Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs

Abstract

Severe pneumonia is the main single cause of death worldwide in children under five years of age. The main etiological agent of pneumonia is the G+ bacterium Streptococcus pneumoniae, which accounts for up to 45% of all cases. Intriguingly, patients can still die days after commencing antibiotic treatment due to the development of permeability edema, although the pathogen was successfully cleared from their lungs. This condition is characterized by a dramatically impaired alveolar epithelial-capillary barrier function and a dysfunction of the sodium transporters required for edema reabsorption, including the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed sodium potassium pump (Na+-K+-ATPase). The main agent inducing this edema formation is the virulence factor pneumolysin, a cholesterol-binding pore-forming toxin, released in the alveolar compartment of the lungs when pneumococci are being lysed by antibiotic treatment or upon autolysis. Sub-lytic concentrations of pneumolysin can cause endothelial barrier dysfunction and can impair ENaC-mediated sodium uptake in type II alveolar epithelial cells. These events significantly contribute to the formation of permeability edema, for which currently no standard therapy is available. This review focuses on discussing some recent developments in the search for the novel therapeutic agents able to improve lung function despite the presence of pore-forming toxins. Such treatments could reduce the potentially lethal complications occurring after antibiotic treatment of patients with severe pneumonia.

Randomized Controlled Study of the Safety and Immunogenicity of Pneumococcal Vaccine Formulations Containing PhtD and Detoxified Pneumolysin with Alum or Adjuvant System AS02 V in Elderly Adults

“…The observation of enhanced IgG responses with AS02 V compared to with the alum adjuvant was consistent with studies of other vaccines using MPL-and QS-21-containing adjuvant systems (39), including the previous study on TABLE 2 Percentage of subjects reporting unsolicited adverse events during the 31-day postvaccination period (total vaccinated cohort) AE group % (95% confidence interval) of subjects reporting unsolicited AEs for the indicated vaccination group (n) PhtD-dPly10/AS02 V (23) PhtD-dPly10/alum (24) PhtD-dPly30/AS02 V (24) PhtD-dPly30/alum (24) 8PCV/AS02 V (24) 8PCV/alum (23) 23PPV ( PhtD vaccination in elderly adults (27). Anti-PhtD and anti-Ply antibody responses were also observed in the groups administered 8PCV, which contained 22 g PhtD and 15 g dPly as protein conjugates for two serotypes.…”

“…Participant characteristic Data for the indicated group (n) PhtD-dPly10/AS02 V (23) PhtD-dPly10/alum (24) PhtD-dPly30/AS02 V (24) PhtD-dPly30/alum (24) 8PCV/AS02 V (24) 8PCV/alum (23) 23PPV (25) Age (mean Ϯ SD) (yr) (i) Immunogenicity of pneumococcal proteins dPly and PhtD. Before vaccination, all subjects in all groups were seropositive for antibodies against Ply (antibody concentration, Ն599 LU/ml) and PhtD (Ն391 LU/ml).…”

“…PhtD is a pneumococcal cell surface protein that appears to have multiple functions, including involvement in metal ion homeostasis, evasion of complement deposition, and adherence of bacteria to host cells (20,21). Ply is a cholesterol-dependent cytolysin produced by S. pneumoniae and a key virulence factor exerting cytolytic effects that contribute to lung injury, permeability edema, and neuronal damage (22,23). Due to the cytolytic effects of native Ply, detoxified Ply (dPly) has been developed as a vaccine candidate (P. Hermand et al, unpublished data).…”

Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function

“…7 GHRH and GHRH-R modulate cell proliferation and apoptosis in many tissues. [8][9][10][11][12][13][14][15][16] Antagonistic analogs of GHRH, synthesized in our laboratory, have been shown to inhibit the growth of various human cancers, 5 in part, by suppressing circulating GH/ IGF-1 levels. 17 Direct mechanisms involved in the dominant antitumor effects of GHRH antagonists appear to be based on blockage of the autocrine action of GHRH on tumors and on inhibition of the local production of IGF-I/II.…”

Liposomes as novel anti-infectives targeting bacterial virulence factors?

“…This is all the more relevant since a toxin like S. pneumoniae' s pneumolysin is released massively following lysis caused by antibiotics, and complications and even death may result days after the onset of antibiotic therapy from the spread of toxins, when tissues are already pathogen-free [9,10]. This agrees with the observation that improved therapeutic efficacy of a b-lactam/macrolide combination in severe pneumococcal disease is associated with a marked reduction in the synthesis and release of pneumolysin [11].…”