In addition to the DNA and RNA tumor viruses affecting the epigenotype of their host cells (see 8), certain viruses which are not directly involved in tumorigenesis interact with the cellular epigenetic regulatory mechanisms, as well. In CD4+ T cells, human immunodeficiency virus infection downregulates interferon-gamma (IFN-γ) expression by inducing de novo methylation of the IFN-γ promoter and silences a tumor suppressor gene (p16INK4A) and the gene coding for N-acetylmannosamine kinase (GNE), a key enzyme in sialylation of surface glycoproteins, in a similar manner. Infection of nonneoplastic cells by hepatitis C virus, a tumor-associated virus, results in epigenetic silencing of IFN-α responsive genes, an effect that influences the success of antiviral therapy, but is not necessarily related to hepatocarcinogenesis. During lytic infection, the immediate-early proteins of human cytomegalovirus block the activity of cellular histone deacetylases (HDACs), facilitating productive virus replication. Pathogenic bacteria, including Listeria monocytogenes, Streptococcus pneumoniae, Clostridium perfringens, and Aeromonas hydrophila produce toxins that alter modified histones or secrete butyric acid, a HDAC inhibitor, like Porphyromonas gingivalis, a causative agent of periodontal disease. Others, as exemplified by Shigella flexneri, Anaplasma phagocytophilum, and Mycobacterium tuberculosis, synthesize effector proteins that change the pattern of histone modifications around host defense gene promoters, facilitating immune evasion. In principle, the protein methyltransferases of Chlamydia trachomatis and Chlamydophila pneumoniae may also elicit epigenetic reprogramming in infected cells by methylating host histones. Hypermethylation of cellular promoters may be the patho-epigenetic mechanism resulting in intrauterine growth restriction in association with Campylobacter rectus infection. Uropathogenic Escherichia coli can also induce CpG methylation at distinct cellular promoters in vitro. Similarly, profound alterations in the methylation pattern of the host cell DNA accompany the development of gastric carcinoma in Helicobacter pylori-infected individuals. Pathogenic protozoa use their own epigenetic regulatory mechanisms to control virulence gene expression and differentiation. Although their influence on the host cell epigenome remains to be elucidated at greater depth, the unique features of the protozoan epigenetic machineries may provide excellent targets for novel therapeutic drugs.
ASJC Scopus subject areas
- Immunology and Microbiology(all)