The immune evasion roles of Staphylococcus aureus protein A and impact on vaccine development

Abstract

While Staphylococcus aureus (S. aureus) bacteria are part of the human commensal flora, opportunistic invasion following breach of the epithelial layers can lead to a wide array of infection syndromes at both local and distant sites. Despite ubiquitous exposure from early infancy, the life-long risk of opportunistic infection is facilitated by a broad repertoire of S. aureus virulence proteins. These proteins play a key role in inhibiting development of a long-term protective immune response by mechanisms ranging from dysregulation of the complement cascade to the disruption of leukocyte migration. In this review we describe the recent progress made in dissecting S. aureus immune evasion, focusing on the role of the superantigen, staphylococcal protein A (SpA). Evasion of the normal human immune response drives the ability of S. aureus to cause infection, often recurrently, and is also thought to be a major hindrance in the development of effective vaccination strategies. Understanding the role of S. aureus virulence protein and determining methods overcoming or subverting these mechanisms could lead to much-needed breakthroughs in vaccine and monoclonal antibody development.

Keywords: B cells; Protein A; Staphylococcus aureus; immune evasion; super antigen; vaccine development.

Figure 1

Common sites of staphylococcal infection. S. aureus infection can lead to multiple infection endpoints depending on the route of entry and the tissue infected. This figure shows the type of infection (infections of the internal organs, skin infections, orthopaedic infections) with examples for the subset of infection type shown. Created with BioRender.com.

Figure 2

The immune response to S. aureus infection and the ways in which its proteins interact. (A) There are three activation pathways for the complement cascade; the classical (marked in red), the lectin (marked in light blue), and the alternative (marked in green). The classical pathway is activated when C1q binds the IgG generated by infection and forms the C1 complex with C1r/C1s, which goes on to convert C2/C4 to C4b2b. This process can be inhibited by SpA stopping the formation of the C1 complex with an antibody and also by C1-inhibitor (C1-inh), which is in turn blocked by staphylococcal superantigen-like protein 5 (SSL5). In the lectin pathway mannan-binding lectin serine protease 1/2 (MASP1/2) or mannose-binding lectin (MBL) acts as the initiator and converts C2/C4 to C4b2b. In the alternative pathway continuous low level activation leads to the conversion of C3(H2O) to C3(H20)Bb. Both C4b2b and C3(H2O)Bb then go on to convert C3 to C3a and C3b: this conversion can be blocked by staphylococcal complement inhibitor (SCIN). C3b then complexes with the two C3 convertases to form C5 convertases with converts C5 to C5a and C5b. C5b goes on to form the membrane attack complex (MAC). Adapted from Shinjyo, Kagaya and Pekna, 2021 (Shinjyo et al., 2021). (B) S. aureus is able to interact and interfere with both the innate and adaptive immune response in a number of ways. During the innate response macrophages (marked in orange) can target S. aureus, this in turn is blocked in its action by ClfA, additionally the initial innate response can be hampered by the action of SSL5 degrading PSGL-1 reducing the ability of neutrophils (marked in pink) to migrate into the infected tissue. A key part of the immune response is through the generation of B cells (marked in light blue) and the subsequent generation of antibodies however this process is hampered by the superantigenic binding by SpA, the B cell mediated immune response is further inhibited by SpA due to the role it plays in generating a clonal expansion and collapse. SpA plays a further role in limiting the adaptive immune response, by altering and downregulating the factors required in the niche for an LLPC to form. Further S. aureus proteins such as SEA and LukAB inhibit the transition from an innate to adaptive response targeting APC (marked in purple) death with further dysregulation of the adaptive T cell response mediated by SpA.

Figure 3

Figures displaying sequence information for SpA and its 3D structure. (A) Graphical description of the SpA genome with the 5 binding regions displayed by their letter. The Xr and linker regions are also shown. The Xr region is a region of variable length while the linker region contains the motifs required for binding the bacterial cell wall. Additionally the IgG binding regions for each domain are visualised along with the mutants generated when these sites are knocked out. (B) Aligned sequences of the 5 binding regions, the amino acids are marked up by colour and alignment is displayed along the bottom with * denoting perfect alignment and: denoting close alignment. The regions related to each helix are noted along the bottom. (C) 3D structure of the SpA protein (in pink) in complex with the Fab fragment of an IgM molecule. Produced in Pymol using structure 1DEE (Graille et al., 2000). Created with BioRender.com.

Figure 4

Varying routes of B cell death resulting from SpA binding and ending in either necrosis or apoptosis. This shows the paths that B cell death can occur via with B cells represented in lilac, IgG represented in blue and SpA represented in orange. B cell death can occur via either apoptosis or necrosis with each resulting in a markedly different manner of cell death displaying multiple different cell markers. Fox et al., reported that the previously noted apoptosis method was resultant of murine IgG and when instead carried out with human IgG necrosis was the primary method of cell death. A higher degree of crosslinking is noted in the necrosis case.