There are a number of striking

Pevonedistat mw differences as well. GlcNAc-6P is the inducer of the NagC regulon. Just as inactivation of nagB causes induction of SiaR-regulated genes, the inactivation of nagA, and the subsequent accumulation of GlcNAc-6P, induces NagC-related genes [22]. NagC is displaced from its binding site in the presence of GlcNAc-6P [22] while SiaR appears to always be bound to its operator. In E. coli, the alteration of phasing between NagC operator sequences results in derepression of both divergently transcribed operons. This is due to the inability of NagC to form a repression loop that is required for NagC-mediated repression [24]. This differs significantly with what we observed in SiaR regulation. In our studies, the alteration of phasing did not result in derepression, but instead uncoupled SiaR- and CRP-mediated regulation of the nanE and siaP genes. The differences

between SiaR and NagC PD0332991 clinical trial suggest that, while some functional similarity exists between the two regulators, selleckchem they both employ different mechanisms. Given the nature of regulation by SiaR and CRP, the nan and siaPT operons will never be maximally expressed when H. influenzae is in its natural environment. This is due to a number of factors, including the low abundance of sialic acid in the host and the rapid utilization of intracellular sialic acid. Instead, regulation acts to subtly modulate expression of the operons, keeping expression under constant control so that catabolism does not outpace utilization and the expression of the transporter is appropriate for the availability of the ligand. These requirements are also in balance with the need to prevent the accumulation of inhibitory

amounts of sialic acid, however, this need is likely minimal Isotretinoin considering the factors of sialic acid availablity and utilization discussed above. The role of CRP in the regulation of sialic acid transport and catabolism suggests that sialic acid is utilized as an emergency carbon source in the host. H. influenzae can use sialic acid as a sole carbon source as efficiently as glucose [10]. Sialic acid catabolism is not required for virulence as a nanA mutant exhibits increased fitness in multiple infection models [13]. However, the fact that catabolism is present and conserved among H. influenzae strains suggests that it provides some advantage to the organism. The previous study examining virulence of a nanA mutant was performed using an encapsulated, invasive type B strain rather than a non-typeable strain and did not test all possible environments within the host [13]. Additionally, intranasal mixed-challenge experiments did not reveal an advantage for either the wild-type or nanA mutant strain [13]. Therefore, it is possible that sialic acid catabolism is advantageous in certain conditions or has increased importance for non-typeable strains.