†Score refer to the CMap score. It represents the level of similarity
between transcriptional effects induced by BCG and each of the
compounds.
‡ Validation refers to the presence of any supporting evidence from the
biomedical literature that the predicted BCG mimics have any antiviral
activities. Antiviral means there is evidence that the compound is used
as or has antiviral activity; SARS-CoV-2 means that the compound should
antiviral activity against SARS-CoV-2; Corona viruses means that the
compound showed antiviral activity against corona viruses other than
SARS-CoV-2.
§ COVID-19 CT: there is evidence that the compound is being tested in
clinical trials for COVID-19. There are 12 Studies found for Ruxolitinib
in COVID-19 on clinicaltrials.gov.
Figure 1. Workflow for drug and vaccine repurposing. ① A gene
signature is identified/derived and a consensus gene signature is
prioritized, all genes are nomenclated according to HUGO Gene
Nomenclature Committee (HGNC). ② The consensus gene signature is used to
query the CMap to identify positive connections capable of producing
gene signatures similar to BCG-CGS. ③ Prioritize genes and compounds
that induce transcriptional changes similar to those induced by BCG: A)
key hubs predicted by causal reasoning; B) Positive genes and compound
connections from the connectivity map. ④ Prioritize top enriched pathway
map explaining the biological effects of BCG (gene annotations on the
pathway map are assigned by Clarivate Analytics, IFN-gamma is an alias
for INFG, GM-CSF is an alias for CSF2, MIP-1-alpha is an alias for
CCL3).
Figure 2. BCG’s consensus gene signature (BCG-CGS) and highly
enriched pathways. (A) A heat map of the log2FC of the
gene expression for differentially expressed genes representing BCG’s
consensus gene signature. Upregulated genes have positive
log2FC denoted in red color, and down regulated genes
have negative values for log2FC denoted in blue color.
(B) Core network for BCG-CGS showing highly connected genes in BCG-CGS,
deleting all singleton genes. Nodes are color-coded using a split pie
chart coloring scheme indicating pathway/gene set contribution to each
node from the top 5 most enriched pathways/gene lists. All details about
pathway/gene set ID are found in Table S2 (Supporting Information).
Figure 3. High-confidence expanded network for BCG-CGS.
Nodes are color-coded using a split pie chart coloring scheme indicating
pathway/gene set contribution to each node from the top 5 most enriched
pathways/gene lists. Core network is composed of genes in the BCG-CGS
that are not singletons. Step 1 expansion, added 10 additional nodes
(i.e., genes) to the core network. Step 2 expansion, added another 10
nodes for the first expansion. Step 3 expansion, added another 10 nodes
to the second expansion. Expansions were performed to see which pathways
remained most statistically significant, and therefore are considered
high confidence pathways.
Figure 4. (A) A venn diagram showing overlaps between BCG
genetic mimics and key hubs with SARS-CoV-2 and Corona viruses
interactomes. (B) Top “pathway map” with the highest level of
enrichment by genes in BCG-CGS. This map is generated using MetaCore
from Clarivate Analytics. Red thermometers indicate genes overexpressed
in response to BCG treatment, and the hight of the red bars is
representative of the differential gene expression level (i.e.,
log2 values of the fold change). The numbers under the
thermometers 1- 5 refer to the experiment number: 1) gene expression on
day 1 in response to BCG vaccination to a BCG-naïve population on day 1;
2) gene expression on day 1 in response to BCG re-vaccination to a
previously vaccinated population; 3) gene expression on day 1 in
response to BCG vaccination to a BCG-naïve population on day 14; 4) gene
expression on day 14 in response to BCG re-vaccination to a previously
vaccinated population, and 5) positive connections from the connectivity
map, and the red bar in the thermometer number 5 represents presence of
the gene only.