Influenza A viruses are negative-stranded RNA viruses that are capable of infecting a variety of avian and mammalian species. These viruses are responsible for the annual epidemics that cause severe illnesses in millions of people worldwide. The initial innate immune responses to influenza A viruses have to restrict virus spread before the adaptive immune responses fully develop. Macrophages are the key players of innate immune system and they have a central role in the activation of host response during viral infections. However, the host factors that are involved in the activation of innate immune response during influenza A virus infection are incompletely understood. Here, we have characterized in detail the nuclear, mitochondrial and cytoplasmic proteomes, as well as the secretome from influenza A virus-infected human primary macrophages to get a global view of host factors that are affected by the infection. Our approach allowed us to identify several novel host factors that contribute to innate immune system during influenza A virus infections. These include lysomal proteases cathepsins, P2X 7 receptor, src family tyrosine kinases as well as several dangerassociated molecular patterns.