Evading the host response: Staphylococcus “hiding” in cortical bone canalicular system causes increased bacterial burden

Abstract

Extremity reconstruction surgery is increasingly performed rather than amputation for patients with large-segment pathologic bone loss. Debate persists as to the optimal void filler for this “limb salvage” surgery, whether metal or allograft bone. Clinicians focus on optimizing important functional gains for patients, and the risk of devastating implant infection has been thought to be similar regardless of implant material. Recent insights into infection pathophysiology are challenging this equipoise, however, with both basic science data suggesting a novel mechanism of infection of Staphylococcus aureus (the most common infecting agent) into the host lacunar–canaliculi network, and also clinical data revealing a higher rate of infection of allograft over metal. The current translational study was therefore developed to bridge the gap between these insights in a longitudinal murine model of infection of allograft bone and metal. Real-time Staphylococci infection characteristics were quantified in cortical bone vs metal, and both microarchitecture of host implant and presence of host immune response were assessed. An orders-of-magnitude higher bacterial burden was established in cortical allograft bone over both metal and cancellous bone. The establishment of immune-evading microabscesses was confirmed in both cortical allograft haversian canal and the submicron canaliculi network in an additional model of mouse femur bone infection. These study results reveal a mechanism by which Staphylococci evasion of host immunity is possible, contributing to elevated risks of infection in cortical bone. The presence of this local infection reservoir imparts massive clinical implications that may alter the current paradigm of osteomyelitis and bulk allograft infection treatment.

Antimicrobial Activity of Non-steroidal Anti-inflammatory Drugs on Biofilm: Current Evidence and Potential for Drug Repurposing

“…are also present in PJI, which could be linked to biofilm formation. Intracellular internalization of staphylococci, particularly “Small colony variant” strains, besides invasion and colonization of the lacuna-canalicular system of cortical bone are other causes of PJIs ( Parvizi et al, 2013 ; Zoller et al, 2020 ). A clinical study explored if ASA could promote infection control for patients with periprosthetic joint infections (PJIs) ( Wei et al, 2020 ).…”

Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid

“…The recent discovery of S. aureus colonization of the osteocyte lacuno canalicular network (OLCN) of live bone via transmission electron microscopy (TEM) analyses of infected bone from mice, and bone biopsies from patients with chronic osteomyelitis, has provided new insights into the problems of antibiotic therapy to treat bone infections [ 16 , 17 , 18 , 19 ]. Specifically, S. aureus within the OLCN is a permanent reservoir of bacteria that cannot be eradicated by host responses or any known treatments short of amputation [ 9 , 20 , 21 , 22 ]. While in vivo bromodeoxyuridine labeling studies in mice have demonstrated that orally administered small molecules have access to S. aureus at the leading edge of the colony within the OLCN [ 17 ], we have also shown that both methicillin-sensitive S. aureus (MSSA) [ 23 ] and methicillin-resistant S. aureus (MRSA) [ 24 ] OLCN invasion cannot be prevented or eradicated by combined high-dose local and systemic antibiotics, likely due to its well-known adaptive responses that are associated with persister cells and small colony variants (SCVs) [ 10 ].…”

Staphylococcus aureus Cell Wall Biosynthesis Modulates Bone Invasion and Osteomyelitis Pathogenesis

“…This submicron-scale invasion of bone permits S. aureus long-term survival and evasion of immune cell attack. Despite the challenges associated with identifying S. aureus bacterial cells deep within the infected bone, like finding a needle in a haystack, additional studies in models of fracture-related infection and implant-associated infection have been able to corroborate this novel mode of persistence (Alder et al, 2020;Zoller et al, 2020).…”