Cytomegalovirus Induces Stage-Dependent Enamel Defects and Misexpression of Amelogenin, Enamelin and Dentin Sialophosphoprotein in Developing Mouse Molars

Abstract

Of the approximately 8,400 children born each year in the US with cytomegalovirus (CMV)-induced birth defects, more than one third exhibit hypoplasia and hypocalcification of tooth enamel. Our prior studies indicated that CMV severely delayed, but did not completely interrupt, early mouse mandibular first molar morphogenesis in vitro. The aim of the present study was to examine the effects of CMV infection on progressive tooth differentiation and amelogenesis. Since initial CMV infection in human fetuses can occur at different developmental times, we varied the stage of initial viral infection (that is, Cap stage, Early Bell stage and Bell stage), as well as the duration of infection. CMV infection of embryonic mouse mandibular first molars in vitro induces tooth dysmorphogenesis and enamel defects in a developmental stage- and duration-dependent manner. Cap stage- and Early Bell stage-infected molars exhibit enamel agenesis and Bell stage-infected molars exhibit enamel hypoplasia. This viral-induced pathology is coincident with stage-dependent changes in Amelx, Enam and Dspp gene expression, distribution of amelogenin, enamelin and DSP proteins, cell proliferation localization and dedifferentiation of secretory ameloblasts. Importantly, our data indicate that specific levels of Amelx and Dspp gene expression define whether mouse CMV induces enamel agenesis or hypoplasia.

Small molecule inhibitors of the host cell COX/AREG/EGFR/ERK pathway attenuate cytomegalovirus-induced pathogenesis

“…Thus, the central interest of systems genetics is on networks of interaction between genes and phenotypes. Though scores of genes may at first seem to be critical to such interactions, they and their cognate networks can be prioritized using unbiased learning methods such as probabilistic neural network analysis (Melnick et al, 2001, 2006, 2009; Jaskoll et al, 2010). A priori predictions that follow from a high priority network model can be tested in the usual manner (gene mutations, small molecule inhibitors, environmental exposures).…”

Low‐cost periodontal therapy

“…Epstein–Barr virus is also associated with pregnancy gingivitis and other types of gingivitis (100), and is an etiologic agent of oral hairy leukoplakia and lymphoid and epithelial malignancies (315). Cytomegalovirus is involved in severe types of periodontitis (179, 299) and in embryopathosis affecting tooth morphogenesis (148, 328), osteogenesis of the jaws (31, 149) and salivary gland development (203). Herpesvirus infections may trigger an overgrowth of periodontopathic bacteria (303) and, paradoxically, anti‐herpesvirus immune responses may contribute to both tissue destruction and the arrest of periodontal breakdown (63).…”

Developmental enamel defects in the primary dentition: aetiology and clinical management

“…Infectious diseases caused by bacteria and viruses such as infections of the urinary tract, otitis and upper respiratory disease have been associated with DDE . Although uncommon in developed countries, congenital syphilis acquired from maternal Treponema pallidum infections can cause enamel hypoplasia or ‘notching’ of the incisor teeth, and viral infections such as chicken pox, rubella, measles, mumps, and influenza have been associated with DDE in both primary and permanent dentitions, while cytomegalovirus (CMV) has been reported to cause enamel hypoplasia or hypocalcification in approximately one‐third of affected infants …”