Editorial: Coronavirus disease (COVID-19): pathophysiology, epidemiology, clinical management and public health response

During a pandemic, there are multiple concurrent clinical and scientific priorities, including the need to understand the pathophysiology of the disease, the different modes of transmission, how patient care can be optimized, as well as the need to develop mathematical models that can now cast and forecast the progression of infections within given populations and/or geographical regions. When the current SARS-CoV2 pandemic was declared a Public Health Emergency of International Concern by the World Health Organization, a formal declaration of its gravity, it became evident that there was an acute need to understand all of the above aspects. In doing so, by 11th February 2020, a special topic, entitled “Coronavirus Disease (COVID-19): Pathophysiology, Epidemiology, Clinical Management and Public Health Response,” was initiated with a dedicated team of handling editors to facilitate the timely peer-review and publication of relevant manuscripts (1). Frontiers, as the publisher of this special topic, took the bold step of waiving any article processing charges so that financial constraints would not be a barrier to communicating crucial information about the pandemic to a broad audience. Furthermore, this was the most extensive special topic to date in the Frontiers portfolio, in terms of the numbers of participating Frontiers journals, disciplines, and sections. This reflected the acute need for the scientific community to understand the many aspects of the pandemic. This special Research Topic captured the entire first wave in the northern hemisphere, from February to May 2020, and the intensity of the associated editorial work is evident by the reported numbers. Within 4 months, 194 abstracts were received; in total 851 manuscripts were submitted, of which 453 were rejected while 398 were published. From the scientific community perspective, by June 2020 the special topic achieved over 2 million views, by December 2020 over 4 million views, and by August 2021 over 8 million views. As an example of the breadth of subjects covered, manuscripts included the attempt by Larsen et al. to model the onset of symptoms of COVID-19; the observed gender differences on COVID-19 patients’ severity and mortality by Jin et al., the correlation between poverty levels and rates of COVID-19 incidence and death in the United States by Finch and Finch, as well as the careful review of the cytokine storm in COVID-19 (Tang et al.

Metabolomics with Nuclear Magnetic Resonance Spectroscopy in a Drosophila melanogaster Model of Surviving Sepsis

Patients surviving sepsis demonstrate sustained inflammation, which has been associated with long-term complications. One of the main mechanisms behind sustained inflammation is a metabolic switch in parenchymal and immune cells, thus understanding metabolic alterations after sepsis may provide important insights to the pathophysiology of sepsis recovery. In this study, we explored metabolomics in a novel Drosophila melanogaster model of surviving sepsis using Nuclear Magnetic Resonance (NMR), to determine metabolite profiles. We used a model of percutaneous infection in Drosophila melanogaster to mimic sepsis. We had three experimental groups: sepsis survivors (infected with Staphylococcus aureus and treated with oral linezolid), sham (pricked with an aseptic needle), and unmanipulated (positive control). We performed metabolic measurements seven days after sepsis. We then implemented metabolites detected in NMR spectra into the MetExplore web server in order to identify the metabolic pathway alterations in sepsis surviving Drosophila. Our NMR metabolomic approach in a Drosophila model of recovery from sepsis clearly distinguished between all three groups and showed two different metabolomic signatures of inflammation. Sham flies had decreased levels of maltose, alanine, and glutamine, while their level of choline was increased. Sepsis survivors had a metabolic signature characterized by decreased glucose, maltose, tyrosine, beta-alanine, acetate, glutamine, and succinate

Dichloroacetate-induced metabolic reprogramming improves lifespan in a Drosophila model of surviving sepsis.

Sepsis is the leading cause of death in hospitalized patients and beyond the hospital stay and these long-term sequelae are due in part to unresolved inflammation. Metabolic shift from oxidative phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome. We propose a shift from aerobic glycolysis to oxidative phosphorylation as a sepsis therapy by targeting the pathways involved in the conversion of pyruvate into acetyl-CoA via pyruvate dehydrogenase (PDH). Chemical manipulation of PDH using dichloroacetic acid (DCA) will promote oxidative phosphorylation over glycolysis and decrease inflammation. We tested our hypothesis in a Drosophila melanogaster model of surviving sepsis infected with Staphylococcus aureus. Drosophila were divided into 3 groups: unmanipulated, sham and sepsis survivors, all treated with linezolid; each group was either treated or not with DCA for one week following sepsis. We followed lifespan, measured gene expression of Toll, defensin, cecropin A, and drosomycin, and levels of lactate, pyruvate, acetyl-CoA as well as TCA metabolites. In our model, metabolic effects of sepsis are modified by DCA with normalized lactate, TCA metabolites, and was associated with improved lifespan of sepsis survivors, yet had no lifespan effects on unmanipulated and sham flies. While Drosomycin and cecropin A expression increased in sepsis survivors, DCA treatment decreased both and selectively increased defensin

Cost of surviving sepsis: a novel model of recovery from sepsis in Drosophila melanogaster

