Hfe Permease and Haemophilus influenzae Manganese Homeostasis

Haemophilus influenzae is a commensal
of the human upper respiratory tract that can infect diverse host
niches due, at least in part, to its ability to withstand both endogenous
and host-mediated oxidative stresses. Here, we show that hfeA, a gene previously linked to iron import, is essential for H. influenzae manganese recruitment via the HfeBCD transporter. Structural analyses show that metal binding
in HfeA uses a unique mechanism that involves substantial rotation
of the C-terminal lobe of the protein. Disruption of hfeA reduced H. influenzae manganese acquisition
and was associated with decreased growth under aerobic conditions,
impaired manganese-superoxide dismutase activity, reduced survival
in macrophages, and changes in biofilm production in the presence
of superoxide. Collectively, this work shows that HfeA contributes
to H. influenzae manganese acquisition
and virulence attributes. High conservation of the hfeABCD permease in Haemophilus species suggests
that it may serve similar roles in other pathogenic Pasteurellaceae.