Critical Dynamics in Host–Pathogen Systems

Abstract

Host-pathogen interactions provide a fascinating example of two or more active genomes directly exerting mutual influence upon each other. These encounters can lead to multiple outcomes from symbiotic homeostasis to mutual annihilation, undergo multiple cycles of latency and lysogeny, and lead to coevolution of the interacting genomes. Such systems pose numerous challenges but also some advantages to modeling, especially in terms of functional, mathematical genome representations. The main challenges for the modeling process start with the conceptual definition of a genome for instance in the case of host-integrated viral genomes. Furthermore, hardly understood influences of the activity of either genome on the other(s) via direct and indirect mechanisms amplify the needs for a coherent description of genome activity. Finally, genetic and local environmental heterogeneities in both the host's cellular and the pathogen populations need to be considered in multiscale modeling efforts. We will review here two prominent examples of host-pathogen interactions at the genome level, discuss the current modeling efforts and their shortcomings, and explore novel ideas of representing active genomes which promise being particularly adapted to dealing with the modeling challenges posed by host-pathogen interactions.

HMGA1 recruits CTIP2-repressed P-TEFb to the HIV-1 and cellular target promoters

“…The identification of host-cellular factors involved in HIV-1 silencing, as accomplished here, contributes to a more detailed understanding of how viral latency is established and maintained and thus may open ways to novel therapeutic approaches for fighting HIV infection (42,43,44). …”

“…Taken together, the HMGA1-mediated recruitment of CTIP2-repressed P-TEFb not only affects endogenous gene expression in microglial cells but, moreover, also modulates the expression of the HIV-1 genome. The identification of host-cellular factors involved in HIV-1 silencing, as accomplished here, contributes to a more detailed understanding of how viral latency is established and maintained and thus may open ways to novel therapeutic approaches for fighting HIV infection ( 42 , 43 , 44 ).…”

Systems virology: host-directed approaches to viral pathogenesis and drug targeting

“…This is particularly true in light of evidence (discussed above) that the magnitude and timing of the host response to respiratory viruses are crucial determinants of the eventual disease outcome. Similar evidence is accumulating that the outcome of HIV infection is also related to the activation dynamics of host gene regulation 77 , 78 . However, high-throughput data are typically static and often not adequate for modelling dynamic systems.…”

Non-coding RNAs: novel players in chromatin-regulation during viral latency

“…Such ncRNAs could represent novel therapeutic targets in order to eradicate latent viral reservoirs, which could in turn support ART to cure retroviral infection. Especially systems approaches applying recent powerful technologies such as next generation sequencing -as pioneered by Peng et al [65] and Chang et al [66 ] -RNA-seq, RIP-Seq or 5 0 mC-Seq will substantially improve the detection of regulatory ncRNA networks during viral infection to advance our current knowledge about the establishment of viral latency and host-pathogen interactions in general [67].…”