Cytomegalovirus-induced embryopathology: mouse submandibular salivary gland epithelial-mesenchymal ontogeny as a model.
BACKGROUND
Human studies suggest, and mouse models clearly demonstrate, that cytomegalovirus (CMV) is dysmorphic to early organ and tissue development. CMV has a particular tropism for embryonic salivary gland and other head mesenchyme. CMV has evolved to co-opt cell signaling networks so to optimize replication and survival, to the detriment of infected tissues. It has been postulated that mesenchymal infection is the critical step in disrupting organogenesis. If so, organogenesis dependent on epithelial-mesenchymal interactions would be particularly vulnerable. In this study, we chose to model the vulnerability by investigating the cell and molecular pathogenesis of CMV infected mouse embryonic submandibular salivary glands (SMGs).


RESULTS
We infected E15 SMG explants with mouse CMV (mCMV). Active infection for up to 12 days in vitro results in a remarkable cell and molecular pathology characterized by atypical ductal epithelial hyperplasia, apparent epitheliomesenchymal transformation, oncocytic-like stromal metaplasia, beta-catenin nuclear localization, and upregulation of Nfkb2, Relb, Il6, Stat3, and Cox2. Rescue with an antiviral nucleoside analogue indicates that mCMV replication is necessary to initiate and maintain SMG dysmorphogenesis.


CONCLUSIONS
mCMV infection of embryonic mouse explants results in dysplasia, metaplasia, and, possibly, anaplasia. The molecular pathogenesis appears to center around the activation of canonical and, perhaps more importantly, noncanonical NFkappaB. Further, COX-2 and IL-6 are important downstream effectors of embryopathology. At the cellular level, there appears to be a consequential interplay between the transformed SMG cells and the surrounding extracellular matrix, resulting in the nuclear translocation of beta-catenin. From these studies, a tentative framework has emerged within which additional studies may be planned and performed.
Melnick
Michael
M
Laboratory for Developmental Genetics, University of Southern California, Los Angeles, CA 90089-0641, USA. mmelnick@usc.edu
Mocarski
Edward S
ES
Abichaker
George
G
Huang
Jing
J
Jaskoll
Tina
T
D000818:Animals; D002478:Cells, Cultured; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000473:pathology* / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D008648:Mesoderm / Q000473:pathology* / Q000821:virology; D051379:Mice; D011247:Pregnancy; D012469:Salivary Glands / Q000196:embryology / Q000473:pathology / Q000821:virology; D013363:Submandibular Gland / Q000196:embryology* / Q000473:pathology* / Q000821:virology; D013997:Time Factors