Abstract
Tuberculosis is caused by the infection of Mycobacterium tuberculosis (Mtb), and Mtb is one of the oldest human pathogens and evolves complex strategies for survival. Lung is the first organ exposed to aerosol-transmitted Mtb during gaseous exchange. Therefore, the guards of the immune system in lung such as macrophages (Mϕs) and dendritic cells (DCs) are the most important defense against Mtb infection. To date, although there are several studies discussing the functions of Mϕs and DCs during Mtb infection, the genome-wide pathways and networks are still incomplete. Besides, the immune responses in Mϕs and DCs are also different. Thus, we analyzed the genome-wide genetic-and-epigenetic interspecies networks (GWGEINs) of Mϕs and DCs both infected with Mtb to find out the different mechanisms of both host and pathogen between Mϕs and DCs during early Mtb infection. We first used databases mining to construct candidate GWGEINs of Mϕs and DCs. Then we used the two-sided microarray data from human Mϕs and DCs both infected with Mtb H37Rv to prune the false-positive edges in candidate GWGEINs due to big database mining. We used gene regulation models and protein-protein interaction (PPI) models of both host and pathogen to determine the association abilities of connective edges of genes and proteins by constrained least square method, and we deleted the false-positives by pruning the insignificant edges in the candidate GWGEINs out of system order (number of edges) determined by Akaike information criterion (AIC), constructing the GWGEINs in Mϕs and DCs both infected with Mtb. After constructing GWGEINs, the principal network projection (PNP) method is employed to construct the host-pathogen core networks (HPCNs) in both Mϕs and DCs. Thus, we can investigate the underlying cross-talk mechanisms between host and pathogen and find out how the pathogen counteracts the offensive mechanisms by host in Mϕs and in DCs during Mtb H37Rv early infection. Finally, we predicted Rv1675c as a potential drug target because of its important defensive role of Mtb in Mϕs. Besides, the membrane proteins Rv1438, Rv1098c, Rv0967, Rv0969, Rv0970, Rv0667, Rv1696 and Rv2404c in Mtb might be also potential drug targets because of their important roles on the survival of Mtb in both cell types and their being easily targeted by drugs. Further, a dealing of multiple molecules drug including Lopinavir, TMC207, ATSM and GTSM is also suggested for potential therapeutic treatment of Mtb infection by targeting above potential drug targets.