Respiratory viral infections trigger a robust inflammatory response in the lung, producing cytokines, chemokines, and growth factors that promote infiltration of effector leukocytes. The timely recruitment of the appropriate cell types is critical for mounting a proper immune response, clearance of the virus and recovery from infection.

We examined the communication between Sendai virus (SeV) or influenza virus infected lung and other lymphoid organs, with emphasis on the interaction between the lung and the bone marrow (BM). The BM is known as the major site of hematopoiesis in the adult mammal and as such is likely to be the main producer of cells during the course of infection. This work focuses on two cytokines which are induced in the virus infected lung: type I interferons (IFNs) and granulocyte colony-stimulating factor (G-CSF). We describe how type I IFNs affect cells developing in the BM by changing their transcriptional regulation and immunological function and the absolute requirement for G-CSF expression in recovery from infection.

Type I IFNs are considered to be the main inducers of an antiviral state. Previous research from our group and others have shown that exposure of cells in vitro to type I IFNs enhances their ability to perform their immunological function and resist infection. Here we examined whether the priming effect reported in vitro could be observed in vivo and the functional consequence of such priming. We found that, while in the BM, leukocytes exposed to lung derived type I IFNs activate an antiviral transcriptional program and become resistant to infection with different viruses. These protected bone marrow leukocytes are capable of migrating to the infected lung and are required for immunity against the virus.

G-CSF is of major importance in the differentiation of neutrophils in the BM and is also known to induce the release of cells from the BM to the blood. It is well known that G-CSF deficiencies lead to severe neutropenia and susceptibility to bacterial infections. We describe here that G-CSF deficient mice are unable to clear SeV or influenza virus from the lung and succumb to the infection. The enhanced susceptibility to virus infection in the absence of G-CSF is likely due to a reduced phagocytic capacity in these mice.

Pro-inflammatory cytokines, including G-CSF and type I IFNs were solely expressed in the infected lung and therefore the response observed in the periphery resulted from systemic cytokine dissemination through the blood. These findings emphasize the importance of continuous communication between the infected organ and the BM for antiviral instruction, cell development and their release from the BM for effective control of infection.