Staphylococcal Immune Evasion Proteins: Structure, Function, and Host Adaptation

Abstract

Staphylococcus aureus is a successful human and animal pathogen. Its pathogenicity is linked to its ability to secrete a large amount of virulence factors. These secreted proteins interfere with many critical components of the immune system, both innate and adaptive, and hamper proper immune functioning. In recent years, numerous studies have been conducted in order to understand the molecular mechanism underlying the interaction of evasion molecules with the host immune system. Structural studies have fundamentally contributed to our understanding of the mechanisms of action of the individual factors. Furthermore, such studies revealed one of the most striking characteristics of the secreted immune evasion molecules: their conserved structure. Despite high-sequence variability, most immune evasion molecules belong to a small number of structural categories. Another remarkable characteristic is that S. aureus carries most of these virulence factors on mobile genetic elements (MGE) or ex-MGE in its accessory genome. Coevolution of pathogen and host has resulted in immune evasion molecules with a highly host-specific function and prevalence. In this review, we explore how these shared structures and genomic locations relate to function and host specificity. This is discussed in the context of therapeutic options for these immune evasion molecules in infectious as well as in inflammatory diseases.

Immune evasion by a staphylococcal inhibitor of myeloperoxidase

“…The triple-helix motif is a thermodynamically stable structure which can accommodate high sequence diversity and adapt to binding a wide variety of targets (28). However, this simple structural motif is typically modified by an N-terminal extension that imparts specific function to the protein in question (27).…”

The TLR2 Antagonist Staphylococcal Superantigen-Like Protein 3 Acts as a Virulence Factor to Promote Bacterial Pathogenicity in vivo

“…We should keep in mind, however, that inducing overexpression of a virulence trait is artificial and does not resemble the natural situation. Human S. aureus strains are highly adapted to the human system and are not capable to easily establish infection in mice, which can partly be explained by the human specificity of many virulence factors [5] , but might also be related to differential expression of virulence determinants in humans and mice. With the current lack of more suitable in vivo models, the development of this SSL3-overproducing S. aureus strain provided a valuable tool to study the effect of SSL3 in a mouse model in vivo enabling us to determine its relative contribution to bacterial virulence.…”

“…It secretes two small proteins that potently interfere with TLR2 signaling: staphylococcal superantigen-like protein 3 (SSL3) and 4 (SSL4) [17] . SSL3 and SSL4 are part of a larger, structurally related family of staphylococcal proteins that have diverse functions but are all involved in immune modulation [5] . SSL3 is the more potent inhibitor of the two, and the crystal structure of the complex of SSL3 and TLR2 revealed that SSL3 inhibits TLR2 through interfering with both lipopeptide binding and dimerization [18] .…”

“…It has emerged as a pathogen of global importance in humans and animals mainly through increases in antibiotic resistance [4] . Furthermore, the wide amount of secreted virulence factors, also called immune evasion molecules, play an important role in the pathogenicity of this bacterium [5] .…”

Hydrogen Sulfide and Reactive Sulfur Species Impact Proteome S-Sulfhydration and Global Virulence Regulation in Staphylococcus aureus

“…The success of S. aureus is linked to its ability to express a vast array of virulence genes to allow adaption to host immune systems and survival in challenging microenvironments. 1 Although mammals have developed both innate and adaptive immune strategies to fight invasive microbes, S. aureus has coevolved with these host defense systems and secretes a variety of immune evasion determinants including staphylococcal super-antigen-like proteins to manipulate host immune responses. 2 The expression of a large number of virulence factors is coordinately regulated during pathogenesis and requires both two-component regulatory systems and members of the SarA protein family, comprising an interdependent and tightly controlled network.…”