Differential binding of human and murine IgGs to catalytic and cell wall binding domains of Staphylococcus aureus peptidoglycan hydrolases

Abstract

Staphylococcus aureus is an opportunistic pathogen causing high morbidity and mortality. Since multi-drug resistant S. aureus lineages are nowadays omnipresent, alternative tools for preventive or therapeutic interventions, like immunotherapy, are urgently needed. However, there are currently no vaccines against S. aureus. Surface-exposed and secreted proteins are regarded as potential targets for immunization against S. aureus infections. Yet, many potential staphylococcal antigens of this category do not elicit protective immune responses. To obtain a better understanding of this problem, we compared the binding of serum IgGs from healthy human volunteers, highly S. aureus-colonized patients with the genetic blistering disease epidermolysis bullosa (EB), or immunized mice to the purified S. aureus peptidoglycan hydrolases Sle1, Aly and LytM and their different domains. The results show that the most abundant serum IgGs from humans and immunized mice target the cell wall-binding domain of Sle1, and the catalytic domains of Aly and LytM. Interestingly, in a murine infection model, these particular IgGs were not protective against S. aureus bacteremia. In contrast, relatively less abundant IgGs against the catalytic domain of Sle1 and the N-terminal domains of Aly and LytM were almost exclusively detected in sera from EB patients and healthy volunteers. These latter IgGs may contribute to the protection against staphylococcal infections, as previous studies suggest that serum IgGs protect EB patients against severe S. aureus infection. Together, these observations focus attention on the use of particular protein domains for vaccination to direct potentially protective immune responses towards the most promising epitopes within staphylococcal antigens.

Phage display of environmental protein toxins and virulence factors reveals the prevalence, persistence, and genetics of antibody responses

“…Loss of peptidoglycan hydrolase activity interferes with the dissemination of S. aureus and thus decreases its virulence in a murine model (Kajimura et al, 2005). Host antibody responses that interfere with peptidoglycan hydrolase activity may, therefore, diminish the efficiency of staphylococcal tissue invasion (Wang et al, 2021). The small subset of individuals who appear to lack these antibodies may, therefore, be at a greater risk of more serious staphylococcal infections.…”

Staphylococcus aureuscell wall maintenance – the multifaceted roles of peptidoglycan hydrolases in bacterial growth, fitness, and virulence

“…Until now, it is not known how the intact LytM becomes activated, but this most likely occurs through the interaction with partner proteins rather than proteolytic processing since the full-size LytM is readily detectable in the growth medium of S. aureus (Wang et al . 2021 ).…”

“…However, disentangling the different roles of PGHs will be important, since they are potentially druggable targets for novel antibiotics, or passive or active anti-staphylococcal immunization approaches (Wang et al . 2021 ). PGHs are particularly attractive targets for drugs or immunization not only because they are exposed on the bacterial cell surface and have shown high immunogenicity (Pastrana et al .…”

“… 2020 , Wang et al . 2021 ), but also because they play vital roles in cell growth and division. In view of this potential opportunity to develop novel preventive or therapeutic approaches to fight staphylococcal infections, the present review is aimed at providing a detailed overview of what is currently known about the physiological roles and specificity of the different PGHs of S. aureus and how they are expressed and function during different stages in the bacterial cell cycle and during infection.…”

One fold, many functions—M23 family of peptidoglycan hydrolases

“…Further research studies revealed that attenuated virulence of S. aureus LytM − is consistent with the decreased levels of staphylococcal protein A (SpA; Becker et al, 2014 ), which affects the immune evasion potential of this pathogen ( O’Halloran et al, 2015 ). It must be noted that LytM, on its own, potentiates a strong antibody response, therefore, it can be considered to be used as the antigen in the vaccines that protect against refractory S. aureus infections ( Wang et al, 2021 ).…”