Abstract
Invading bacteria from the Neisseriaceae, Acinetobacteriaceae, Bordetellaceae and Moraxellaceae families express the conserved outer-membrane zinc transporter zinc-uptake component D (ZnuD) to overcome nutritional restriction imposed by the host organism during infection. Here we demonstrate that ZnuD is required for efficient systemic infections by the causative agent of bacterial meningitis, Neisseria meningitidis, in a mouse model. We also combine X-ray crystallography and molecular dynamics simulations to gain insight into the mechanism of zinc recognition and transport across the bacterial outer-membrane by ZnuD. Because ZnuD is also considered a promising vaccine candidate against N. meningitidis, we use several ZnuD structural intermediates to map potential antigenic epitopes, and propose a mechanism by which ZnuD can maintain high sequence conservation yet avoid immune recognition by altering the conformation of surface-exposed loops.
Highlights
Invading bacteria from the Neisseriaceae, Acinetobacteriaceae, Bordetellaceae and Moraxellaceae families express the conserved outer-membrane zinc transporter zinc-uptake component D (ZnuD) to overcome nutritional restriction imposed by the host organism during infection
This suggests that znuD is not required for bacterial survival at the mucosal surface which is consistent with the assumption that zinc is not limiting in the upper respiratory tract tissues[20]
To better understand the role of ZnuD during neisserial pathogenesis, we compared the ability of WT or znuDdeleted strains from N. meningitidis serogroup B strain B16B6 to establish a systemic infection in mice (Fig. 1b)
Summary
Invading bacteria from the Neisseriaceae, Acinetobacteriaceae, Bordetellaceae and Moraxellaceae families express the conserved outer-membrane zinc transporter zinc-uptake component D (ZnuD) to overcome nutritional restriction imposed by the host organism during infection. Because ZnuD is considered a promising vaccine candidate against N. meningitidis, we use several ZnuD structural intermediates to map potential antigenic epitopes, and propose a mechanism by which ZnuD can maintain high sequence conservation yet avoid immune recognition by altering the conformation of surface-exposed loops Transition metals, such as iron, zinc and manganese, play essential roles in many biological processes, where they function as enzyme co-factors, regulatory elements or structural factors. To investigate the role of the vaccine candidate ZnuD during neisserial infection, we initially characterized both the wild-type (WT) and the znuD deletion mutant strains of N. meningitidis in a mouse infection model This model provided the first evidence that ZnuD is required to establish systemic infection, promoting blood colonization despite the zinc shortage imposed by the host’s nutritional immunity. Our determination of multiple ZnuD structural intermediates provides a critical advance to guide the rational design of ZnuD derivatives that could be used as vaccine antigens to protect against N. meningitidis infections
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