Gene Expression Signature-Based Screening Identifies New Broadly Effective Influenza A Antivirals
Figure 5
Gene expression-based screening identifies eight potential antiviral molecules.
A. List of cellular genes chosen to query the Connectivity Map. A circumscribed signature of infection was derived from the 300 genes discriminating mock and infected samples by selecting genes with a fold change > 2 or <−2. The fold change is defined as the ratio of the mean gene expression in infected samples to the mean for the corresponding mock infection in log2. This selection resulted in a list of 20 genes, 12 being up-regulated during infection and 8 down-regulated (see Table 1). These genes constituted the signature used to query the online database Connectivity Map. B. Drugs with significant enrichment to influenza virus infections in the Connectivity Map. Significance cut-off was set at p-value <0.005. The permutation p-value estimates the likelihood that the results would be observed by random chance. Mean: the arithmetic mean of the connectivity scores for the post-dose changes (or instances) by the given molecule; n: the number of instances of a given molecule in the CMAP database; Enrichment: a measure of the enrichment of those instances in the order list of all instances, Positive enrichment scores are of interest if perturbagens inducing the biological state represented by the signature used to produce the result are sought. Likewise, if reversal or repression of the biological state encoded in the query signature is required, perturbagens with negative enrichment scores are of interest. The specificity value is defined as the frequency at which the enrichment of a set of instances equals or exceeds that of the same set of instances in queries executed on 312 published, experimentally derived signatures using the Molecular Signatures Database. Lower values are associated with a greater specificity; the non null percentage represents a measure of the support for the connection between a set of instances and a signature of interest based on the behavior of the individual instances in that set. C. 8 molecules are negatively connected to influenza virus infection (p-value <0.005). A graphical representation of the location of the signature of infection is depicted for each molecule, taking the instance with the most negative connectivity score of each molecule. The x-axis represents the genes of the expression profile of the molecule, rank ordered according to their differential expression relative to the control. The location of each gene of the infection signature is appreciated along the x-axis.