Polyamine transporter in Streptococcus pneumoniae is essential for evading early innate immune responses in pneumococcal pneumonia.

Aswathy N Rai,John Stokes,Bindu Nanduri,Edwin Swiatlo,Justin A Thornton,Imran Sunesara

doi:10.1038/srep26964

Abstract

Streptococcus pneumoniae is the most common bacterial etiology of pneumococcal pneumonia in adults worldwide. Genomic plasticity, antibiotic resistance and extreme capsular antigenic variation complicates the design of effective therapeutic strategies. Polyamines are ubiquitous small cationic molecules necessary for full expression of pneumococcal virulence. Polyamine transport system is an attractive therapeutic target as it is highly conserved across pneumococcal serotypes. In this study, we compared an isogenic deletion strain of S. pneumoniae TIGR4 in polyamine transport operon (ΔpotABCD) with the wild type in a mouse model of pneumococcal pneumonia. Our results show that the wild type persists in mouse lung 24 h post infection while the mutant strain is cleared by host defense mechanisms. We show that intact potABCD is required for survival in the host by providing resistance to neutrophil killing. Comparative proteomics analysis of murine lungs infected with wild type and ΔpotABCD pneumococci identified expression of proteins that could confer protection to wild type strain and help establish infection. We identified ERM complex, PGLYRP1, PTPRC/CD45 and POSTN as new players in the pathogenesis of pneumococcal pneumonia. Additionally, we found that deficiency of polyamine transport leads to up regulation of the polyamine synthesis genes speE and cad in vitro.

Highlights

Streptococcus pneumoniae is the most common bacterial cause of community-acquired pneumonia (CAP), and otitis media worldwide[1,2,3]
These results demonstrate that the deletion of the polyamine transporter in a capsular type 4 strain renders it more invasive yet susceptible to bacterial clearance mechanisms than the parent strain at early stages of infection
We used a polyamine transporter-deficient mutant to identify host innate immune effectors that normally serve to protect against pneumococcal pneumonia

Summary

Introduction

Streptococcus pneumoniae (pneumococcus) is the most common bacterial cause of community-acquired pneumonia (CAP), and otitis media worldwide[1,2,3]. Protein based vaccine targets that are effective against all serotypes are attractive alternates to PCVs10. Our earlier findings showed that isogenic deletion of potABCD in TIGR4 (ΔpotABCD), a type 4 strain, led to attenuation in a mouse model of pneumococcal pneumonia 48 h following infection compared to the wild type (WT) strain, and active immunization with recombinant PotD affords protection against systemic infection[18,24,25]. We compared the early host immune responses to WT and polyamine transport deficient strain, in an intranasal challenge model of pneumococcal pneumonia in mice. A thorough understanding of dedicated polyamine transport in the pneumococcus is an attractive avenue for developing small molecule based intervention strategies that do not depend on host immune status

Methods

Results

Conclusion