scholarly journals Secreted ORF8 is a pathogenic cause of severe Covid-19 and potentially targetable with select NLRP3 inhibitors

2021 ◽  
Author(s):  
Xiaosheng Wu ◽  
Michelle K. Manske ◽  
Gordon Ruan ◽  
Kevin E. Nowakowski ◽  
Jithma P. Abeykoon ◽  
...  
Keyword(s):  
Severe Disease ◽  
Acute Infection ◽  
Cytokine Response ◽  
Specific Factor ◽  
Reading Frame ◽  
Disease Trajectory ◽  
Pyrin Domain ◽  
Life Threatening ◽  
New Treatment

ABSTRACTDespite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe Covid-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro and in patients with newly diagnosed Covid-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14+/CD16+ monocytes to induce an inflammasomal cytokine response. The levels of ORF8 protein in the blood correlate with disease mortality in patients with acute infection, and the disease trajectory in patients with severe Covid-19. Furthermore, in vitro the ORF8-induced inflammasome response can be readily inhibited by the select NLRP3 inhibitor MCC950. Our results identify the pathogenic cause and mechanism of severe disease, and a potential new treatment of severe Covid-19.

scholarly journals In VitroandIn VivoEfficacies of Mefloquine-Based Treatment against Alveolar Echinococcosis

2010 ◽  
Vol 55 (2) ◽  
pp. 713-721 ◽  
Author(s):  
Tatiana Küster ◽  
Britta Stadelmann ◽  
Corina Hermann ◽  
Sabrina Scholl ◽  
Jennifer Keiser ◽  
...  
Keyword(s):  
Alveolar Echinococcosis ◽  
Severe Disease ◽  
Treatment Options ◽  
Drug Candidate ◽  
Combined Application ◽  
New Treatment ◽  
Complete Detachment ◽  
Laminated Layer

ABSTRACTAlveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapewormEchinococcus multilocularisand causes severe disease in the human liver, and occasionally in other organs, that is fatal when treatment is unsuccessful. The present chemotherapy against AE is based on mebendazole and albendazole. Albendazole treatment has been found to be ineffective in some instances, is parasitostatic rather than parasiticidal, and usually involves the lifelong uptake of large doses of drugs. Thus, new treatment options are urgently needed. In this study we investigated thein vitroandin vivoefficacy of mefloquine againstE. multilocularismetacestodes. Treatment using mefloquine (20 μM) againstin vitrocultures of metacestodes resulted in rapid and complete detachment of large parts of the germinal layer from the inner surface of the laminated layer within a few hours. Thein vitroactivity of mefloquine was dependent on the dosage.In vitroculture of metacestodes in the presence of 24 μM mefloquine for a period of 10 days was parasiticidal, as determined by murine bioassays, while treatment with 12 μM was not. Oral application of mefloquine (25 mg/kg of body weight administered twice a week for a period of 8 weeks) inE. multilocularis-infected mice was ineffective in achieving any reduction of parasite weight, whereas treatment with albendazole (200 mg/kg/day) was highly effective. However, when the same mefloquine dosage was applied intraperitoneally, the reduction in parasite weight was similar to the reduction seen with oral albendazole application. Combined application of both drugs did not increase the treatment efficacy. In conclusion, mefloquine represents an interesting drug candidate for the treatment of AE, and these results should be followed up in appropriatein vivostudies.

scholarly journals Longitudinal multi-omics analysis identifies responses of megakaryocytes, erythroid cells and plasmablasts as hallmarks of severe COVID-19 trajectories

2020 ◽  
Author(s):  
Joana P. Bernardes ◽  
Neha Mishra ◽  
Florian Tran ◽  
Thomas Bahmer ◽  
Lena Best ◽  
...  
Keyword(s):  
Single Cell ◽  
Severe Disease ◽  
Disease Outcome ◽  
Host Responses ◽  
Erythroid Cell ◽  
Type I ◽  
Disease Trajectory ◽  
Life Threatening ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

