A stark limitation of arrayed siRNA screens is the requirement for ''single gene'' phenotypic penetrance. This can limit sensitivity of detection of relevant molecular entities due to insufficient protein depletion and/or the presence of functionally redundant gene products. As a mechanism to potentially reveal combinatorial contributions of gene function to viral replication and cytopathic effects, we repeated the original screen using a library of 426 human microRNA mimics. These reagents have the advantage of inducing multigenic perturbations, though accurate assignment of target space is a significant challenge. This effort identified a small cohort of miRNA mimics that either enhanced or deflected H1N1induced cell death ( Figure 6A , B, Table 6 in Supporting Information S1). 11 of these were further examined for consequences on H1N1 viral protein production in HBEC30 cells, which identified both sensitizers and resistors that enhanced or repressed viral replication ( Figure 6C ). Of note, a test for ''hits'' that also have activity against the recent pandemic strain Cal/04/ 09 identified two miRNA mimics that impair Cal/04/09 protein production in A549 cells (hsa-miR-495 and hsa-miR-519a, Figure 6D ). To infer biological processes that may be engaged by the miRNAs that can impair H1N1 replication, we examined the intersection of predicted miRNA targets and single-gene perturbations that behaved similarly to the subject miRNA. Candidate miRNA target genes were selected based on seed sequence presence in 39 UTRs as defined by Target Scan context scores. These predictions were intersected with siRNA data from this study and those of the 4 whole-genome siRNA screens that measured influenza virus replication [4] [5] [6] [7] . When considered as a heuristic, this analysis produced three subnetworks that may correspond to the miRNA mode of action, namely the glycosylphosphatidylinositol transamidase, viral and host protein ubiquitylation [30, 31] and alternative mRNA splicing ( Figure 6E ).