Influenza A infection is associated with pathological changes throughout the respiratory tract, however the major site of impact appears to be the respiratory epithelia. Bronchoscopy of patients with uncomplicated influenza infections reveals alterations in the ciliated epithelia of the larynx, trachea, and bronchi that includes vacuolization, loss of cilia, and desquamation of columnar epithelial cells and goblet cells down to the basal cell layer. Importantly, viral antigen is found predominantly in the epithelial cells and mononuclear cells [1] . Therefore, for the studies described here, we employed telomerase-immortalized human bronchial epithelial cells (HBEC30) that retain the capacity to differentiate into a polarized ciliated epithelial sheet [9] . In undifferentiated cell culture, we found that 100% of HBEC30 in culture display viral protein production after a 24-hour exposure to mouse-adapted virus at an MOI of 5 ( Figure 1A , B). This leads to an approximately 50% decrease in cell viability 48-hours post infection ( Figure 1C ). Given these observations, we adopted a whole genome siRNA screening strategy that involved a 48-hour incubation post siRNA transfection, followed by a 48 hour exposure to influenza A/WSN/1933 or carrier, with cell viability as the endpoint assay. Raw viability values were converted to viability Z-scores with a metric that normalized for both position and batch effects ( Figure 1D , see methods). The dynamic range of viability scores observed under screening conditions potentially affords the opportunity to identify both enhancers and resistors of viral pathogenicity ( Table 1 in Supporting Information S1). Considering siRNA pools associated with Z-scores that were equal to or greater than 3 standard deviations above (resistors) or below (sensitizers) the mean of the population, 53 candidate resistors and 182 candidate sensitizers were identified ( Table 2 in Supporting Information S1). A representative sample of targets was further tested for consequences on viral protein accumulation and viral replication. As might be expected, the majority of the siRNA pools that deflect a viral cytopathic response resulted in reduced viral protein accumulation, as detected by quantitation of viral proteins at single cell resolution, and reduced production of infectious particles ( Figure 2A ). Among these, IVNS1ABP and the splicing factor SFPQ directly interact with the viral pathogenicity factor NS1, presumably reflecting a positive role in support of viral corruption of host machinery for viral protein production [10] . Of interest in this class is RRAGD, a small G-protein that supports the amino-acid responsiveness of mTOR as a component of the ''ragulator'' [11] . Several reports have highlighted the importance of viral induction of mTOR for viral replication, but the mechanism is not fully elaborated [6, 12] . Given the participation of endosomes as a viral entry mechanism [13] , it is tempting to speculate that RRAGD is a limiting host factor for viral corruption of mTOR regulation. Additional factors in this group are involved with the host defense response, p53-mediated cell death and vesicle maturation and trafficking. To test for false positives arising from off-target effects of siRNA treatment, we retested 88 siRNA pools as four individual oligos. Approximately 60% of siRNAs retested with two or more oligos reproducing the original phenotype ( Figure S1 ).