The pandemic spread of the potentially life-threatening disease COVID-19 requires a thorough understanding of the longitudinal dynamics of host responses. Temporal resolution of cellular features associated with a severe disease trajectory will be a pre-requisite for finding disease outcome predictors. Here, we performed a longitudinal multi-omics study using a two-centre German cohort of 13 patients (from Cologne and Kiel, cohort 1). We analysed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. The results from single-cell and bulk transcriptome analyses were validated in two independent cohorts of COVID-19 patients from Bonn (18 patients, cohort 2) and Nijmegen (40 patients, cohort 3), respectively. We observed an increase of proliferating, activated plasmablasts in severe COVID-19, and show a distinct expression pattern related to a hyperactive cellular metabolism of these cells. We further identified a notable expansion of type I IFN-activated circulating megakaryocytes and their progenitors, indicative of emergency megakaryopoiesis, which was confirmed in cohort 2. These changes were accompanied by increased erythropoiesis in the critical phase of the disease with features of hypoxic signalling. Finally, projecting megakaryocyte- and erythroid cell-derived co-expression modules to longitudinal blood transcriptome samples from cohort 3 confirmed an association of early temporal changes of these features with fatal COVID-19 disease outcome. In sum, our longitudinal multi-omics study demonstrates distinct cellular and gene expression dynamics upon SARS-CoV-2 infection, which point to metabolic shifts of circulating immune cells, and reveals changes in megakaryocytes and increased erythropoiesis as important outcome indicators in severe COVID-19 patients.

scholarly journals SARS-CoV-2 infection: can ferroptosis be a potential treatment target for multiple organ involvement?

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Ming Yang ◽  
Ching Lung Lai
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Science Studies ◽  
Severe Disease ◽  
Multiple Organ ◽  
Organ Involvement ◽  
Treatment Target ◽  
New Treatment

AbstractSince the outbreak of the new coronavirus in 2019 (SARS-CoV-2), many studies have been performed to better understand the basic mechanisms and clinical features of the disease. However, uncertainties of the underlying mechanisms of multiple organ involvement remain. A substantial proportion of severe coronavirus disease 2019 (COVID-19) patients have lymphopenia, low serum iron levels, and multiple organ involvement. Several therapeutic agents have been used for different stages of the disease, but the treatment for severe disease is still suboptimal. Understanding the mechanism of programmed cell death in COVID-19 may lead to better therapeutic strategies for these patients. On the basis of observations of basic science studies and clinical researches on COVID-19, we hypothesize that ferroptosis, a novel programmed cell death, may be an important cause of multiple organ involvement in COVID-19 and it might serve as a new treatment target. In spite of the existing findings on the involvement of ferroptosis in SARS-CoV-2 infection, there is no reported study to uncover how does ferroptosis acts in SARS-CoV-2 infection yet. Uncovering the role of ferroptosis in SARS-CoV-2 infection is essential to develop new treatment strategies for COVID-19. Intracellular cell iron depletion or new generation of ferroptosis inhibitors might be potential drug candidates for COVID-19. We hope this hypothesis may launch a new wave of studies to uncover the association of ferroptosis and SARS-CoV-2 infection in vitro and in vivo.

scholarly journals Plasmodium falciparum Associated with Severe Childhood Malaria Preferentially Expresses PfEMP1 Encoded by Group A var Genes

2004 ◽  
Vol 199 (9) ◽  
pp. 1179-1190 ◽  
Author(s):  
Anja T.R. Jensen ◽  
Pamela Magistrado ◽  
Sarah Sharp ◽  
Louise Joergensen ◽  
Thomas Lavstsen ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Falciparum Malaria ◽  
Antigenic Variation ◽  
Severe Disease ◽  
Asymptomatic Infection ◽  
Var Genes ◽  
Life Threatening ◽  
Group A ◽  
Var Gene

