Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner

Nutrient iron sequestration is the most significant form of nutritional immunity and causes bacterial pathogens to evolve strategies of host iron scavenging. Cigarette smoking contains iron particulates altering lung and systemic iron homeostasis, which may enhance colonization in the lungs of patients suffering chronic obstructive pulmonary disease (COPD) by opportunistic pathogens such as nontypeable. NTHi is a heme auxotroph, and the NTHi genome contains multiple heme acquisition systems whose role in pulmonary infection requires a global understanding. In this study, we determined the relative contribution to NTHi airway infection of the four heme-acquisition systems HxuCBA, PE, SapABCDFZ, and HbpA-DppBCDF that are located at the bacterial outer membrane or the periplasm. Our computational studies provided plausible 3D models for HbpA, SapA, PE, and HxuA interactions with heme. Generation and characterization of single mutants in the hxuCBA, hpe, sapA, and hbpA genes provided evidence for participation in heme binding-storage and inter-bacterial donation. The hxuA, sapA, hbpA, and hpe genes showed differential expression and responded to heme. Moreover, HxuCBA, PE, SapABCDFZ, and HbpA-DppBCDF presented moonlighting properties related to resistance to antimicrobial peptides or glutathione import, together likely contributing to the NTHi-host airway interplay, as observed upon cultured airway epithelia and in vivo lung infection. The observed multi-functionality was shown to be system-specific, thus limiting redundancy. Together, we provide evidence for heme uptake systems as bacterial factors that act in a coordinated and multi-functional manner to subvert nutritional- and other sources of host innate immunity during NTHi airway infection.

Bibliographic Details

Main Authors:	Rodríguez-Arce, Irene, Al-Jubair, Tamim, Euba, Begoña, Fernández-Calvet, Ariadna, Gil-Campillo, Celia, Martí, Sara, Törnroth-Horsefield, Susanna, Riesbeck, Kristian, Garmendia, Juncal
Other Authors:	Universidad Pública de Navarra
Format:	artículo biblioteca
Language:	English
Published:	Taylor & Francis 2019
Subjects:	Haemophilus influenzae, Heme binding, Iron nutritional immunity, Protein moonlighting, Respiratory infection,
Online Access:	http://hdl.handle.net/10261/191874 http://dx.doi.org/10.13039/501100007680 http://dx.doi.org/10.13039/501100005934 http://dx.doi.org/10.13039/501100009738 http://dx.doi.org/10.13039/501100000780 http://dx.doi.org/10.13039/501100003329 http://dx.doi.org/10.13039/501100004587
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