A Jack of All Trades: The Role of Pneumococcal Surface Protein A in the Pathogenesis of Streptococcus pneumoniae

Abstract

Streptococcus pneumoniae (Spn), or the pneumococcus, is a Gram-positive bacterium that colonizes the upper airway. Spn is an opportunistic pathogen capable of life-threatening disease should it become established in the lungs, gain access to the bloodstream, or disseminate to vital organs including the central nervous system. Spn is encapsulated, allowing it to avoid phagocytosis, and current preventative measures against infection include polyvalent vaccines composed of capsular polysaccharide corresponding to its most prevalent serotypes. The pneumococcus also has a plethora of surface components that allow the bacteria to adhere to host cells, facilitate the evasion of the immune system, and obtain vital nutrients; one family of these are the choline-binding proteins (CBPs). Pneumococcal surface protein A (PspA) is one of the most abundant CBPs and confers protection against the host by inhibiting recognition by C-reactive protein and neutralizing the antimicrobial peptide lactoferricin. Recently our group has identified two new roles for PspA: binding to dying host cells via host-cell bound glyceraldehyde 3-phosphate dehydrogenase and co-opting of host lactate dehydrogenase to enhance lactate availability. These properties have been shown to influence Spn localization and enhance virulence in the lower airway, respectively. Herein, we review the impact of CBPs, and in particular PspA, on pneumococcal pathogenesis. We discuss the potential and limitations of using PspA as a conserved vaccine antigen in a conjugate vaccine formulation. PspA is a vital component of the pneumococcal virulence arsenal - therefore, understanding the molecular aspects of this protein is essential in understanding pneumococcal pathogenesis and utilizing PspA as a target for treating or preventing pneumococcal pneumonia.

Keywords: Streptococcus pneumoniae; choline-binding proteins; pathogenesis; pneumococcal surface protein A (PspA); vaccine.

Figure 1

Major virulence factors of Streptococcus pneumoniae including choline-binding proteins. Inset picture shows PspA bound to phosphorylcholine on wall teichoic acid and lipoteichoic acid as part of the cell wall and membrane, respectively. Key (left to right): Pneumolysin (Ply), Immunoglobulin A1 protease (ZmpB), Pneumococcal serine-rich repeat protein (PsrP), Neuraminidase (NanA), Pneumococcal surface adhesin A (PsaA), Pneumococcal iron acquisition A (PiaA), Pneumococcal iron uptake A (PiuA), Choline-binding protein D (CbpD), Choline-binding protein A (CbpA), Choline-binding protein E (CbpE), Pneumococcal choline-binding protein A (PcpA), Pneumococcal surface protein A (PspA), Wall teichoic acid (WTA), Phosphorylcholine (PC), Lipoteichoic acid (LTA).

Figure 2

Domain structure of PspA. Illustration shows the N-terminal signal sequence (SS), 280–380 aa α-helix region (αHD), the ~90 amino acid proline rich domain (PRD), and the ~200 aa choline binding repeat domain (CBD) with its short 17 aa C-terminal tail. The clade-defining region (CDR) within the αHD is represented as light blue. The GAPDH binding region (240-327) and Lactoferrin (LF) binding region (222-317) within αHD of WU2 serotype 3 are represented as red and cyan lines, respectively. The non-proline block (NPB)/Lactate dehydrogenase (LDH) binding region within PRD domain is boxed as pink (based upon Mukerji et al., 2018). The PRD composition of PspA from TIGR4, GA44128 and WU2 strains representing each group of PRD are shown in inset (adapted from Park et al., 2021a).

Figure 3

Proposed model of PspA-mediated binding to host-derived GAPDH on necroptotic cells. hGAPDH binds to dying cells via phosphatidylserine (PS) residues flipped from the inner to outer membrane during programmed cell death. Host cell death during Spn infection is primarily due to pneumolysin-mediated necroptosis. PspA binds to hGAPDH during this process. New data indicates that sensitivity of lung cells to pneumolysin-mediated necroptosis is drastically exacerbated by concomitant influenza A virus (IAV) infection (Gonzalez-Juarbe et al., 2020).

Figure 4

Distribution of PspA families across several countries. The proportion of PspA family 1(blue), 2 (orange), 3 (grey), and non-typable (NT-Yellow) from each study is represented as percentage (%). The origin of Spn and the number of isolates from each study are detailed in Table 2 along with the corresponding reference. For some studies, not all Spn strains examined carried the gene for PspA. In these instances the % distribution of PspA is less than 100%.

Figure 5

PspA interacts with Streptococcus pneumoniae as a “Jack of All Trades.” The pneumococcus with PspA (in blue) extending beyond the capsule which blocks the binding of C-reactive protein (CRP) to phosphorylcholine (PC) on the bacterial surface and acts as an adhesin by binding to host GAPDH. Spn co-opts host lactate dehydrogenase (LDH) bound to the non-proline block (in pink) of the proline-rich domain (in green) on PspA and uses converted lactate as a nutrient in poor environmental conditions. PspA on the surface of the pneumococcus also binds to lactoferrin (LF) to protect the bacterium from killing by lactoferricin.