TABLE 4.

Mechanisms of the synergistic relationships between viruses and bacteria in periodontitis

Steps	Mechanisms of synergism	Bacterial and herpesvirus factors	Plausibility and strength of evidence
Initial colonization and infection	Exposure of cryptic receptors of the host cells via degradation for bacterial or viral adherence	Porphyromonas gingivalis proteolytic enzymes	Moderate
	Physical interaction between bacteria and viruses to increase access of the microorganisms to the host tissue	Not available	Low
	Activation of cell surface receptors for bacterial or viral adherence	Not available	Low
	Exposure of new tissues for bacterial adherence	Herpesvirus lytic infection	Moderate
Bacterial growth and viral replication	Tissue destruction associated with viral lytic infection, leading to an increase in available nutrients for bacteria	Herpesvirus lytic infection	High
	Activation of latent viral infection via bacterial infection	Various mechanisms of bacterial infection	High
Modulation of host innate immunity	Killing of neutrophils and macrophages	Aggregatibacter actinomycetemcomitans leukotoxin and cytolethal distending toxin	High
	Suppression of production or functions of cytokines, including interleukin-8 and −10, leading to immune suppression and host defense paralysis	Porphyromonas gingivalis SerB; herpesvirus Vhs, UL11, vIL-10, US27, US28, UL33 and UL78, vGPCR, vIL-6, microRNA	High
	Suppression of pathogen-associated molecular pattern recognition/activation by the innate immunity to promote bacterial and viral infection	Atypical P. gingivalis lipopolysaccharide as a toll-like recepter-4 antagonist; herpesvirus UL37, ICP0, US3, ICP27, ICP24, VP16, pUL83, UL31, pUL82, US9, IE86, RTA, ORF36, dUTPase, vGAT/ORF75, ORF63, ORF52, LANA, vIRF1	High
Modulation of host adaptive immunity	Interfering with antigen presentation leading to dampened adaptive host immune response	Porphyromonas gingivalis Mfa1 and gingipains to promote intracellular survival of bacteria in macrophages and dendritic cells; herpesvirus ICP47, US3, US2, US10 and US11, US6, US3, UL82, UL83, US4–1, K3, K5, and BILF1/ vGPCR to interfere with antigen presentation	Low
Tissue destruction	Killing of epithelial cells, fibroblasts, endothelial cells	Aggregatibacter actinomycetemcomitans leukotoxin and cytolethal distending toxin; herpetic lytic infection	High
Transmission	Shedding of viruses in the saliva for transmission	Activation of latent herpesvirus infection by bacterial infection	High

Abbreviations: BILF1, G-protein coupled receptor BILF1; ICP, infected cell protein;IE86, immediate early 86 kDalton protein; LANA, latency-associated nuclear antigen; ORF, open reading frame; SerB, phosphoserine phosphatase; RTA, replication and transcription activator; UL, unique long; US, unique short; v, viral; Vhs, virion host shutoff; VP, virion protein.