Abstract
Neuraminidase A (NanA) is an important virulence factor that is anchored to the pneumococcal cell wall and cleaves sialic acid on host substrates. We noted that a secreted allele of NanA was over-represented in invasive pneumococcal isolates and promoted the development of meningitis when swapped into the genome of non-meningitis isolates replacing cell wall-anchored NanA. Both forms of recombinant NanA directly activated transforming growth factor (TGF)-β, increased SMAD signalling and promoted loss of endothelial tight junction ZO-1. However, in assays using whole bacteria, only the cell-bound NanA decreased expression of ZO-1 and showed NanA dependence of bacterial invasion of endothelial cells. We conclude that NanA secretion versus retention on the cell surface does not influence neurotropism of clinical isolates. However, we describe a new NanA-TGF-β signalling axis that leads to decreased blood-brain barrier integrity and enhances bacterial invasion.
Highlights
Streptococcus pneumoniae is one of the leading causes of bacterial meningitis in young children and adults with a fatality rate up to 37 % and development of long-term sequelae in half of the survivors [1]
We focused on the ability of neuraminidases, such as those from influenza virus and Clostridium perfringens, to activate latent transforming growth factor-b (LTGF-b) [16]
We focused on the role of the differential activity of the previously unstudied, truncated form of NanA that is secreted from the neurotropic TIGR4 strain in comparison to the cell wall-anchored form found in the non-neurotropic D39 strain as a possible explanation of strain-dependent neurotropism
Summary
Streptococcus pneumoniae is one of the leading causes of bacterial meningitis in young children and adults with a fatality rate up to 37 % and development of long-term sequelae in half of the survivors [1]. Neuraminidase activity has been implicated in many interactions of pneumococci with host epithelial and endothelial cells including the BBB. We focused on the role of the differential activity of the previously unstudied, truncated form of NanA that is secreted from the neurotropic TIGR4 strain in comparison to the cell wall-anchored form found in the non-neurotropic D39 strain as a possible explanation of strain-dependent neurotropism.
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