title: Type I IFNs Act upon Hematopoietic Progenitors To Protect and Maintain Hematopoiesis during Pneumocystis Lung Infection in Mice.
abstract: Although acquired bone marrow failure (BMF) is considered a T cell-mediated autoimmune disease, few studies have considered contributing roles of innate immune deviations following otherwise innocuous infections as a cause underlying the immune defects that lead to BMF. Type I IFN signaling plays an important role in protecting hematopoiesis during systemic stress responses to the opportunistic fungal pathogen Pneumocystis. During Pneumocystis lung infection, mice deficient in both lymphocytes and type I IFN receptor (IFrag(-/-)) develop rapidly progressing BMF associated with accelerated hematopoietic cell apoptosis. However, the communication pathway eliciting the induction of BMF in response to this strictly pulmonary infection has been unclear. We developed a conditional-null allele of Ifnar1 and used tissue-specific induction of the IFrag(-/-) state and found that, following Pneumocystis lung infection, type I IFNs act not only in the lung to prevent systemic immune deviations, but also within the progenitor compartment of the bone marrow to protect hematopoiesis. In addition, transfer of sterile-filtered serum from Pneumocystis-infected mice as well as i.p. injection of Pneumocystis into uninfected IFrag(-/-) mice induced BMF. Although specific cytokine deviations contribute to induction of BMF, immune-suppressive treatment of infected IFrag(-/-) mice ameliorated its progression but did not prevent loss of hematopoietic progenitor functions. This suggested that additional, noncytokine factors also target and impair progenitor functions; and interestingly, fungal β-glucans were also detected in serum. In conclusion, our data demonstrate that type 1 IFN signaling protects hematopoiesis within the bone marrow compartment from the damaging effects of proinflammatory cytokines elicited by Pneumocystis in the lung and possibly at extrapulmonary sites via circulating fungal components.
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718; and.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Prigge
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718; and.
authors.forename: Teri R
authors.initials: TR
authors.lastname: Hoyt
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718; and.
authors.forename: Erin
authors.initials: E
authors.lastname: Dobrinen
authors.affiliation: Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718; and.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Schmidt
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718; and natascha.meissner@montana.edu.
authors.forename: Nicole
authors.initials: N
authors.lastname: Meissner
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D017209:Apoptosis; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics; D007370:Interferon Type I / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D011010:Pneumocystis / Q000276:immunology*; D011020:Pneumonia, Pneumocystis / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology; D047071:beta-Glucans / Q000097:blood
chemical_list: D018398:Homeodomain Proteins; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D047071:beta-Glucans; C064658:RAG-1 protein; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma