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BIRMINGHAM, Alabama – A fight with the flu virus can be tough, but when Streptococcus pneumonia gets into the mix it can turn deadly.
Now, researchers have found another reason for the severity of this dual infection by identifying a new virulence mechanism for a surface protein on the bacteria responsible for pneumonia. S. pneumoniae. This idea comes more than three decades after the discovery of this surface protein, called pneumococcal surface protein A, or PspA.
This new mechanism had been missed in the past because it facilitates bacterial adhesion only to dead or dying lung epithelial cells, and not to living cells. Until now, researchers have generally used monolayers of healthy lung cells to search for bacterial adhesins that promote infection. Viral destruction of lung cells during influenza has been shown to pave the way for S. pneumonia attachment to the airways, thereby aggravating disease and pneumonia.
The research, published in the journal Cell reports, was led by Carlos Orihuela, Ph.D., and David Briles, Ph.D., Professor and Professor Emeritus at the University of Alabama in the Department of Microbiology, Birmingham. Orihuela and Briles say their findings provide further explanation for how an influenza A virus infection – followed by S. pneumoniae superinfection – causes severe pneumonia and a high death rate. The mechanism also indicates possible improvements for disease treatment and vaccination.
A historical example of the deadly synergy of influenza infection followed by S. pneumoniae superinfection is found in samples of lungs banked from the 1918 Spanish influenza pandemic that killed 40 to 50 million people – the vast majority of these samples showed co-infection or secondary infection with S. pneumonia.
UAB’s research into PspA began with head scratching results of experimental lung infections in influenza A infected mice, followed by S. pneumonia which has the PspA gene intact, or a mutant S. pneumoniae which lacks PspA. Pulmonary homogenates from wild-type infected mice exhibited a much higher number of S. pneumonia bacteria than the lungs infected with the mutant. However, when the researchers washed the inside of the lungs and collected this bronchoalveolar lavage fluid, they counted a similar number of wild-type specimens. S. pneumonia and the mutant.
“This unexpected result was interpreted to mean that the wild type S. pneumoniae were more resistant to dislodgement than S. pneumonia with a deletion of the pspA gene, and this served as a rationale for further experiments, ”said Orihuela.
From this clue, the researchers were able to show that PspA functions as an adhesin for dying host cells, in addition to its several other previously established virulence mechanisms. The researchers also detailed the molecular mechanism of this bacterial adhesion.
Influenza A infection and the release of S. pneumoniae pneumolysin toxin causes death of lung epithelial cells. As they die, the phosphatidylserine residues of cells return to the outer cell membrane, where they bind to the host enzyme glyceraldehyde-3-phosphate dehydrogenase, or GAPDH. In turn, the S. pneumoniae The PspA on the surface of the bacteria binds to GAPDH. Increased PspA-GAPDH-mediated binding to lung cells S. pneumoniae localization in the lower respiratory tract, and this was reinforced by exposure to pneumolysin or co-infection with influenza A virus.
Tests with fragments of the PspA protein showed that a 52 amino acid portion of the protein – from amino acids 230 to 281 – was required for binding to GAPDH. Instillation of one of these binding fragments into the lungs of influenza-infected mice reduced the severity of the disease. S. pneumoniae superinfection, presumably by binding competition.
“Our results support the targeting of PspA regions for therapeutic and vaccine development against influenza A /Streptococcus pneumoniae superinfections, ”said Orihuela. “Importantly, and despite more than 30 years since its discovery, PspA has not previously been shown to function as an adhesin. Thus, our discovery of the role of PspA in adhesion considerably advances our knowledge of the interactions of S. pneumoniae with his host. “
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