Bone marrow failure by cytomegalovirus is associated with an in vivo deficiency in the expression of essential stromal hemopoietin genes.
Bone marrow (BM) failure associated with cytomegalovirus (CMV) infection is a feared complication after clinical BM transplantation. Experiments in long-term BM cultures have indicated that BM stromal cells (BMSC) are targets of productive CMV infection, but an in situ infection of BM stroma remained to be documented, and the pathomechanism is open to question. Here we describe a murine in vivo model of lethal CMV aplastic anemia (CMV-AA). The reconstitution of hematopoietic progenitor cells expressing stem cell factor (SCF) receptor was found to be defective in CMV-AA. While murine CMV replication in permissive parenchymal tissues is cytolytic, the hematopoietic cord was found to be a site of very limited virus production with foci of reticular BMSC expressing the intranuclear viral IE1 protein, but with only a few BMSC positive for viral genome in the in situ hybridization. XX-XY BM chimeras were established in order to quantitate Y-chromosome-tagged BMSC by a PCR specific for the male-sex-determining gene Tdy. This approach revealed that murine CMV infection is not associated with a significant loss of BMSC. Despite the physical integrity of the stromal network, the functional integrity of the stroma was impaired. While housekeeping genes were expressed normally in BMSC of infected mice, the expression of genes encoding the essential hemopoietins SCF, granulocyte colony-stimulating factor, and interleukin-6 was markedly reduced. In conclusion, the mechanism of BM failure is not a stromal lesion but an insufficient stromal function. These findings explain CMV-AA as a manifestation of multiple hemopoietin deficiency.
Mayer
A
A
Institute for Virology, Johannes Gutenberg-University, Mainz, Germany.
Podlech
J
J
Kurz
S
S
Steffens
H P
HP
Maiberger
S
S
Thalmeier
K
K
Angele
P
P
Dreher
L
L
Reddehase
M J
MJ
D000741:Anemia, Aplastic / Q000382:microbiology* / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000473:pathology / Q000503:physiopathology*; D003586:Cytomegalovirus Infections / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics; D006410:Hematopoiesis; D016298:Hematopoietic Cell Growth Factors / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D019089:Stem Cell Factor / Q000235:genetics
D016298:Hematopoietic Cell Growth Factors; D015850:Interleukin-6; D012333:RNA, Messenger; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit