Pneumolysin as a target for new therapies against pneumococcal infections: A systematic review

Abstract

Background This systematic review evaluates pneumolysin (PLY) as a target for new treatments against pneumococcal infections. Pneumolysin is one of the main virulence factors produced by all types of pneumococci. This toxin (53 kDa) is a highly conserved protein that binds to cholesterol in eukaryotic cells, forming pores that lead to cell destruction. Methods The databases consulted were MEDLINE, Web of Science, and Scopus. Articles were independently screened by title, abstract, and full text by two researchers, and using consensus to resolve any disagreements that occurred. Articles in other languages different from English, patents, cases report, notes, chapter books and reviews were excluded. Searches were restricted to the years 2000 to 2021. Methodological quality was evaluated using OHAT framework. Results Forty-one articles describing the effects of different molecules that inhibit PLY were reviewed. Briefly, the inhibitory molecules found were classified into three main groups: those exerting a direct effect by binding and/or blocking PLY, those acting indirectly by preventing its effects on host cells, and those whose mechanisms are unknown. Although many molecules are proposed as toxin blockers, only some of them, such as antibiotics, peptides, sterols, and statins, have the probability of being implemented as clinical treatment. In contrast, for other molecules, there are limited studies that demonstrate efficacy in animal models with sufficient reliability. Discussion Most of the studies reviewed has a good level of confidence. However, one of the limitations of this systematic review is the lack of homogeneity of the studies, what prevented to carry out a statistical comparison of the results or meta-analysis. Conclusion A panel of molecules blocking PLY activity are associated with the improvement of the inflammatory process triggered by the pneumococcal infection. Some molecules have already been used in humans for other purposes, so they could be safe for use in patients with pneumococcal infections. These patients might benefit from a second line treatment during the initial stages of the infection preventing acute respiratory distress syndrome and invasive pneumococcal diseases. Additional research using the presented set of compounds might further improve the clinical management of these patients.

The single D380 amino acid substitution increases pneumolysin cytotoxicity toward neuronal cells

“…The new PLY variant from the different clinical isolates, recombinantly produced, had different cytotoxic capabilities, in fact, neurons treated with the new PLY variant from the pneumococcal clinical isolates exhibited higher neuronal cell death. Taken together, these results demonstrate that, even though PLY is highly conserved, 9 different clinical isolates of S. pneumoniae express a variant of PLY which, with just one single amino acid substitution, causes more severe cell damage. Furthermore, scanning electron microscopy analysis revealed that not only more, but also bigger pores were formed on the neuronal plasma membrane when neurons were treated with the PLY from the pneumococcal clinical isolates containing the critical D4 domain mutation, therefore proving that the higher cytotoxicity of the new PLY variant is due to a higher pore-forming activity.…”

Recent progress in pneumococcal protein vaccines

“…PLY is a vital cholesterol-dependent cytolysin produced by S. pneumoniae ( Table 1 ) ( 23 ). With 471 amino acids (53 kDa) and a distinct tertiary structure consisting of four domains, PLY binds to eukaryotic cell membranes’ cholesterol and creates membrane pores, leading to cellular destruction ( 20 ). Domains 1, 2, and 3 are essential for oligomerization and pore formation, while domain 4, located in the C-terminal region, facilitates cholesterol binding ( 20 ).…”

“…With 471 amino acids (53 kDa) and a distinct tertiary structure consisting of four domains, PLY binds to eukaryotic cell membranes’ cholesterol and creates membrane pores, leading to cellular destruction ( 20 ). Domains 1, 2, and 3 are essential for oligomerization and pore formation, while domain 4, located in the C-terminal region, facilitates cholesterol binding ( 20 ). PLY serves as a critical virulence factor in various stages of pneumococcal disease, including transmission, colonization, and infection ( 23 ).…”

“…Identification of key virulence factors and surface proteins involved in host-pathogen interactions has facilitated the selection of potential vaccine candidates ( 19 ). Pneumolysin (PLY), pneumococcal surface protein A (PspA), pneumococcal surface protein C (PspC), pneumococcal histidine triad proteins (Pht), pneumococcal surface antigen A (PsaA), pneumococcal iron uptake A (PiuA) and pneumococcal iron acquisition A (PiaA) are among the most extensively studied protein candidates, each with unique immunogenic properties and mechanisms of immune protection ( Figure 1 ) ( 16 , 20 – 22 ). In this review, we aim to comprehensively explore the progress made in pneumococcal protein vaccines, focusing on key protein candidates and future directions.…”

The Global Burden of Community-Acquired Pneumonia in Adults, Encompassing Invasive Pneumococcal Disease and the Prevalence of Its Associated Cardiovascular Events, with a Focus on Pneumolysin and Macrolide Antibiotics in Pathogenesis and Therapy

“…Many strategies, which target the reactivity of Ply have been described and represent the topic of several recent reviews [ 25 , 39 , 109 ]. These include a number of small molecules of natural and synthetic origin, monoclonal antibodies, liposome-encased cholesterol, and vaccine-based strategies.…”