SARS-CoV-2's continued global health impact underscores the importance of ongoing pathogenesis research. Insights into the host's first line of defense against severe COVID-19 identify actionable biom Show more
SARS-CoV-2's continued global health impact underscores the importance of ongoing pathogenesis research. Insights into the host's first line of defense against severe COVID-19 identify actionable biomarkers, informing disease management or therapeutics. Yet, the innate immune response, including cytokines, chemokines, adenosine deaminases (ADAs) and Toll-like receptors (TLRs), relevant to COVID-19 remain incompletely characterized. Peripheral blood was longitudinally collected between May 2020 and March 2021 from COVID-19 hospitalized adults (N = 79) and healthy controls (HCs) (N = 14; not tested, assumed COVID-negative, no viral exposure or symptoms). Heparinized blood was fractionated for plasma cryopreservation and in vitro whole blood TLR-stimulation employing TLR-3, -4, and -7/8 agonists. Post-stimulation culture supernatants were analyzed using multiplex and enzymatic assays. Upon hospitalization, plasma concentrations of IFNγ, IL-6, CXCL10, and ADAs were significantly upregulated compared to convalescent time points and HCs. Participants with fatal COVID-19 exhibited higher IL-27, CXCL10, and ADAs concentrations upon admission. Plasma cytokines, chemokines, and ADAs were positively correlated and associated with distinct temporal patterns. TLR-stimulated cell cultures from patients produced reduced IFNα2, IFNγ, IL-12p40, and IL-12p70 compared to HCs or later time points. Higher plasma concentrations of IL-27, CXCL10, and ADAs at admission were associated with severe COVID-19 and mortality. Reduced TLR-mediated IFNα2, IFNγ, and IL-12p70 production suggests COVID dampens Th1-polarizing innate immune responses, providing insight into immunological sequelae of SARS-CoV-2 infection. Show less
Microorganisms can takeover critical metabolic pathways in host cells to fuel their replication. This interaction provides an opportunity to target host metabolic pathways, in addition to the pathogen Show more
Microorganisms can takeover critical metabolic pathways in host cells to fuel their replication. This interaction provides an opportunity to target host metabolic pathways, in addition to the pathogen-specific ones, in the development of antimicrobials. Host-directed therapy (HDT) is an emerging strategy of anti-infective therapy, which targets host cell metabolism utilized by facultative and obligate intracellular pathogens for entry, replication, egress or persistence of infected host cells. This review provides an overview of the host lipid metabolism and links it to the challenges in the development of HDTs for viral and bacterial infections, where pathogens are using important for the host lipid enzymes, or producing their own analogous of lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) thus interfering with the human host's lipid metabolism. Show less