While beta interferon (IFN-β)-deficient (IFN-β−/−) mice are highly susceptible to PR8, they exhibited delayed death upon Sp3 superinfection, indicating that while IFN-β was protective against influenza, it negatively impacted the host response to Sp3. IFN-β-treated WT macrophages selectively suppressed Sp3-induced CXCL1/CXCL2 transcriptionally, as evidenced by reduced recruitment of RNA polymerase II to the CXCL1 promoter. The gene discussed is CXCL1; the disease is influenza.