Parasite-encoded variant surface antigens (VSAs) like the var gene–encoded Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family are responsible for antigenic variation and infected red blood cell (RBC) cytoadhesion in P. falciparum malaria. Parasites causing severe malaria in nonimmune patients tend to express a restricted subset of VSA (VSASM) that differs from VSA associated with uncomplicated malaria and asymptomatic infection (VSAUM). We compared var gene transcription in unselected P. falciparum clone 3D7 expressing VSAUM to in vitro–selected sublines expressing VSASM to identify PfEMP1 responsible for the VSASM phenotype. Expression of VSASM was accompanied by up-regulation of Group A var genes. The most prominently up-regulated Group A gene (PFD1235w/MAL7P1.1) was translated into a protein expressed on the infected RBC surface. The proteins encoded by Group A var genes, such as PFD1235w/MAL7P1.1, appear to be involved in the pathogenesis of severe disease and are thus attractive candidates for a vaccine against life-threatening P. falciparum malaria.

scholarly journals Features of the modern antihistamines use in the treatment of allergic rhinitis

2021 ◽  
pp. 101-108
Author(s):  
A. A. Krivopalov ◽  
S. A. Rebrova ◽  
P. A. Shamkina
Keyword(s):  
Allergic Rhinitis ◽  
Treatment Plan ◽  
Severe Disease ◽  
Treatment Options ◽  
Individual Treatment ◽  
Allergen Specific Immunotherapy ◽  
Ocular Symptoms ◽  
New Treatment

Allergic rhinitis remains one of the most relevant problems of modern otorhinolaryngology. The widespread prevalence, late diagnosis, underestimation of the possible risks of disease progression, the development of complications (including asthma) prompts the development and improvement of new treatment options for allergic rhinitis. Allergic rhinitis is a heterogeneous disease that presents with various clinical phenotypes, and therefore the severity of nasal symptoms can vary from mild malaise to severe disease.. Today, pharmacotherapy remains the most frequently used treatment tactic for patients with allergic rhinitis. While prescribing therapy the doctor develops an individual treatment plan based on the principles of personalized medicine, considering: the dominant symptoms, anamnesis data on previous therapy and the effect of treatment, the type of inflammation (Th2-type, mixed inflammation), concomitant diseases (conjunctivitis, asthma, etc.) etc.) and patient preferences. The tissue effects of the histamine mediator lead to the development of symptoms during the course of the disease, which determines the wide-spread use of antihistamines in the treatment of rhinitis. Antihistamines of the second generation are devoid of sedative effects, have a long-lasting effect and a good safety profile. One of the modern II generation antihistamines is bilastine. The research results proved the high antihistaminic activity of bilastine 20 mg in vitro and in vivo, the absence of cardiac and sedative side effects on the central nervous system, the ability to eliminate the nasal and ocular symptoms of disease and improve the quality of life of patients with allergic rhinitis. Thus, bilastine fully complies with current EAACI / WAO ARIA requirements for drugs used to treat AR. The paper presents a clinical case of a patient with chronic persistent allergic rhinitis, household sensitization with a slight uncontrolled course. The oral antihistamine bilastine was added to intranasal glucocorticosteroids, which help to relieve symptoms of the disease, stabilize the condition and prepare the patient for subsequent allergen-specific immunotherapy. 

scholarly journals High throughput screen identifies IFN-γ-dependent inhibitors of Toxoplasma gondii growth

2018 ◽  
Author(s):  
Joshua B. Radke ◽  
Kimberly L. Carey ◽  
Subrata Shaw ◽  
Shailesh R. Metkar ◽  
Carol Mulrooney ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
High Throughput ◽  
Severe Disease ◽  
Acute Infection ◽  
Congenital Infection ◽  
Host Cells ◽  
High Throughput Screen ◽  
Chronic Infections ◽  
Ifn Γ

AbstractToxoplasma gondii is an obligate intracellular parasite capable of causing severe disease due to congenital infection and in patients with compromised immune systems. Control of infection is dependent on a robust Th1 type immune response including production of interferon gamma (IFN-γ), which is essential for control. IFN-γ activates a variety of anti-microbial mechanisms in host cells, which are then able to control intracellular parasites such as T. gondii. Despite the effectiveness of these pathways in controlling acute infection, the immune system is unable to eradicate chronic infections that can persist for life. Similarly, while antibiotic treatment can control acute infection, it is unable to eliminate chronic infection. To identify compounds that would act synergistically with IFN-γ, we performed a high-throughput screen of diverse small molecule libraries to identify inhibitors of T. gondii. We identified a number of compounds that inhibited parasite growth in vitro at low μM concentrations and that demonstrated enhanced potency in the presence of low level of IFN-γ. A subset of these compounds act by enhancing the recruitment of LC3 to the parasite-containing vacuole, suggesting they work by an autophagy-related process, while others were independent of this pathway. The pattern of IFN-γ-dependence was shared among the majority of analogs from 6 priority scaffolds and analysis of structure activity relationships for one such class revealed specific stereochemistry associated with this feature. Identification of these IFN-γ-dependent leads may lead to development of improved therapeutics due to their synergistic interactions with immune responses.

