Thermoregulation of Meningococcal fHbp, an Important Virulence Factor and Vaccine Antigen, Is Mediated by Anti-ribosomal Binding Site Sequences in the Open Reading Frame.

Edmund Loh,Hayley Lavender,Felicia Tan,Christoph M Tang,Alexander Tracy,Xavier Nassif

doi:10.1371/journal.ppat.1005794

Edmund Loh, Hayley Lavender + Show 4 more

Open Access

https://doi.org/10.1371/journal.ppat.1005794

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Journal: PLoS Pathogens	Publication Date: Aug 25, 2016
Citations: 34	License type: CC BY 4.0

Affiliation: University of Oxford

Abstract

During colonisation of the upper respiratory tract, bacteria are exposed to gradients of temperatures. Neisseria meningitidis is often present in the nasopharynx of healthy individuals, yet can occasionally cause severe disseminated disease. The meningococcus can evade the human complement system using a range of strategies that include recruitment of the negative complement regulator, factor H (CFH) via factor H binding protein (fHbp). We have shown previously that fHbp levels are influenced by the ambient temperature, with more fHbp produced at higher temperatures (i.e. at 37°C compared with 30°C). Here we further characterise the mechanisms underlying thermoregulation of fHbp, which occurs gradually over a physiologically relevant range of temperatures. We show that fHbp thermoregulation is not dependent on the promoters governing transcription of the bi- or mono-cistronic fHbp mRNA, or on meningococcal specific transcription factors. Instead, fHbp thermoregulation requires sequences located in the translated region of the mono-cistronic fHbp mRNA. Site-directed mutagenesis demonstrated that two anti-ribosomal binding sequences within the coding region of the fHbp transcript are involved in fHbp thermoregulation. Our results shed further light on mechanisms underlying the control of the production of this important virulence factor and vaccine antigen.

Highlights

Neisseria meningitidis is a harmless member of the human nasopharyngeal flora in a significant proportion of healthy individuals [1]
The bacterium Neisseria meningitidis is exquisitely adapted to survive in the human host, and possesses several mechanisms to interact with host cells in the upper airway and to circumvent immune responses
We show that thermoregulation of factor H binding protein (fHbp) occurs gradually over a physiological range of temperatures found in the upper airway, the site of colonisation

Summary

Introduction

Neisseria meningitidis is a harmless member of the human nasopharyngeal flora in a significant proportion of healthy individuals [1]. To survive in the human host, the meningococcus has evolved several mechanisms that enable it to evade the immune system [4]. The bacterium evades complement mediated killing by expressing a polysaccharide capsule, sialylation of its lipopolysaccharide, and by binding complement factor H (CFH), the major negative regulator of the alternative complement pathway [7]. CFH is recruited by high affinity interactions with factor H binding protein (fHbp) [8]. CFH competes with complement factor H related protein-3 (CFHR3) for binding to fHbp on the meningococcus [9]; CFHR3 is a competitive inhibitor of CFH binding to the meningococcal surface, and relative levels of CFH and CFHR3 in individuals are likely to determine host genetic susceptibility to meningococcal disease in the general population [9]. FHbp is a surface lipoprotein which is an important component of two vaccines which are licensed for preventing meningococcal disease [10,11]

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