Mechanisms of Immune Evasion and Bone Tissue Colonization That Make Staphylococcus aureus the Primary Pathogen in Osteomyelitis

Abstract

Purpose of review: Staphylococcus aureus is the primary pathogen responsible for osteomyelitis, which remains a major healthcare burden. To understand its dominance, here we review the unique pathogenic mechanisms utilized by S. aureus that enable it to cause incurable osteomyelitis.

Recent findings: Using an arsenal of toxins and virulence proteins, S. aureus kills and usurps immune cells during infection, to produce non-neutralizing pathogenic antibodies that thwart adaptive immunity. S. aureus also has specific mechanisms for distinct biofilm formation on implants, necrotic bone tissue, bone marrow, and within the osteocyte lacuno-canicular networks (OLCN) of live bone. In vitro studies have also demonstrated potential for intracellular colonization of osteocytes, osteoblasts, and osteoclasts. S. aureus has evolved a multitude of virulence mechanisms to achieve life-long infection of the bone, most notably colonization of OLCN. Targeting S. aureus proteins involved in these pathways could provide new targets for antibiotics and immunotherapies.

Keywords: Adaptive immunity; Canalicular invasion; Immune proteome; Orthopedic infections; Osteomyelitis; Staphylococcus aureus.

Figure 1:. “Four Acts” of immune evasion and bacterial persistence during S. aureus osteomyelitis.

S. aureus in the bone environment is presented with several immune challenges. Four important immune mechanisms of S. aureus persistence in the context of osteomyelitis are: 1) abscesses formation; 2) biofilm formation; 3) invasion of the osteocyte-lacuno canalicular network (OLCN) of bone; and 4) intracellular colonization. A) S. aureus hijacks the host-induced abscess formation process to create an abscess with protected bacterial cells at its core, which are inaccessible to immune cell infiltration. S. aureus deploys numerous cell-wall associated and secreted virulence proteins to trigger the formation of this multilayered structure. B) Necrotic bone or metal implants are ideally suited for S. aureus biofilm formation. As illustrated, the process of biofilm development involves bacterial colonization/attachment, maturation, detachment, and dissemination. Dozens of MSCRAMMs, and virulence molecules such as Ica, PSMs play critical roles in this process. These factors are regulated by agr quorum-sensing system. C) A recently uncovered mechanism of chronic bacterial persistence is the invasion of the sub-micron channels deep within the cortical bone. Electron microscopy analyses of infected necrotic bone revealed the presence of S. aureus, which usually is a micron in diameter, in these sub-micron channels. Several surface adhesins, cell wall synthesis proteins, and cell division enzymes are hypothesized, but not yet confirmed, to play significant roles in OCLN invasion. D) Several in vitro, but not in vivo, studies have also demonstrated that S. aureus can survive intracellularly in non-professional phagocytes such as osteoblasts, osteoclasts, and osteocytes during osteomyelitis. Specific proteins involved in this process of internalization have yet to be fully deciphered. It is also believed that in all the aforementioned mechanisms, S. aureus can also transform into a quasi-dormant small colony variant (SCV, illustrated as red bacteria) and persist in the bone for long periods of time.