Congenital cytomegalovirus infection: molecular mechanisms mediating viral pathogenesis

Abstract

Human cytomegalovirus (CMV) is responsible for approximately 40,000 congenital infections in the United States each year. Congenital CMV disease frequently produces serious neurodevelopmental disability, as well as vision impairment and sensorineural hearing loss. Development of a CMV vaccine is therefore considered to be a major public health priority. The mechanisms by which CMV injures the fetus are complex and likely include a combination of direct fetal injury induced by pathologic virally-encoded gene products, an inability of the maternal immune response to control infection, and the direct impact of infection on placental function. CMV encodes gene products that function, both at the RNA and the protein level, to interfere with many cellular processes. These include gene products that modify the cell cycle; interfere with apoptosis; induce an inflammatory response; mediate vascular injury; induce site-specific breakage of chromosomes; promote oncogenesis; dysregulate cellular proliferation; and facilitate evasion of host immune responses. This minireview summarizes current concepts regarding these aspects of the molecular virology of CMV and the potential pathogenic impact of viral gene expression on the developing fetus. Areas for potential development of novel therapeutic intervention are suggested for improving the outcome of this disabling congenital infection.

Fig. (1)

Electron microscopic visualization of morphology of cytomegalovirus particles. Human foreskin fibroblasts were inoculated with the Toledo strain of cytomegalovirus and, following 7 days of incubation, cells were fixed with paraformaldehyde, stained with phosphotungstic acid, and visualized by EM (University of Minnesota). A) Image demonstrating cell-associated virus particles [virions and dense bodies (DB)]. B) Comparison of mature virion and non-infectious enveloped particle (NIEP, arrow), which contains capsid proteins but no DNA and is hence replication-defective. C) Comparison of virions and DB (arrow). In contrast to virions, DB are larger, contain no viral DNA and no capside proteins, and are non-infectious.

Fig. (2)

Schematic of CMV Genome. A) Structure of the CMV genome. The CMV genome is organized as two regions of unique sequences, unique long (UL) and unique short (US), flanked by two sets of inverted repeats (TRL/IRL) and (IRS/TRS) (light shaded boxes). UL - Unique long; US - Unique short; TRL - Terminal repeat long; IRL - Internal repeat long; inverted repeat of TRL; TRS -Terminal repeat short; IRS - Internal repeat short; inverted repeat of TRS. This genome structure allows one of four potential isomeric configurations to be represented in any given infectious virus particle. Figure originally published in [41] and used with permission. B) Genetic map of wild-type CMV. Related groupings of protein-encoding regions are indicated by colored arrows, with gene family nomenclature indicated below. Many CMV genes are spliced and these introns are indicated as narrow white bars. Colors also delineate whether genes are conserved in all Herpesviridae (core genes) or between the Betaherpesviridae (CMV, HHV6, HHV7) and Gammaherpesviridae (Epstein-Barr virus, HHV-8; sub-core genes). A group of 22 ORFs (ORFs ~133-150 in the UL region of the genome) are prone to rapid deletion/mutation/rearrangement when CMV is subjected to laboratory passage in fibroblast cell culture: this represents the so-called ULb’ region of the genome (see text for details). Figure reproduced from [42] and used with permission, Copyright 2000, National Academy of Sciences, U.S.A.

Fig. (3)

Impact of CMV infection on cellular physiology, gene expression, and function. Following CMV infection, a variety of fates potentially await the infected cell, depending on the target organ and embryological state of the cell. These include transformation/dysregulation of cellular replication; immune activation and/or immune evasion; modification of apoptosis mechanisms and perturbation of cell cycle regulation; changes in cellular metabolism; and global perturbations in transcriptional and proteomic profiles. Cell death and lysis may also occur following infection. The synergy of these effects on the infected cell likely mediates much of the pathology and pathogenesis associated with congenital infection.