Interspecies Variations in Bordetella Catecholamine Receptor Gene Regulation and Function

Abstract

Bordetella bronchiseptica can use catecholamines to obtain iron from transferrin and lactoferrin via uptake pathways involving the BfrA, BfrD, and BfrE outer membrane receptor proteins, and although Bordetella pertussis has the bfrD and bfrE genes, the role of these genes in iron uptake has not been demonstrated. In this study, the bfrD and bfrE genes of B. pertussis were shown to be functional in B. bronchiseptica, but neither B. bronchiseptica bfrD nor bfrE imparted catecholamine utilization to B. pertussis. Gene fusion analyses found that expression of B. bronchiseptica bfrA was increased during iron starvation, as is common for iron receptor genes, but that expression of the bfrD and bfrE genes of both species was decreased during iron limitation. As shown previously for B. pertussis, bfrD expression in B. bronchiseptica was also dependent on the BvgAS virulence regulatory system; however, in contrast to the case in B. pertussis, the known modulators nicotinic acid and sulfate, which silence Bvg-activated genes, did not silence expression of bfrD in B. bronchiseptica. Further studies using a B. bronchiseptica bvgAS mutant expressing the B. pertussis bvgAS genes revealed that the interspecies differences in bfrD modulation are partly due to BvgAS differences. Mouse respiratory infection experiments determined that catecholamine utilization contributes to the in vivo fitness of B. bronchiseptica and B. pertussis. Additional evidence of the in vivo importance of the B. pertussis receptors was obtained from serologic studies demonstrating pertussis patient serum reactivity with the B. pertussis BfrD and BfrE proteins.

Enhancement of immune response against Bordetella spp. by disrupting immunomodulation

“…This analysis revealed a network with connections to many other factors, some of which are known to be involved in complex interactions with the host. In addition to T3SS, this analysis indicated that btrS is connected with other genes encoding known virulence regulators such as hfq 39,40 and sigE (RpoE) 41,42 , as well as iron and heme sensors 30,43,44 , transporters, and other membrane proteins. Roles for some of these factors in immunomodulation and/or pathogenesis of several organisms has been reported 45–59 .…”

Disrupting Bordetella Immunosuppression Reveals a Role for Eosinophils in Coordinating the Adaptive Immune Response in the Respiratory Tract

“…It is well-established that Bordetella spp. sense details of the local host environment [ 65 , 92 , 93 , 94 , 95 ] and carefully and coordinately regulate multiple mechanisms to modulate host immune responses, suppressing the generation of robust immunity [ 55 , 92 , 96 ]. The type 3 and type 6 secretion systems [ 97 , 98 ], adenylate cyclase toxin [ 99 , 100 , 101 ], pertussis toxin [ 102 , 103 ], and other immunomodulators can affect immune cells in vitro and in vivo, and disrupting their carefully choreographed expression can lead to much more robust adaptive immunity [ 55 ].…”

Integrated Signaling Pathways Mediate Bordetella Immunomodulation, Persistence, and Transmission

“…Armstrong et al hypothesized that Bordetella spp. may be exposed to nutritionally relevant catecholamine concentrations in the local microenvironment during infection, either on the mucosal surface via serum exudation or through interaction with immune cells [34]. Noradrenaline has been shown to have a strong iron shuttling activity, allowing Bordetella spp.…”

“…In the absence of siderophores, catecholamines would remove the iron from transferrin and lactoferrin to directly bind it to B. bronchiseptica [13]. The mechanisms by which these neuroendocrine catecholamines; including epinephrine, norepinephrine, and dopamine, function is by increasing transcription of bfeA (outer membrane protein) of B. bronchiseptica, which is involved in transporting ferric catechol [13,34].…”