The Yin and Yang of Pneumolysin During Pneumococcal Infection

Abstract

Pneumolysin (PLY) is a pore-forming toxin produced by the human pathobiont Streptococcus pneumoniae, the major cause of pneumonia worldwide. PLY, a key pneumococcal virulence factor, can form transmembrane pores in host cells, disrupting plasma membrane integrity and deregulating cellular homeostasis. At lytic concentrations, PLY causes cell death. At sub-lytic concentrations, PLY triggers host cell survival pathways that cooperate to reseal the damaged plasma membrane and restore cell homeostasis. While PLY is generally considered a pivotal factor promoting S. pneumoniae colonization and survival, it is also a powerful trigger of the innate and adaptive host immune response against bacterial infection. The dichotomy of PLY as both a key bacterial virulence factor and a trigger for host immune modulation allows the toxin to display both “Yin” and “Yang” properties during infection, promoting disease by membrane perforation and activating inflammatory pathways, while also mitigating damage by triggering host cell repair and initiating anti-inflammatory responses. Due to its cytolytic activity and diverse immunomodulatory properties, PLY is integral to every stage of S. pneumoniae pathogenesis and may tip the balance towards either the pathogen or the host depending on the context of infection.

Streptococcus pneumoniaeinfection of lung epithelial cells induces internalization of surface GPI-anchored proteins through pneumolysin-mediated activation of host Rho GTPases

“…Among these bacterial factors is a 53-kDa heat-labile cholesterol-dependent cytotoxin (CDC), pneumolysin (PLY), which is a highly conserved and important virulence factor that promotes the establishment of infection and evasion of host immune responses [9, 10]. PLY creates pores in the cell membrane [11–13] through a multistep process [14] in which 30-50 toxin monomers insert in the cholesterol-rich domains of host cells, oligomerize to form a large pre- pore complex [15, 16] that then undergoes conformational changes to produce a large 25-nm β-barrel pore in the membrane [11, 17]. Numerous studies have highlighted the role of PLY in damaging the pulmonary epithelium, activating the classical complement pathway, inducing inflammation, and inhibiting neutrophil function [8, 12].…”

Cells Responding to Closely Related Cholesterol-Dependent Cytolysins Release Extracellular Vesicles with a Common Proteomic Content Including Membrane Repair Proteins

“…Monomers of CDCs directly bind PM cholesterol residues, oligomerize and undergo conformational changes that allow their stable insertion across the PM, forming a large well-defined pore including around 40 monomers [ 10 , 11 ]. The toxin concentration critically determines the level of the induced PM damage, which in turn dictates cell fate [ 12 ]. While cells are unable to cope with high toxin concentrations engaging in cell death pathways, at sub-lytic concentrations of PFTs, the cells orchestrate a multifactorial repair response that supports cell survival and limits the progression of the infection [ 4 , 12 , 13 ].…”

“…The toxin concentration critically determines the level of the induced PM damage, which in turn dictates cell fate [ 12 ]. While cells are unable to cope with high toxin concentrations engaging in cell death pathways, at sub-lytic concentrations of PFTs, the cells orchestrate a multifactorial repair response that supports cell survival and limits the progression of the infection [ 4 , 12 , 13 ].…”

“…To further assess whether repair mechanisms were conserved among damage induced by different CDCs, we used two different toxins and performed a comparative analysis. Purified listeriolysin O (LLO) and pneumolysin (PLY), which are produced by the pathogenic gram-positive bacteria Listeria monocytogenes and Streptococcus pneumoniae , respectively, were used [ 12 , 23 ]. A previous study determined the proteomic content of vesicles released by cells intoxicated with PLY [ 21 ].…”

Quantification of differential toxin expressions and their relation to distinct lifespans of bacterial subpopulations associated with diverse host immune mechanisms

“…Streptococcus pneumoniae (SPN), the Gram-positive opportunistic pathogen, commonly resides in the upper respiratory tract of healthy individuals as commensal. But time to time it disperses from its niche and causes life-threatening diseases such as pneumonia, septicemia, endocarditis and meningitis [4]. Although typically considered an extracellular pathogen, it does have a brief intracellular stint which is particularly pertinent during trafficking across host barriers, such as the blood-brain barrier (BBB) and lung epithelial barrier [5] which are key aspects of its disease pathogenesis.…”