RESUMEN
Cytomegalovirus (CMV) has a high prevalence worldwide, is often fatal for immunocompromised patients, and causes bone marrow suppression. Deficiency of signal transducer and activator of transcription 1 (STAT1) results in severely impaired antiviral immunity. We have used cell-type restricted deletion of Stat1 to determine the importance of myeloid cell activity for the defense against murine CMV (MCMV). We show that myeloid STAT1 limits MCMV burden and infection-associated pathology in the spleen but does not affect ultimate clearance of infection. Unexpectedly, we found an essential role of myeloid STAT1 in the induction of extramedullary hematopoiesis (EMH). The EMH-promoting function of STAT1 was not restricted to MCMV infection but was also observed during CpG oligodeoxynucleotide-induced sterile inflammation. Collectively, we provide genetic evidence that signaling through STAT1 in myeloid cells is required to restrict MCMV at early time points post-infection and to induce compensatory hematopoiesis in the spleen.
Asunto(s)
Hematopoyesis Extramedular , Infecciones por Herpesviridae/fisiopatología , Muromegalovirus , Células Mieloides/fisiología , Factor de Transcripción STAT1/fisiología , Animales , Células Cultivadas , Femenino , Eliminación de Gen , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/metabolismo , Células Asesinas Naturales/inmunología , Masculino , Ratones Endogámicos C57BL , Muromegalovirus/fisiología , Receptor de Interferón alfa y beta/genética , Receptores de Interferón/genética , Receptores de Interleucina/genética , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Bazo/patología , Bazo/virología , Estrés Fisiológico , Replicación ViralRESUMEN
Tyrosine kinase 2 (TYK2) has a pivotal role in immunity to infection and tumor surveillance. It is associated with several cytokine receptor chains including type I interferon (IFN) receptor 1 (IFNAR1), interleukin- (IL-) 12 receptor beta 1 (IL-12Rb1) and IL-10R2. We have generated a mouse with a conditional Tyk2 null allele and proved integrity of the conditional Tyk2 locus. TYK2 was successfully removed by the use of ubiquitous and tissue-specific Cre-expressing mouse strains. Myeloid TYK2 was found to critically contribute to the defense against murine cytomegalovirus. Ubiquitous TYK2 ablation severely impaired tumor immunosurveillance, while deletion in myeloid, dendritic or T cells alone showed no effect. The conditional Tyk2 mouse strain will be instrumental to further dissect TYK2 functions in infection, inflammation and cancer.
Asunto(s)
Muromegalovirus/genética , Neoplasias/genética , TYK2 Quinasa/genética , Animales , Ratones , Ratones Transgénicos , Muromegalovirus/patogenicidad , Neoplasias/patología , Transducción de Señal/genética , Linfocitos T , TYK2 Quinasa/biosíntesisRESUMEN
Signal transducer and activator of transcription (STAT) 1 is a key player in interferon (IFN) signaling, essential in mediating host defense against viruses and other pathogens. STAT1 levels are tightly regulated and loss- or gain-of-function mutations in mice and men lead to severe diseases. We have generated a doxycycline (dox) -inducible, FLAG-tagged Stat1 expression system in mice lacking endogenous STAT1 (i.e. Stat1(ind) mice). We show that STAT1 expression depends on the time and dose of dox treatment in primary cells and a variety of organs isolated from Stat1(ind) mice. In bone marrow-derived macrophages, a fraction of the amount of STAT1 present in WT cells is sufficient for full expression of IFN-induced genes. Dox-induced STAT1 established protection against virus infections in primary cells and mice. The availability of the Stat1(ind) mouse model will enable an examination of the consequences of variable amounts of STAT1. The model will also permit the study of STAT1 dose-dependent and reversible functions as well as of STAT1's contributions to the development, progression and resolution of disease.
