CCR7 impairs hematopoiesis after hematopoietic stem cell transplantation increasing susceptibility to invasive aspergillosis.
Hematopoietic stem cell transplantation (HSCT) is limited by patient susceptibility to opportunistic infections. One of the most devastating infections after HSCT is invasive aspergillosis (IA), a life-threatening disease caused by Aspergillus fumigatus. Transplantation of hematopoietic stem cells (HSCs) and myeloid progenitor cells (MPCs) has been shown to mediate protection against IA, but little is known about the factors that regulate HSC and MPC cell expansion after transplantation. Herein, we investigated the role of CCR7 in a murine model of IA after combined HSC and MPC transplantation into lethally irradiated wild-type (WT) mice. Nonirradiated CCR7(-/-) mice had expanded populations of HSCs in the bone marrow and spleen, compared with WT mice. Irradiated WT mice reconstituted with CCR7(-/-) HSCs and MPCs had increased survival, decreased fungal burden, and enhanced myeloid leukocyte numbers during IA, compared with WT controls. In addition, WT mice reconstituted with WT HSCs and MPCs and treated with anti-CCR7 exhibited accelerated myeloid cell expansion similar to that observed in CCR7(-/-)→WT chimeras. Thus, removal of the inhibitory effects of CCR7 through genetic alteration or ligand immunoneutralization enhanced myeloid reconstitution, thereby accelerating fungal clearance in a murine model of IA.
Hartigan
Adam J
AJ
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Kallal
Lara E
LE
Hogaboam
Cory M
CM
D000818:Animals; D001228:Aspergillosis / Q000517:prevention & control*; D004198:Disease Susceptibility; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000637:transplantation; D009894:Opportunistic Infections; D054400:Receptors, CCR7 / Q000172:deficiency* / Q000502:physiology
C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7