Identification of Potential Cerebrospinal Fluid Biomarkers To Discriminate between Infection and Sterile Inflammation in a Rat Model of Staphylococcus epidermidis Catheter Infection

Abstract

Staphylococcus epidermidis cerebrospinal fluid (CSF) shunt infection is a common complication of hydrocephalus treatment, creating grave neurological consequences for patients, especially when diagnosis is delayed. The current method of diagnosis relies on microbiological culture; however, awaiting culture results may cause treatment delays, or culture may fail to identify infection altogether, so newer methods are needed. To investigate potential CSF biomarkers of S. epidermidis shunt infection, we developed a rat model allowing for serial CSF sampling. We found elevated levels of interleukin-10 (IL-10), IL-1β, chemokine ligand 2 (CCL2), and CCL3 in the CSF of animals implanted with S. epidermidis-infected catheters compared to sterile controls at day 1 postinfection. Along with increased chemokine and cytokine expression early in infection, neutrophil influx was significantly increased in the CSF of animals with infected catheters, suggesting that coupling leukocyte counts with inflammatory mediators may differentiate infection from sterile inflammation. Mass spectrometry analysis revealed that the CSF proteome in sterile animals was similar to that in infected animals at day 1; however, by day 5 postinfection, there was an increase in the number of differently expressed proteins in the CSF of infected compared to sterile groups. The expansion of the proteome at day 5 postinfection was interesting, as bacterial burdens began to decline by this point, yet the CSF proteome data indicated that the host response remained active, especially with regard to the complement cascade. Collectively, these results provide potential biomarkers to distinguish S. epidermidis infection from sterile postoperative inflammation.

Cutibacterium acnes Central Nervous System Catheter Infection Induces Long-Term Changes in the Cerebrospinal Fluid Proteome

“…We demonstrated preferential biofilm growth with C. acnes consistent with our previous studies. (37) CSF and brain tissue samples from animals with C. acnes infected catheters revealed elevated IL-1β, IL-6, CCL2 and IL-10 at day 1 post-infection compared to controls. The brain tissue of rats with C. acnes demonstrated a greater influx of neutrophils and monocytes/macrophages compared to animals with sterile catheters.…”

“…Bacteria from the logarithmic phase were used to inoculate silicone catheters and incubated for 24 h to create an adherent biofilm on the catheter, which were implanted into rats. (37,38) This approach was previously successful in our rat model of S. epidermidis CNS catheter infection to avoid confounds from bacterial efflux from the catheter lumen if organisms were injected into the catheter because of the high CSF pressure. (37) Catheters demonstrated several log higher bacterial burden than surrounding brain tissue at day 1 post-infection (p=0.043)), reflecting a biofilm model of infection ( Figure 1B).…”

“…However, our results are consistent with our prior study as well as those from human shunt infection. (36,37,44) Secondly, this is an animal model and the results may not be immediately translatable to human studies; however, this model allows us to establish an informed basis for future clinical trials. We only examined a single strain of C. acnes CNS catheter infection in this report and shunt infections can be caused by a wide variety of organisms, including S. epidermidis that was investigated in our prior study.…”

“…To begin to address this gap, our laboratory previously developed a rat model of Staphylococcus epidermidis CNS catheter infection. (37) This model facilitates discrimination between the inflammatory response induced by shunt infection versus that induced by the foreign body alone. This novel model also allowed for sampling of CSF in response to biofilm infection in vivo, as well as clinical signs of illness, reflecting the evolution of infection and the immune response in a way that mimics human disease.…”

“…Interleukin 1 beta (IL-1β), (C-C motif) ligand 2 (CCL2), and (C-C motif) ligand 3 (CCL3) were significantly elevated in the CSF of animals with S. epidermidis infected catheters compared to baseline CSF and post-operative CSF. (37) While these are promising biomarkers for S. epidermidis shunt infection, further analysis is needed to elucidate potential biomarkers for C. acnes. Both of these gram-positive organisms are capable of forming biofilm; however, C. acnes is a more indolent bacteria, which may elicit a on December 13, 2020 by guest http://iai.asm.org/ Downloaded from unique host immune response.…”