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C. acnes CNS catheter infection elicits modest early inflammatory changes but long term alterations in the CSF proteome

ABSTRACT: Shunt infections lead to grave neurologic morbidity for patients especially when there is a delay in diagnosis. C. acnes is the third most common cause of cerebrospinal fluid (CSF) shunt infection and is underdiagnosed due to the difficulty in culturing this fastidious, slow growing pathogen. Currently the gold standard for diagnosis of CSF shunt infections is microbiologic culture, however, in the case of C. acnes diagnostic cultures may be falsely negative. Therefore, new diagnostic methods are needed. To investigate potential CSF biomarkers of C. acnes CSF shunt infection we adapted a previously published rat model of CSF shunt infection to C. acnes. We found elevated levels of IL-1β, IL-6, CCL2 and IL-10 in the CSF and brain tissues of animals implanted with C. acnes infected catheters compared to sterile controls at day 1 post-infection. We found modest increases in neutrophils in the CSF and to a greater extend the brain tissue of animals with C. acnes infection which mirrors the clinical findings in C. acnes shunt infection. Mass spectrometry revealed that the CSF proteome is altered during C. acnes shunt infection and changes over the course of infection with an acute phase and pathogen neutralization response at day 1 post-infection to a more biosynthetic and metabolic response at day 28 post-infection relating to healing. Collectively, these results demonstrate that it is possible to distinguish C. acnes infection from sterile post-operative inflammation and CSF proteins could be useful in a diagnostic strategy for this pathogen that is difficult to diagnose.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Cerebrospinal Fluid

SUBMITTER: Ishwor Thapa

LAB HEAD: Gwenn L. Skar

PROVIDER: PXD020527 | Pride | 2022-02-15

REPOSITORIES: Pride

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

Beaver Matthew M Lagundzin Dragana D Thapa Ishwor I Lee Junghyae J Ali Hesham H Kielian Tammy T Skar Gwenn L GL

Infection and immunity 20210317 4

Cutibacterium acnes is the third most common cause of cerebrospinal fluid (CSF) shunt infection and is likely underdiagnosed due to the difficulty in culturing this pathogen. Shunt infections lead to grave neurologic morbidity for patients especially when there is a delay in diagnosis. Currently, the gold standard for identifying CSF shunt infections is microbiologic culture. However, C. acnes infection often results in falsely negative cultures; therefore, new diagnostic methods a ...[more]

PMID: 33288649

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Project description:Proprionibacterium acnes is a Gram positive bacterium found ubiquitously on human skin, where it is typically considered to assume a commensal relationship with its host. However, it is also closely associated with the skin condition acne vulgaris. More controversially, it has a postulated involvement in infections of implanted prosthetic devices and has been isolated from malignant prostate tissues. The role of P. acnes in these pathologies remains undetermined, although both bacterial and host factors are implicated. By microarray analysis, we have identified fundamental differences in the global transcriptional profiles of keratinocyte and prostate cells to P. acnes infection. Notably, P. acnes infection of the keratinocyte cell line, HaCaT, elicited a robust, but acute inflammatory response. By contrast, the inflammatory response of the prostate cell line, RWPE1, was delayed and persisted for longer times. Immunofluorescence and electron microscopy revealed higher numbers of internalized P. acnes bacteria in RWPE1 cells, which could still be detected intracellularly three weeks post infection. This contrasted with HaCaT cells, which P. acnes largely failed to invade. Moreover, P. acnes induced a delayed, sustained activation of NFM-NM-:B in RWPE1 cells, which was absent in HaCaT cells. Further characterization of the host-cell response to infection revealed that the intermediate filament protein, vimentin, was a key determinant of P. acnes invasion, persistence and inflammatory profile in RWPE1 cells. siRNA mediated knock down of vimentin in RWPE1 cells attenuated bacterial invasion and the inflammatory response to infection; similarly, overexpression of vimentin in HaCaT cells increased bacterial invasion. We conclude that vimentin-dependent host-tissue tropism, in part, determines P. acnes invasion and inflammatory capacity. This could contribute to P. acnes pathology at non-skin infection sites. Microarray experiments were performed as dual-color hybridizations. In order to compensate specific effects of the dyes and to ensure statistically relevant data analysis, a color-swap dye-reversal was performed.

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Dataset Information

C. acnes CNS catheter infection elicits modest early inflammatory changes but long term alterations in the CSF proteome

Dataset's files

Publications

<i>Cutibacterium acnes</i> Central Nervous System Catheter Infection Induces Long-Term Changes in the Cerebrospinal Fluid Proteome.

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