled T cell activation are unclear. Physiological activation of T cells leads to upregulation of not only activation molecules but also inhibitory receptors such as PD-1. We hypothesized that the uncontrolled activation of CD28SA-stimulated T cells is due to both the enhanced expression of activation molecules and the lack of or reduced inhibitory signals. In this study, we show that anti-CD3 antibody-stimulated human T cells undergo time-limited controlled DNA synthesis, proliferation and interleukin-2 secretion, accompanied by PD-1 expression. In contrast, CD28SA-activated T cells demonstrate uncontrolled activation parameters including enhanced expression of LFA-1 and CCR5 but fail to express PD-1 on the cell surface. We demonstrate the functional relevance of the lack of PD-1 mediated regulatory mechanism in CD28SA-stimulated T cells. Our findings provide a molecular explanation for the dysregulated activation of CD28SA-stimulated T cells and also highlight the potential for the use of differential expression of PD-1 as a biomarker of safety for T cell immunostimulatory biologics.