Submitted by Janaína Nascimento ([email protected]) on 2019-04-10T13:14:51Z No. of bitstreams: 1 ve_Kaynar_Ata_etal_INI_2016.pdf: 1792156 bytes, checksum: fd4ed5589dce0b49eaa9636408521f8b (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-04-17T20:05:04Z (GMT) No. of bitstreams: 1 ve_Kaynar_Ata_etal_INI_2016.pdf: 1792156 bytes, checksum: fd4ed5589dce0b49eaa9636408521f8b (MD5)Made available in DSpace on 2019-04-17T20:05:05Z (GMT). No. of bitstreams: 1 ve_Kaynar_Ata_etal_INI_2016.pdf: 1792156 bytes, checksum: fd4ed5589dce0b49eaa9636408521f8b (MD5) Previous issue date: 2016University of Pittsburgh. School of Medicine. Department of Critical Care Medicine. Clinical Research, Investigation, and Systems Modeling of Acute Illness. Laboratory. Pittsburgh, PA, USA.University of Pittsburgh. School of Medicine. Department of Critical Care Medicine. Clinical Research, Investigation, and Systems Modeling of Acute Illness. Laboratory. Pittsburgh, PA, USA.University of Pittsburgh. School of Medicine. Department of Medicine. Pittsburgh, PA, USA.Université Paris Descartes. Paris, France.Eulji University. Department of Pulmonology and Allergy. Seoul, Korea.University of Pittsburgh. Department of Pharmacology and Chemical Biology. Pittsburgh, PA, USA / The Children’s Hospital of Philadelphia. Center of Mitochondrial and Epigenomic Medicine. Philadelphia, PA, USA.University of Pittsburgh. School of Medicine. Department of Medicine. Pittsburgh, PA, USA.University of Western Australia. School of Population Health. Perth, WA, Australia.University of Pittsburgh. Department of Pharmacology and Chemical Biology. Pittsburgh, PA, USA.Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil.University of Pittsburgh. School of Medicine. Department of Medicine. Pittsburgh, PA, USA.University of Pittsburgh. School of Medicine. Department of Critical Care Medicine. Clinical Research, Investigation, and Systems Modeling of Acute Illness. Laboratory. Pittsburgh, PA, USA.Background: Multiple organ failure, wasting, increased morbidity, and mortality following acute illness complicates the health span of patients surviving sepsis. Persistent inflammation has been implicated, and it is proposed that insulin signaling contributes to persistent inflammatory signaling during the recovery phase after sepsis. However, mechanisms are unknown and suitable pre-clinical models are lacking. We therefore developed a novel Drosophila melanogaster model of sepsis to recapitulate the clinical course of sepsis, explored inflammation over time, and its relation to impaired mobility, metabolic disturbance, and changes in lifespan. Methods: We used wild-type (WT), Drosomycin-green fluorescent protein (GFP), and NF-κB-luc reporter male Drosophila melanogaster 4–5 days of age (unmanipulated). We infected Drosophila with Staphylococcus aureus (infected without treatment) or pricked with aseptic needles (sham). Subsets of insects were treated with oral linezolid after the infection (infected with antibiotics). We assessed rapid iterative negative geotaxis (RING) in all the groups as a surrogate for neuromuscular functional outcome up to 96 h following infection. We harvested the flies over the 7-day course to evaluate bacterial burden, inflammatory and metabolic pathway gene expression patterns, NF-κB translation, and metabolic reserve. We also followed the lifespan of the flies. Results: Our results showed that when treated with antibiotics, flies had improved survival compared to infected without treatment flies in the early phase of sepsis up to 1 week (81 %, p = 0.001). However, the lifespan of infected with antibiotics flies was significantly shorter than that of sham controls (p = 0.001). Among infected with antibiotic sepsis survivors, we observed persistent elevation of NF-κB in the absence of any obvious infection as shown by culturing flies surviving sepsis. In the same group, geotaxis had an early (18 h) and sustained decline compared to its baseline. Geotaxis in infected with antibiotics sepsis survivors was significantly lower than that in sham and age-matched unmanipulated flies at 18 and 48 h. Expression of antimicrobial peptides (AMP) remained significantly elevated over the course of 7 days after sepsis, especially drosomycin (5.7-fold, p = 0.0145) on day 7 compared to that of sham flies. Infected with antibiotics flies had a trend towards decreased Akt activation, yet their glucose stores were significantly lower than those of sham flies (p = 0.001). Sepsis survivors had increased lactate levels and LDH activity by 1 week, whereas ATP and pyruvate content was similar to that of the sham group. Conclusions: In summary, our model mimics human survivors of sepsis with persistent inflammation, impaired motility, dysregulated glucose metabolism, and shortened lifespan

Zinc deficiency enhances sensitivity to influenza A associated bacterial pneumonia in mice

Abstract Although zinc deficiency (secondary to malnutrition) has long been considered an important contributor to morbidity and mortality of infectious disease (e.g. diarrhea disorders), epidemiologic data (including randomized controlled trials with supplemental zinc) for such a role in lower respiratory tract infection are somewhat ambiguous. In the current study, we provide the first preclinical evidence demonstrating that although diet‐induced acute zinc deficiency (Zn‐D: ~50% decrease) did not worsen infection induced by either influenza A (H1N1) or methicillin‐resistant staph aureus (MRSA), Zn‐D mice were sensitive to the injurious effects of superinfection of H1N1 with MRSA. Although the mechanism underlying the sensitivity of ZnD mice to combined H1N1/MRSA infection is unclear, it was noteworthy that this combination exacerbated lung injury as shown by lung epithelial injury markers (increased BAL protein) and decreased genes related to epithelial integrity in Zn‐D mice (surfactant protein C and secretoglobins family 1A member 1). As bacterial pneumonia accounts for 25%–50% of morbidity and mortality from influenza A infection, zinc deficiency may be an important pathology component of respiratory tract infections