Genetic-and-Epigenetic Interspecies Networks for Cross-Talk Mechanisms in Human Macrophages and Dendritic Cells during MTB Infection.
Tuberculosis is caused byMycobacterium tuberculosis(Mtb) infection.Mtbis one of the oldest human pathogens, and evolves mechanisms implied in human evolution. The lungs are the first organ exposed to aerosol-transmittedMtbduring gaseous exchange. Therefore, the guards of the immune system in the lungs, such as macrophages (Mϕs) and dendritic cells (DCs), are the most important defense againstMtbinfection. There have been several studies discussing the functions of Mϕs and DCs duringMtbinfection, but the genome-wide pathways and networks are still incomplete. Furthermore, the immune response induced by Mϕs and DCs varies. Therefore, we analyzed the cross-talk genome-wide genetic-and-epigenetic interspecies networks (GWGEINs) between Mϕs vs.Mtband DCs vs.Mtbto determine the varying mechanisms of both the host and pathogen as it relates to Mϕs and DCs during earlyMtbinfection. First, we performed database mining to construct candidate cross-talk GWGEIN between human cells andMtb. Then we constructed dynamic models to characterize the molecular mechanisms, including intraspecies gene/microRNA (miRNA) regulation networks (GRNs), intraspecies protein-protein interaction networks (PPINs), and the interspecies PPIN of the cross-talk GWGEIN. We applied a system identification method and a system order detection scheme to dynamic models to identify the real cross-talk GWGEINs using the microarray data of Mϕs, DCs andMtb. After identifying the real cross-talk GWGEINs, the principal network projection (PNP) method was employed to construct host-pathogen core networks (HPCNs) between Mϕs vs.Mtband DCs vs.Mtbduring infection process. Thus, we investigated the underlying cross-talk mechanisms between the host and the pathogen to determine how the pathogen counteracts host defense mechanisms in Mϕs and DCs duringMtbH37Rv early infection. Based on our findings, we propose Rv1675c as a potential drug target because of its important defensive role in Mϕs. Furthermore, the membrane essential proteins v1098c, and Rv1696 (or cytoplasm for Rv0667), inMtbcould also be potential drug targets because of their important roles inMtbsurvival in both cell types. We also propose the drugs Lopinavir, TMC207, ATSM, and GTSM as potential therapeutic treatments forMtbinfection since they target the above potential drug targets.
Laboratory of Control and Systems Biology, National Tsing Hua University Hsinchu, Taiwan.
Cheng-Wei
CW
Li
Laboratory of Control and Systems Biology, National Tsing Hua University Hsinchu, Taiwan.
Yun-Lin
YL
Lee
Laboratory of Control and Systems Biology, National Tsing Hua University Hsinchu, Taiwan.
Bor-Sen
BS
Chen
D019295:Computational Biology; D003713:Dendritic Cells / Q000276:immunology*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D057131:Immune Evasion; D008264:Macrophages / Q000276:immunology*; D046228:Microarray Analysis; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D014376:Tuberculosis / Q000276:immunology*
Mycobacterium tuberculosis infection; cross-talk mechanism; dendritic cells; genetic and epigenetic interspecies network; macrophages; multi-molecule drug; potential drug targets; principal network projection (PNP)