Staphylococcus aureus lipoproteins in infectious diseases

Abstract

Infections with the Gram-positive bacterial pathogen Staphylococcus aureus remain a major challenge for the healthcare system and demand new treatment options. The increasing antibiotic resistance of S. aureus poses additional challenges, consequently inflicting a huge strain in the society due to enormous healthcare costs. S. aureus expresses multiple molecules, including bacterial lipoproteins (Lpps), which play a role not only in immune response but also in disease pathogenesis. S. aureus Lpps, the predominant ligands of TLR2, are important for bacterial survival as they maintain the metabolic activity of the bacteria. Moreover, Lpps possess many diverse properties that are of vital importance for the bacteria. They also contribute to host cell invasion but so far their role in different staphylococcal infections has not been fully defined. In this review, we summarize the current knowledge about S. aureus Lpps and their distinct roles in various infectious disease animal models, such as septic arthritis, sepsis, and skin and soft tissue infections. The molecular and cellular response of the host to S. aureus Lpp exposure is also a primary focus.

Keywords: Staphylococcus aureus; TLR2; host-pathogen interactions; immunity; infection; lipopeptides; lipoproteins; metabolic fitness.

Figure 1

The biosynthetic pathway of Staphylococcus aureus lipoproteins. S. aureus lipoproteins are synthesized as preprolipoprotein precursors, which comprise an N-terminal signal peptide sequence (depicted as light-green cylinder), and are translocated across the cytoplasmic membrane (CM) by either the general secretory (Sec) or twin arginine translocation (TAT) pathways. The first enzyme, the preprolipoprotein diacylglyceryl transferase Lgt enables the transfer of a diacylglyceryl moiety to the indispensable cysteine residue (depicted as a beige circle with the letter, C), which forms a prolipoprotein. This lipid modification is followed by the second enzyme, the prolipoprotein signal peptidase Lsp., which cleaves the signal peptide and generates a mature diacylated lipoprotein. A third enzyme is required in order to form a mature triacylated lipoprotein. This lipid acylation is catalyzed by lipoprotein N-acylation transferase system LnsA/B. When lgt is deleted (Δlgt mutant), the maturation of lipoproteins is inhibited and lipidation no longer occurs.

Figure 2

Chemical structure of Staphylococcus aureus Lpps (triacylated, diacylated and unlipidated lipoproteins) and synthetic peptides (Pam₂CSK₄ and Pam₃CSK₄). Cystein is marked in red.

Figure 3

Schematic illustration of the effects of Staphylococcus aureus lipoprotein (Lpp) in hematogenous and local S. aureus arthritis models. Left panel: S. aureus parental strain, expressing Lpp (S. aureus Lpp), significantly aggravates systemic infection with increased mortality, weight loss, and bacterial burden in the kidneys (1) compared to the derivative lgt mutant strain, lacking Lpp (S. aureus Δlgt) (2). However, both S. aureus strains have similar outcomes with regard to bone erosion. Right panel: Lpp has dual effects in the local knee model. Intra-articular injection of purified Lpp (S. aureus Lpl1) induces rapid TLR2-dependent infiltration of phagocytes. Moreover, Lpl1 causes severe joint inflammation and bone erosions dependent on monocytes/macrophages through TLR2 (3). In contrast, live S. aureus Lpps act as adjuvants, triggering recognition by TLR2 and subsequent neutrophil recruitment, leading to more efficient bacterial killing and diminished bone destruction (4). CFU, colony-forming units.

Figure 4

Overview of the proposed functions of lipoproteins (Lpps) in Staphylococcus aureus infections. S. aureus Lpps play a distinct role depending on the route of infection. Following systemic administration of Lpp-expressing S. aureus, increased metabolic fitness and increased bacterial survival are observed (1). Local administration of S. aureus Lpps has dual effects depending on the affected organ. In the knee joint infection, Lpps have a protective role by triggering the innate immunity, leading to more efficient bacterial elimination with subsequent diminished bone destruction (2). In skin infection, in contrast, Lpp-expressing S. aureus leads to increased abscess formation, facilitating the bacteria to evade the innate immunity and resulting in increased bacterial survival (3). Furthermore, Lpp prompts S. aureus host cell invasion via direct interplay with the heat shock proteins Hsp90α and Hsp90ß, consequently leading to bacterial survival (4).