scholarly journals Cinchona Bark For The Treatment Of Covid-19 Pnemonia: A Modern Review Of The Potential Anti-Viral Therapuetic Applications Of An Old Treatment

2020 ◽  
Vol 7 (05) ◽  
pp. 4795-4801
Author(s):  
James Inklebarger J Inklebarger J ◽  
Mr. Giles Gyer ◽  
Nikiforos Galanis ◽  
Mr. Jimmy Michael ◽  
Dr. Ghulam Adel
Keyword(s):  
Perceived Risk ◽  
Acute Infection ◽  
Cost Effective ◽  
Drug Risk ◽  
Historical Text ◽  
Life Threatening ◽  
Cost Effective Alternative ◽  
Online Book ◽  
A Current

PURPOSE: The Coronavirus 2019 (COVID-19) pandemic is an international public health emergency. Vaccines, and acute infection drugs are currently unknown, and when available, expense and distribution issues may impede distribution in undeserved areas. The aim of this systematic review was to summarize the evidence regarding cinchona bark (CB) for its potential anti-viral properties against COVID-19   STUDY DESIGN: A current literature and historical text review was conducted, limited to articles having full text or abstracts available in English, using Google Scholar, Pubmed-NCBI, ScienceDirect, and WebMD, and online book publications,  with key search words, including synthetic CB analogues: chloroquine-hydroxychloroquine (CQ/HCQ) derivatives.   RESULTS: Several related in-vitro studies, editorials, and expert consensus papers on quinine analogue anti-viral treatment papers and historical treatises have been published. A March 2020 CQ drug trial ongoing in China, has just reported breakthrough efficacy evidence for COVID-19 pneumonia. However, there are severe CQ shortages and direct evidence for the anti-viral therapeutic use of CB is sparse, several centuries old, and controversial.   CONCLUSION: CB was for centuries known to be a natural source of quinine from which modern synthetically manufactured analogues anti-viral purposed drugs such as CQ/HCQ are based. CB may also possess anti COVID-19 activity as its historical derivatives, but with the same potential for life-threatening adverse reactions and severe drug interaction complications akin to its analogues. Issues with herbal quality control, prescriber dose inexperience, perceived risk underestimation by self-prescribers, and a misinformed propensity for consumer fraud are other concerns. However, analogue drug risk-benefit ratios indicate CB may also have some value for acute COVID-19 (cytokine storm) infection management. The existing evidence and evolving breakthrough CQ efficacy findings in China, shadowed by CQ shortage, highlight a need for modern and timely investigation of CB as cost-effective alternative COVID-19 pneumonia monotherapy.       

scholarly journals Immune Responses in an Infant with Congenital Heart Disease and Severe COVID-19 

2021 ◽  
Author(s):  
Paul Licciardi ◽  
Danielle Wurzel ◽  
Melanie Neeland ◽  
Jeremy Anderson ◽  
Yara-Natalie Abo ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Severe Disease ◽  
Acute Infection ◽  
Immune Memory ◽  
Cell Populations ◽  
Initial Increase ◽  
Older Children ◽  
Immune Correlates

