Pathogens hijack the epigenome: a new twist on host-pathogen interactions

Abstract

Pathogens have evolved strategies to promote their survival by dramatically modifying the transcriptional profile and protein content of the host cells they infect. Modifications of the host transcriptome and proteome are mediated by pathogen-encoded effector molecules that modulate host cells through a variety of different mechanisms. Recent studies highlight the importance of the host chromatin and other epigenetic regulators as targets of pathogens. Host gene regulatory mechanisms may be targeted through cytoplasmic signaling, directly by pathogen effector proteins, and possibly by pathogen RNA. Although many of these changes are short-lived and persist only during the course of infection, several studies indicate that pathogens are able to induce long-term, heritable changes that are essential to pathogenesis of infectious diseases and persistence of pathogens within their hosts. In this review, we discuss how pathogens modulate the epigenome of host cells, a new and flourishing avenue of host-pathogen interaction studies.

Figure 1

Summary of epigenetics. A: Mechanisms of epigenomic gene regulation. Gene regulation is controlled by multiple epigenetic mechanisms, including DNA methylation, histone post-translational modifications, chromatin remodeling, and ncRNAs. B: Epigenetic modifications regulate chromatin state. Heterochromatin is tightly packed DNA, in which DNA is often methylated and promoters (red lines) are inaccessible to DNA-binding proteins and transcriptional complexes, rendering such genes inactive or silenced. In euchromatin, DNA is unwound by chromatin regulators and accessible to transcriptional machinery, including RNA polymerase II (RNA pol II) and transcription factors (TFs), thus allowing transcription to occur. DNMT, DNA methyltransferase; H2A, H2B, H3, and H4, histone proteins; TET, Ten-eleven translocation proteins.

Figure 2

Host epigenetic mechanisms affected by pathogens. Pathogens use a wide variety of mechanisms to modulate host chromatin, as discussed further in Molecular Mechanisms of Epigenetic Modification and summarized in Table 1. To prevent chromatin remodeling and, therefore, maintain a silenced state, M. tuberculosis secretes LpqH lipoprotein, which binds to SWI/SWF remodeling complexes and blocks their function. L. monocytogenes regulates chromatin state via the effector protein LntA, which recruits heterochromatin regulator BAHD1 to recruit heterochromatin proteins and induce formation of heterochromatin. HIV, on the other hand, uses vpr protein to target p300/HAT complexes, causing them to dissociate from chromatin. Alternatively, some pathogens express proteins that directly bind DNA to induce transcription or prevent it. Hepatitis C virus expresses NS5A, which binds promoter regions of host genes. S. flexneri prevents transcription by sequestering host transcription factors, such as the Rb tumor-suppressor proteins. Chromatin state is also regulated by histone post-translational modifications, which can be modulated through manipulation of host enzymes or directly through secreted effector enzymes. For example, S. flexneri modulates the phosphorylation of histone H3S10 through the activity of OspF, a secreted phosphothreonine lyase. OspF removes phosphate groups from Erk2 and p38, two members of the MAPK pathway, which prevents MAPK-dependent H3S10 phosphorylation. Gray line, DNA; red line, silenced promoter; red circles, histone PTMs. Me, cytosine methylation.

Figure 3

Long-term epigenetic changes mediated by pathogens. A: Reprogramming of host cells by M. leprae. Mycobacterium leprae induces the Schwann cells it infects to differentiate into stem cell–like progenitor cells, which have the capacity to differentiate into multiple cell types, including smooth muscle or skeletal muscle cells. By inducing the reprogramming of Schwann cells, M. leprae regulates its own dissemination throughout different tissues. B: Transformation of host cells by T. parva. Theileria parva is, to date, the only organism known to induce continuous proliferation of the host cells it infects, which is directly tied to the division of this parasite as it hijacks the cell’s division machinery. Parasites induce transcriptional changes that lead to the suppression of apoptosis and up-regulation of proliferation genes. AT hook-binding proteins are also used to influence the transcriptome of host genes to promote survival of T. parva. C: Oncogenesis induced by chronic H. pylori infection. The bacterium H. pylori induces profound changes in transcription in its target tissue, the gastric epithelium. By secreting enzymes and virulence factors onto the surface of the epithelium and into cells, it induces damage to epithelial cells and a loss of cell polarity. Chronic exposure to H. pylori leads to altered transcription and DNA methylation, mirrored by changes in histone PTMs and eventual dysplasia and carcinogenesis.