Infectious disease meets the epigenome

The study of epigenetics (see Pharyngula's excellent article) has allowed us to see biology and genetics through new eyes. The fact that heritable traits can be encoded in not only the nucleic acid sequences of As, Cs, Ts and Gs but also in the physical conformation of chromosomes and chemical modification of DNA has added a new level of complexity to our understanding of life. Covalent modifications to both DNA and associated histones and chromatin can result in the formation of active or repressed genetic regions; transcription of these genes found in that area is thus activated or repressed. Embryonic development, behaviour and cancer formation  have all been impacted by the discovery of this new genetic system wit deregulated epigentic processes leading to the development of these diseases - but what about in infection, immunity and pathogenesis of associated diseases?

[caption id="" align="aligncenter" width="300" caption="Epigenetics: DNA, histones, ovalent modification and chromatin."][/caption]



Infectious diseases are spread between and among populations of hosts - thus a close relationship exists between these organisms. Potential pathogens have adapted to their hosts and are able to co-opt 'natural' processes occuring inside tissues and cells. Host cells can be entered, metabolic changes occur and significant enegry expenditure is directed toward the pathogen, whether it be an intracellular bacteria or a virus, at the expense of the host which can lead to considerable damage or even death. One of these 'natural' processes occuring within host cells are epigenetic mechanisms which may allow invading pathogens to alter the transcriptional state of that cell. What we are beginning to see is that nay diverse viruses or bacteria are able to hijack this system for their own gain in order to increase replication and avoid the host immune system.

Cell have recently published a review of this host/pathogen interaction by Konstantinos Paschos and Martin J. Allday. In it they consider how both viruses and bacteria direct epigenetic changes to benefit themselves through changes in the expression of genes involved in cell-cycle progresion, immunity or inflammation which would likely contribute to disease pathogenesis - viral latency and associated cancer, AIDs and hepatitis all involve epigenetic changes.. What strikes me is the sheer diversity of pathogens: large DNA viruses such as herpesviruses, smaller ones such as the Adenoviruses and Papillomaviruses, retroviruses such as HIV-1 or even bacterial pathogens -  clearly there is great potential in altering host epigenomes although there are still some types of viruses which are not on that list (maybe this will change as we begin to know more about this?).  Not just humans are affected by this as a number of unicellular eukaryotes also have their epigenomes changed by viral pathogens.

[caption id="" align="aligncenter" width="499" caption="Epstein-Barr virus exploitation of the immune system (entry, initial replication and latency). Where does epigenetics play a role?"][/caption]

One well understood example is that of Epstein-Barr virus, a large DNA herpesvirus that causes latent infection and is involved in the development of a number of human tumours of lymphocytic or epithelial origin. A number of virally encoded genes are involved in epigenomic modifications of the host cell allowing the viral genome to persist unaffected in the host. EBV encoded proteins interact with a positive regulator of apoptosis BIM in lymphocytes allowing EBV infected cells to persist without succombing to cell death. EBV represses BIM expression via epigenetic mechanisms - the directed methlyation and thus repression of histones found around the BIM promotor. A number of other host genes are also repressed by EBV-directed processes and has driven the hypothesis that EBV-associated cancer is initially driven by the epigenetic reprogamming of infected cells.

Other examples are less well understood although a distinct epigenomic change is observed the mechanism of which has been poorly studied. We are beginning to appreciate the importance of epigenetics in all fields of biology and are even applying these studies in our understanding and treatment of disease. Recently, however, we have begun to investigate the role it plays in infectious disease where viruses and bacteria manipulate the cellular epigenome to allow pathogen survival and spread. Although a diverse group of pathogens have been studied so far we should expect to see this list grow in the future and with it we will see more details emerge as to how exactly they achieve reprogramming.

Recent technological advances such as deep-sequencing, microarrays and proteomics will facilitate a more broad understanding of these pathogen-associtaed epigenetic changes but - How will this affect our treatment of infectious disease? What other pathogens use this system? How do they manipulate it? What other host genes, pathways or systems are affected by this change? How did it evolve? What about its role in other hosts other than humans? Does the host use epigenetic modifications to restrict pathogen replication and pathogenesis? Only time, lots of money and well thought out experiments will tell.

Paschos, Konstantinos, and Martin J Allday. 2010. Epigenetic reprogramming of host genes in viral and microbial pathogenesis. Trends in microbiology 18, no. 10 (October): 439-47. doi:10.1016/j.tim.2010.07.003. http://www.ncbi.nlm.nih.gov/pubmed/20724161.