Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

Abstract

Staphylococcus aureus is the major cause of human septic arthritis and osteomyelitis, which deserve special attention due to their rapid evolution and resistance to treatment. The progression of the disease depends on both bacterial presence in situ and uncontrolled disruptive immune response, which is responsible for chronic disease. Articular and bone infections are often the result of blood bacteremia, with the knees and hips being the most frequently infected joints showing the worst clinical outcome. We report the development of a hematogenous model of septic arthritis in murine knees, which progresses from an acute to a chronic phase, similarly to what occurs in humans. Characterization of the local and systemic inflammatory and immune responses following bacterial infection brought to light specific signatures of disease. Immunization of mice with the vaccine formulation we have recently described (4C-Staph), induced a strong antibody response and specific CD4+ effector memory T cells, and resulted in reduced bacterial load in the knee joints, a milder general inflammatory state and protection against bacterial-mediated cellular toxicity. Possible correlates of protection are finally proposed, which might contribute to the development of an effective vaccine for human use.Staphylococcus aureus is a human pathogen responsible for a variety of diseases ranging from minor/mild skin infections to life threatening diseases 1 . It is a major cause of bacteremia, which frequently leads to severe complications like endocarditis, toxic shock syndrome, septic arthritis (SA) and osteomyelitis (OM) 2 . Among others, joint-related diseases deserve special attention because of their rapid evolution and serious clinical outcomes, such as intense pain and impairment due to bone erosion requiring urgent intervention [3][4][5] . Joint infections are frequently localized in the knees and hips, and monoarticular disease is more frequent and less severe than polyarticular infection 6,7 . The mortality rate associated with these infections is around 5-20% in the adult population 3 , but can reach 50% depending on delayed diagnosis, immunodeficiency, older age 3,4 and pre-existing underlying conditions, such as rheumatoid arthritis and diabetes 3,8,9 . Joint and bone disruption is caused by the activity of bacteria in the joints, as well as by uncontrolled activation of the host immune system sustaining a local destructive inflammatory state, which can eventually result in chronic disease [10][11][12][13] . OM is often not treatable with antibiotics, a problem that is presently more evident with the increasing emergence of antibiotic-resistant S. aureus strains [14][15][16][17][18][19] . On the other hand, early application of antibiotic treatment can be efficacious for SA, which however often requires surgical intervention 3,4,7,20 .Given these premises, the development of an efficacious vaccine able to prevent S. aureus-mediated SA and OM would be highly desirable. We have recently demonstrated that an adjuvanted protein comb...

CXCR2 is critical for bacterial control and development of joint damage and pain in Staphylococcus aureus‐induced septic arthritis in mouse

“…Neutrophils are the first cell type recruited to the tissue during bacterial infection and have a potent machinery to control these microorganisms . In an experimental model of septic arthritis induced by intravenous injection of S. aureus , joint swelling and erythema in mice limbs were strictly dependent on the presence of neutrophils in the tissue . The bacterial strain used here did not cause arthritis if injected intravenously in immunocompetent animals (data not shown).…”

Mouse model of hematogenous implant-related Staphylococcus aureus biofilm infection reveals therapeutic targets

“…In general, after a S. aureus i.v. challenge in mice, there is a predilection for the bacteria to cause a septic arthritis in the knee joints (27,28). However, the presence of the orthopedic implant was a major determinant for the hematogenous implant infection, which occurred 70% of the time.…”

“…Other models studied bacteremia that resulted in septic arthritis in mice but in the absence of a surgically placed implant (27,28). The present model of S. aureus hematogenous orthopedic infection represents an advance over these prior models because the recently developed bright bioluminescent S. aureus strain in combination with in vivo BLI provided an opportunity to monitor the anatomic dissemination of the infection in the same animals noninvasively and longitudinally over time.…”

“…In prior models of septic arthritis (in the absence of surgery or an implant), an i.v. S. aureus challenge had an increased propensity to spread to the knee joints of mice (27,28). To evaluate the propensity for the hematogenous infection to spread to the knee joints of mice in the presence and absence of an implant, we used our model of hematogenous orthopedic implant infection and evaluated BLI signals from (i) the (+) implant surgical leg, (ii) the (−) implant surgical leg that had the identical surgical procedure performed but without the placement of an implant, and (iii) the respective nonsurgical contralateral leg (Fig.…”

“…Prior preclinical models of PJI or orthopedic implant infections have involved direct insertion of an implant with bacteria already adherent to its surface (22,23), direct inoculation of bacteria at the surgical site of an implant (24)(25)(26), or bacteremia resulting in septic arthritis in the absence of an implant (27,28). Although each of these models has features of a hematogenous implant infection, they do not fully recapitulate the spread of the Significance Hematogenous implant-related infections are an important clinical problem because bacteria spread from the bloodstream to a previously well-functioning implant and result in infectious complications and failure of a medical device or prosthesis.…”