Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which -by leveraging available transcriptomic and proteomic databases-allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both>96%) the viral effects on cellular host-immune response, resulting in specific cellular SARS-CoV-2 signatures and ii) utilize these cell-specific signatures to identify promising repurposable therapeutics. Powered by this tool, coupled with domain expertise, we identify several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential druggable targets in COVID-19 pathogenesis. Graphical abstract Application of the PHENotype SIMulator: By modeling human host-cell infection with a pathogen in silico - in this case SARS-CoV-2 - we can acquire a cell-specific viral signature and formulate multiple drug repurposing hypotheses;(I) logFold Changes (logFCs) of Differentially Expressed Genes (DEGs) arising from transcriptomic genome wide expression analysis of infected vs. baseline uninfected cells are used to represent a virus in the meta-pathway;(II) we run the PHENSIM simulation by upregulating the viral node and collect all perturbation values computed by PHENSIM for pathway endpoints to define a cell-specific pathogen signature. (III) The same process is applied to expression data arising from whole transcriptome-wide expression analysis of drug treated vs. mock-treated cell lines, yielding a cell-specific drug signature. This process is iterated for each drug we wish to test and collected in a database of drug signatures. (IV) Finally, a Pearson correlation analysis between the pathogen and each drug signature is utilized to score repurposing candidates.Image 1

Application of the PHENotype SIMulator for rapid identification of potential candidates in effective COVID-19 drug repurposing.

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which -by leveraging available transcriptomic and proteomic databases-allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both>96%) the viral effects on cellular host-immune response, resulting in specific cellular SARS-CoV-2 signatures and ii) utilize these cell-specific signatures to identify promising repurposable therapeutics. Powered by this tool, coupled with domain expertise, we identify several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential druggable targets in COVID-19 pathogenesis.

COVID-19 Conversations Within Black/Brown Minority Communities: A Stakeholder and Psychoeducation Approach Using Zoom/Facebook Live.

As communities of color are disproportionately affected by COVID-19, there is an urgent need for dissemination of timely and accurate information to community members. In this article, we describe a stakeholder approach for the implementation, evaluation, and lessons learned from COVID-19 Conversations, a program developed and delivered virtually by researchers and academics at Northwell Health. The goal of the program was to address the mental, physical, and psychosocial needs of community members. The program used Zoom/Facebook Live to deliver interactive discussions on topics ranging from health education on COVID-19 and mental health to resources for unmet social needs. This interprofessional, cross-sector collaboration highlights the importance of public health interventions aimed at reducing the spread of COVID-19 through easy online access and culturally relevant community education and outreach.

Unique Imaging Findings of Neurologic Phantosmia Following Pfizer-BioNtech COVID-19 Vaccination: A Case Report.

ABSTRACT: Olfactory dysfunction related to SARS-CoV-2 infection and COVID-19 disease is now well established in the literature. In December 2020, the FDA approved the Pfizer-BioNTech and Moderna vaccines for use in preventing COVID-19 in the United States. To the best of our knowledge, this is the first report of a phantosmia post-Pfizer COVID-19 vaccination, with positive magnetic resonance imaging radiographic findings in a patient with documented absence of infection by SARS-CoV-2 virus or concomitant sinonasal disease.

The Longitudinal Immune Response to Coronavirus Disease 2019: Chasing the Cytokine Storm.

The clinical progression of the severe acute respiratory syndrome coronavirus 2 infection, coronavirus 2019 (COVID-19), to critical illness is associated with an exaggerated immune response, leading to magnified inflammation termed the "cytokine storm." This response is thought to contribute to the pathogenicity of severe COVID-19. There is an initial weak interferon response and macrophage activation that results in delayed neutrophil recruitment leading to impeded viral clearance. This causes prolonged immune stimulation and the release of proinflammatory cytokines. Elevated inflammatory markers in COVID-19 (e.g., d-dimer, C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6) are reminiscent of the cytokine storm seen in severe hyperinflammatory macrophage disorders. The dysfunctional immune response in COVID-19 also includes lymphopenia, reduced T cells, reduced natural killer cell maturation, and unmitigated plasmablast proliferation causing aberrant IgG levels. The progression to severe disease is accompanied by endotheliopathy, immunothrombosis, and hypercoagulability. Thus, both parts of the immune system-innate and adaptive-play a significant role in the cytokine storm, multiorgan dysfunction, and coagulopathy. This review highlights the importance of understanding the immunologic mechanisms of COVID-19 as they inform the clinical presentation and advise potential therapeutic targets.

ANERGY TO SYNERGY-THE ENERGY FUELING THE RXCOVEA FRAMEWORK.

We write to introduce our novel group formed to confront some of the issues raised by the COVID-19 pandemic. Information about the group, which we named "cure COVid for Ever and for All" (RxCOVEA), its dynamic membership (changing regularly), and some of its activities-described in more technical detail for expert perusal and commentary-are available upon request.

Rapid Emergence of SARS-CoV-2 in the Greater New York Metropolitan Area: Geolocation, Demographics, Positivity Rates, and Hospitalization for 46 793 Persons Tested by Northwell Health.

BACKGROUND: In March 2020, the greater New York metropolitan area became an epicenter for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The initial evolution of case incidence has not been well characterized. METHODS: Northwell Health Laboratories tested 46 793 persons for SARS-CoV-2 from 4 March through 10 April. The primary outcome measure was a positive reverse transcription-polymerase chain reaction test for SARS-CoV-2. The secondary outcomes included patient age, sex, and race, if stated; dates the specimen was obtained and the test result; clinical practice site sources; geolocation of patient residence; and hospitalization. RESULTS: From 8 March through 10 April, a total of 26 735 of 46 793 persons (57.1%) tested positive for SARS-CoV-2. Males of each race were disproportionally more affected than females above age 25, with a progressive male predominance as age increased. Of the positive persons, 7292 were hospitalized directly upon presentation; an additional 882 persons tested positive in an ambulatory setting before subsequent hospitalization, a median of 4.8 days later. Total hospitalization rate was thus 8174 persons (30.6% of positive persons). There was a broad range (>10-fold) in the cumulative number of positive cases across individual zip codes following documented first caseincidence. Test positivity was greater for persons living in zip codes with lower annual household income. CONCLUSIONS: Our data reveal that SARS-CoV-2 incidence emerged rapidly and almost simultaneously across a broad demographic population in the region. These findings support the premise that SARS-CoV-2 infection was widely distributed prior to virus testing availability.