Moreover, since brain endothelia associate principally with laminin 1 and 2, not present in epithelia and endothelia elsewhere [13, 34, 35], we postulate that the observed CNS tropism of pknD may be due to its interaction with CNS-associated laminin isoforms. Bacterial STPKs are candidates for sensing the environment and regulation of microbial metabolic states [36, 37]. The M. tuberculosis
PknD intracellular kinase has been previously demonstrated to associate with and phosphorylate intracellular targets including MmpL7 [38] and the putative anti-anti-sigma factor Rv0516c, regulating sigF-associated genes [39]. M. tuberculosis sigF is an alternative sigma factor implicated in stress response, stationary phase, dormancy, and late-stage disease in vivo [40, 41]. Our previously published data demonstrate {Selleck Anti-infection Compound Library|Selleck Antiinfection Compound Library|Selleck Anti-infection Compound Library|Selleck Antiinfection Compound Library|Selleckchem Anti-infection Compound Library|Selleckchem Antiinfection Compound Library|Selleckchem Anti-infection Compound Library|Selleckchem Antiinfection Compound Library|Anti-infection Compound Library|Antiinfection Compound Library|Anti-infection Compound Library|Antiinfection Compound Library|Anti-infection Compound Library|Antiinfection Compound Library|Anti-infection Compound Library|Antiinfection Compound Library|Anti-infection Compound Library|Antiinfection Compound Library|Anti-infection Compound Library|Antiinfection Compound Library|Anti-infection Compound Library|Antiinfection Compound Library|Anti-infection Compound Library|Antiinfection Compound Library|Anti-infection Compound Library|Antiinfection Compound Library|buy Anti-infection Compound Library|Anti-infection Compound Library ic50|Anti-infection Compound Library price|Anti-infection Compound Library cost|Anti-infection Compound Library solubility dmso|Anti-infection Compound Library purchase|Anti-infection Compound Library manufacturer|Anti-infection Compound Library research buy|Anti-infection Compound Library order|Anti-infection Compound Library mouse|Anti-infection Compound Library chemical structure|Anti-infection Compound Library mw|Anti-infection Compound Library molecular weight|Anti-infection Compound Library datasheet|Anti-infection Compound Library supplier|Anti-infection Compound Library in vitro|Anti-infection Compound Library cell line|Anti-infection Compound Library concentration|Anti-infection Compound Library nmr|Anti-infection Compound Library in vivo|Anti-infection Compound Library clinical trial|Anti-infection Compound Library cell assay|Anti-infection Compound Library screening|Anti-infection Compound Library high throughput|buy Antiinfection Compound Library|Antiinfection Compound Library ic50|Antiinfection Compound Library price|Antiinfection Compound Library cost|Antiinfection Compound Library solubility dmso|Antiinfection Compound Library purchase|Antiinfection Compound Library manufacturer|Antiinfection Compound Library research buy|Antiinfection Compound Library order|Antiinfection Compound Library chemical structure|Antiinfection Compound Library datasheet|Antiinfection Compound Library supplier|Antiinfection Compound Library in vitro|Antiinfection Compound Library cell line|Antiinfection Compound Library concentration|Antiinfection Compound Library clinical trial|Antiinfection Compound Library cell assay|Antiinfection Compound Library screening|Antiinfection Compound Library high throughput|Anti-infection Compound high throughput screening| that M. tuberculosis significantly down-regulate transcription, protein synthesis, and energy metabolism check details very early after invasion by brain endothelia [42]. These data raise the possibility that interaction with the host CNS may mediate bacterial signaling. The two domain structure of PknD invites the hypothesis that an extracellular signal, possibly a host factor,
may induce an intracellular cascade via activity of the kinase and regulation of sigF. An ortholog of M. tuberculosis pknB in Bacillus subtilis has been demonstrated to regulate bacterial dormancy by a similar mechanism [43, 44]. The potential induction of sigF-mediated cellular activity via pknD could confer upon M. tuberculosis a survival advantage in unique conditions such as the brain endothelium. M. tuberculosis are well known to adapt to a quiescent dormant state. However, the precise location of dormant bacilli during human latent
TB Oxymatrine infection remains elusive. Immune surveillance of Nutlin-3a research buy foreign antigens is relatively limited in the CNS [20, 45], and mycobacteria escape immune recognition following direct inoculation into the brain parenchyma [46]. We therefore postulate that the unique microenvironment in the CNS is advantageous for bacterial survival, and may provide a sanctuary to dormant M. tuberculosis. While this study examines and indicates a role for M. tuberculosis pknD in the initial stages of invasion and infection, the role of dormancy in CNS disease will be an active area of research for our future studies. Given the above data, we hypothesize that interaction of PknD protein with a host extracellular factor, possibly laminin, facilitates adhesion of M. tuberculosis to the microvascular endothelium of the CNS. Other neurotropic pathogens have been shown to trigger host-mediated uptake and internalization of bacteria through cytoskeletal rearrangement, thus this represents a possible mechanism for future study [47, 48].