Biology and pathogenesis of cytomegalovirus in periodontal disease

Abstract

Human periodontitis is associated with a wide range of bacteria and viruses and with complex innate and adaptive immune responses. Porphyromonas gingivalis, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, Treponema denticola, cytomegalovirus and other herpesviruses are major suspected pathogens of periodontitis, and a combined herpesvirus-bacterial periodontal infection can potentially explain major clinical features of the disease. Cytomegalovirus infects periodontal macrophages and T-cells and elicits a release of interleukin-1β and tumor necrosis factor-α. These proinflammatory cytokines play an important role in the host defense against the virus, but they also have the potential to induce alveolar bone resorption and loss of periodontal ligament. Gingival fibroblasts infected with cytomegalovirus also exhibit diminished collagen production and release of an increased level of matrix metalloproteinases. This article reviews innate and adaptive immunity to cytomegalovirus and suggests that immune responses towards cytomegalovirus can play roles in controlling, as well as in exacerbating, destructive periodontal disease.

Figure 1

Viral infection steps: entry, replication, dissemination and infection of target cells/organs. Virions enter the host organism and spread to target tissues/organs where they can replicate and/or cause a persistent infection (latency). Latent viruses can become reactivated by several immune‐compromising events, such as smoking, inflammation, stress, trauma and immunosuppressive diseases.

Figure 2

Different pathways of intracellular sorting of viruses. Virions released from stratified epithelium (left) or intestinal epithelium (right), by either apical sorting or basolateral sorting, can infect adjacent cells, enter connective tissue and gain access to blood vessels, or be dispersed into body lumens.

Figure 3

Proposed model linking cytomegalovirus to periodontal breakdown. Cytomegalovirus‐infected cells reach periodontal connective tissues, and reactivation or latency occur within the connective tissues. Virions infect other cells (gingival fibroblasts and inflammatory cells), which results in the release of proinflammatory cytokines and increased susceptibility to tissue breakdown, including loss of aveolar bone and periodontal attachment. GCF, gingival crevicular fluid; IL, interleukin; MHC‐I, major histocompatibility complex class I; MMP, matrix metalloproteinase; TNF‐α, tumor necrosis factor‐α.

Figure 4

Primary culture of gingival fibroblasts infected with cytomegalovirus Towne strain. Gingival fibroblasts are shown before infection (A), 1 day after infection (B), 2 days after infection (C), 4 days after infection (D), 5 days after infection (E) and 6 days after infection (F). Note the characteristic cytopathic effects and the increasing number of infected cells over time.

Figure 5

Indirect immunofluorescence staining of cytomegalovirus‐infected gingival fibroblasts with the primary antibody against the immediate‐early pp72 protein.