We employed SB218078, an investigational CHEK1 inhibitor similar to one currently in clinical trials as an anti-neoplastic agent, with an in vitro IC50 of 0.015 mM and a K i,app. of 1564 [21, 22] . Pretreatment of cultures with 1 uM or 100 nM SB218078 for 12 hours resulted in significant inhibition of viral protein accumulation together with a marked virus-specific death response by 24 hours (Figure 4A , B). While some viral infection was detected at the 100 nM dose, viral protein production was severely limited at single cell resolution ( Figure 4B , C). These observations suggest that SB218078 is releasing a cell death response to viral detection that would otherwise be suppressed during the viral replication cycle. Viral-induced cell death was also observed upon siRNA-mediated CHEK1 depletion (Figure 2A ). The seemingly contradictory increase in infection frequency upon CHEK1 depletion may therefore be an indirect consequence of infection of low density residual cell populations with hypomorphic CHEK1 activity. Remarkably, SB218078 had no consequence on H1N1 replication in A549 cells, a cancer cell line often employed to test for modulators of viral replication and host responses [5, 23, 24] ( Figure 4E , F). However, a nontransformed, telomerase-immortalized bronchial epithelial cell line, derived from a different patient, HBEC3 [25] , was identical to HBEC30 in its re- Figure 4G ). These observations indicate intervention targets may be available in non-tumorigenic cells that are uncoupled from host regulatory networks in cancer cells, and potentially explain why CHEK1 was not identified in other efforts to date that have universally relied on cancer lines as screen hosts [4] [5] [6] [7] 26] . We next queried the behavior of gene depletions identified here that modulate H1N1 cytopathic effects to those in 4 wholegenome siRNA screens which measured influenza virus replication as the end-point assay [4] [5] [6] [7] . This allowed us to parse collective 'hits' into four functional classes ( Figure 3C , Table 5 in Supporting Information S1). Class 1: genes that, when depleted, enhance bronchial epithelial cell survival upon H1N1 exposure, and are required for viral replication. This class presumably represents host factors that facilitate viral infection and/or are required to support viral replication. Class 2: genes that, when depleted, reduce bronchial epithelial cell survival upon H1N1 exposure, and are required for viral replication. This, initially unanticipated but very intriguing class, likely represents host factors that deflect cell death checkpoint responses that would otherwise engage upon detection of viral infection. Class 3: genes that, when depleted, reduce bronchial epithelial cell survival upon H1N1 exposure and enhance viral replication relative to controls. This class presumably represents antiviral restriction factors that normally oppose infection. Class 4: genes, that when depleted, enhance bronchial epithelial cell survival upon H1N1 exposure and enhance viral replication as compared to controls. Of note, Class 2, which may represent novel intervention target opportunities, includes TRRAP, a large multidomain protein of the phosphoinositide 3-kinase-related kinases (PIKK) family that is a component of many histone acetyltransferase (HAT) complexes. TRRAP was recently identified as a bona fide oncogene in melanoma through cancer genome resequencing efforts, however, its transforming mechanism is unknown [27] .