The iron/heme regulated genes of Haemophilus influenzae: Comparative transcriptional profiling as a tool to define the species core modulon

Abstract

Background: Haemophilus influenzae requires heme for aerobic growth and possesses multiple mechanisms to obtain this essential nutrient. Although an understanding of the heme acquisition mechanisms of H. influenzae is emerging, significant gaps in our knowledge remain. Unresolved issues include the identities of all genes exhibiting altered transcription in response to iron and heme availability, the fraction of such genes functioning in iron/heme acquisition, and the heterogeneity of this gene set among clinical isolates. Previously we utilized H. influenzae strain Rd KW20 to demonstrate the utility of transcriptional profiling in defining the genes exhibiting altered transcription in response to environmental iron and heme levels. The current study expands upon those observations by determining the iron/heme modulons of two clinical isolates, the type b isolate 10810 and the nontypeable isolate R2866. These data are used to begin to define the core iron/heme modulon of the species.

Ferric Uptake Regulator and Its Role in the Pathogenesis of Nontypeable Haemophilus influenzae

“…These observations indicated that changes in gene transcription were due to the loss of Fur and that the identified genes are indeed Fur regulated. Finally, we compared our microarray data to previously published data that monitored transcriptional responses of three Haemophilus strains following transition from heme-depleted to heme-replete medium ( Table 2, the NTHi, type b, and Rd columns) (53). There was a strong correlation between changes in gene expression due to the loss of Fur in strain 86-028NP with quantitation of changes in gene expression due to an increase in available iron and heme, an in vitro analog for increased repression of gene expression by Fur (53).…”

Fur-Mediated Global Regulatory Circuits in Pathogenic Neisseria Species

“…Recently, global analyses of iron-and/or Fur-responsive transcriptomes of diverse bacterial pathogens, such as H. pylori, Pseudomonas syringae, Vibrio cholerae, Yersinia pestis, Haemophilus influenzae, S. enterica serovar Typhimurium, and Listeria monocytogenes, have revealed a number of novel regulatory roles for Fur (12,20,40,56,68,94,101,102,107). First, Fur has been demonstrated to repress transcription even in the absence of iron, a process termed apo-Fur regulation (13) (Fig.…”

“…2C). Transcriptome analysis has also identified additional genes that are activated by iron-bound Fur (12,56,68,101,102,107).…”

Otitis media associated polymorphisms in the hemin receptor HemR of nontypeable Haemophilus influenzae

“…Nontypeable H. influenzae are no exception, and have a variable number of systems to scavenge iron and heme from many different host sources, including transferrin, hemoglobin, heme, heme:hemopexin, heme:albumin, hemoglobin:haptoglobin complexes, and siderophores produced by other microorganisms (Morton et al, 2010; Whitby et al, 2009). A number of these systems have been implicated in Hi virulence.…”

“…Similarly, hemR was more common among invasive Hib isolates (97.4%) than among commensal NTHi isolates (86.9%), with a prevalence ratio of 1.15 (p=0.0169). Whitby et al used microarray and qPCR analyses to demonstrate that expression of hemR was increased under iron/heme limiting conditions in OM NTHi strain R2866, capsule deficient type d strain Rd, and invasive Hib strain 10810 (Whitby et al, 2009). …”