Abstract Children have lower hospitalisation and mortality rates for coronavirus disease-2019 (COVID-19) than adults; however, younger children (<4 years of age)1 may develop more severe disease than older children. To date, the immune correlates of severe COVID-19 in young children have been poorly characterized. We report the kinetics of immune responses in relation to clinical and virological features in an infant with acute severe COVID-19. Systemic cellular and cytokine profiling showed initial increase in neutrophils and monocytes with depletion of lymphoid cell populations (particularly CD8+ T and NK cells) and elevated inflammatory cytokines. Expansion of memory CD4+T (but not CD8+T) cells occurred over time, with predominant Th2 bias. Marked activation of T cell populations observed during the acute infection gradually resolved as the child recovered. Significant in vitro activation of T-cell populations and robust cytokine production, in response to inactivated SARS-CoV-2 stimulation, was observed 3 months after infection indicating durable, long-lived cellular immune memory.

scholarly journals Molecular and cellular pathobiology ofEhrlichiainfection: targets for new therapeutics and immunomodulation strategies

2011 ◽  
Vol 13 ◽  
Author(s):  
Jere W. McBride ◽  
David H. Walker
Keyword(s):  
New Technologies ◽  
Vaccine Development ◽  
Severe Disease ◽  
Acute Infection ◽  
Effector Proteins ◽  
Host Pathogen Interactions ◽  
Disease States ◽  
Recent Advances ◽  
Host Pathogen ◽  
Life Threatening

Ehrlichiaare small obligately intracellular bacteria in the order Rickettsiales that are transmitted by ticks and associated with emerging life-threatening human zoonoses. Vaccines are not available for human ehrlichiosis, and therapeutic options are limited to a single antibiotic class. New technologies for exploring host–pathogen interactions have yielded recent advances in understanding the molecular interactions betweenEhrlichiaand the eukaryotic host cell and identified new targets for therapeutic and vaccine development, including those that target pathogen virulence mechanisms or disrupt the processes associated with ehrlichial effector proteins. Animal models have also provided insight into immunopathological mechanisms that contribute significantly to understanding severe disease manifestations, which should lead to the development of immunomodulatory approaches for treating patients nearing or experiencing severe disease states. In this review, we discuss the recent advances in our understanding of molecular and cellular pathobiology and the immunobiology ofEhrlichiainfection. We identify new molecular host–pathogen interactions that can be targets of new therapeutics, and discuss prospects for treating the immunological dysregulation during acute infection that leads to life-threatening complications.

scholarly journals Efficacy of Guanabenz Combination Therapy Against Chronic Toxoplasmosis Across Multiple Mouse Strains

2020 ◽  
Author(s):  
Jennifer Martynowicz ◽  
J. Stone Doggett ◽  
William J. Sullivan
Keyword(s):  
Limit Of Detection ◽  
Acute Infection ◽  
Antagonistic Effect ◽  
Mouse Strains ◽  
Chronic Infections ◽  
Brain Cyst ◽  
Latently Infected ◽  
Life Threatening

AbstractToxoplasma gondii, an obligate intracellular parasite that can cause life-threatening acute disease, differentiates into a quiescent cyst stage to establish lifelong chronic infections in animal hosts, including humans. This tissue cyst reservoir, which can reactivate into an acute infection, is currently refractory to clinically available therapeutics. Recently, we and others have discovered drugs capable of significantly reducing brain cyst burden in latently infected mice, but not to undetectable levels. In this study, we examined the use of novel combination therapies possessing multiple mechanisms of action in mouse models of latent toxoplasmosis. Our drug regimens included combinations of pyrimethamine, clindamycin, guanabenz, and endochin-like quinolones (ELQs), and were administered to two different mouse strains in an attempt to eradicate brain tissue cysts. We observed mouse strain-dependent effects with these drug treatments: pyrimethamine + guanabenz showed synergistic efficacy in C57BL/6 mice, yet did not improve upon guanabenz monotherapy in BALB/c mice. Contrary to promising in vitro results demonstrating toxicity to bradyzoites, we observed an antagonistic effect between guanabenz + ELQ-334 in vivo. While we were unable to completely eliminate brain cyst burden, we found that a combination treatment of ELQ-334 + pyrimethamine impressively reduced brain cysts to 95% in C57BL/6 mice, which approaches the limit of detection. These analyses highlight the importance of evaluating anti-infective drugs in multiple mouse strains and will help inform further preclinical cocktail therapy studies designed to treat chronic toxoplasmosis.

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