Myeloid progenitors protect against invasive aspergillosis and Pseudomonas aeruginosa infection following hematopoietic stem cell transplantation.
Myelotoxic treatments for oncologic diseases are often complicated by neutropenia, which renders patients susceptible to potentially lethal infections. In these studies of murine hematopoietic stem cell transplantation (HSCT), cotransplantation of lineage-restricted progenitors known as common myeloid progenitors (CMP) and granulocyte-monocyte progenitors (GMP) protects against death following otherwise lethal challenge with either of 2 pathogens associated with neutropenia: Aspergillus fumigatus and Pseudomonas aeruginosa. Cotransplantation of CMP/GMP resulted in a significant and rapid increase in the absolute number of myeloid cells in the spleen, most of which were derived from the donor CMP/GMP. Despite persistent peripheral neutropenia, improved survival correlated with the measurable appearance of progenitor-derived myeloid cells in the spleen. A marked reduction or elimination of tissue pathogen load was confirmed by culture and correlated with survival. Localization of infection by P aeruginosa and extent of disease was also assessed by in vivo bioluminescent imaging using a strain of P aeruginosa engineered to constitutively express a bacterial luciferase. Imaging confirmed that transplantation with a graft containing hematopoietic stem cells and CMP/GMP reduced the bacterial load as early as 18 hours after infection. These results demonstrate that enhanced reconstitution of a tissue myeloid pool offers protection against lethal challenge with serious fungal and bacterial pathogens.
BitMansour
Andrew
A
Division of Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, CA, USA.
Burns
Stacy M
SM
Traver
David
D
Akashi
Koichi
K
Contag
Christopher H
CH
Weissman
Irving L
IL
Brown
Janice M Y
JM
D000280:Administration, Inhalation; D000818:Animals; D020296:Animals, Congenic; D001228:Aspergillosis / Q000382:microbiology / Q000517:prevention & control*; D001232:Aspergillus fumigatus; D019070:Cell Lineage; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D007274:Injections, Intraperitoneal; D008163:Luminescent Measurements; D008172:Lung Diseases, Fungal / Q000382:microbiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000502:physiology / Q000637:transplantation*; D009503:Neutropenia / Q000150:complications / Q000188:drug therapy; D011552:Pseudomonas Infections / Q000382:microbiology / Q000517:prevention & control*; D011828:Radiation Chimera; D011994:Recombinant Proteins; D014018:Tissue Distribution
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim