Monitoring Therapeutic Treatments against Burkholderia Infections Using Imaging Techniques

Abstract

Burkholderia mallei, the etiologic agent of glanders, are Category B select agents with biothreat potential, and yet effective therapeutic treatments are lacking. In this study, we showed that CpG administration increased survival, demonstrating protection in the murine glanders model. Bacterial recovery from infected lungs, liver and spleen was significantly reduced in CpG-treated animals as compared with non-treated mice. Reciprocally, lungs of CpG-treated infected animals were infiltrated with higher levels of neutrophils and inflammatory monocytes, as compared to control animals. Employing the B. mallei bioluminescent strain CSM001 and the Neutrophil-Specific Fluorescent Imaging Agent, bacterial dissemination and neutrophil trafficking were monitored in real-time using multimodal in vivo whole body imaging techniques. CpG-treatment increased recruitment of neutrophils to the lungs and reduced bioluminescent bacteria, correlating with decreased bacterial burden and increased protection against acute murine glanders. Our results indicate that protection of CpG-treated animals was associated with recruitment of neutrophils prior to infection and demonstrated, for the first time, simultaneous real time in vivo imaging of neutrophils and bacteria. This study provides experimental evidence supporting the importance of incorporating optimized in vivo imaging methods to monitor disease progression and to evaluate the efficacy of therapeutic treatment during bacterial infections.

Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development

“…In the study by Judy, et al ., a moderate pro-inflammatory response was associated with protection while excessive inflammation caused pulmonary pathology [ 26 ]. Further, the protective effects of CpG treatment to reduce lung pathology were attributed to a reduction in neutrophil and inflammatory monocyte recruitment [ 26 , 50 ]. Similarly, we have previously shown that the virulence of B .…”

Targeting formyl peptide receptor 1 of activated macrophages to monitor inflammation of experimental osteoarthritis in rat

“…In the past decade, FPR1 has demonstrated high specificity and affinity to a synthetic hexapeptide, cinnamoyl‐F‐(D)L‐F‐(D)L‐F (cFLFLF), which was utilized to deliver various payloads to different septic and sterile inflammatory loci for imaging purposes by us and others . For example, we have reported the application of a near infrared fluorescent (NIRF) probe, cFLFLF‐poly(ethylene glycol) ‐cyanine 7 (cFLFLF‐PEG‐Cy7) and a positron emission tomography (PET) probe, cFLFLF‐PEG‐ 64 Cu for non‐invasive imaging of inflammation with different animal models.…”

The Impact of “Omic” and Imaging Technologies on Assessing the Host Immune Response to Biodefence Agents

“…The spread of both wild type and capsule mutant strains of B. pseudomallei has been compared in the BALB/c mouse model with an immunocompentent, hairless SKH-1 mouse strain, that is, particularly useful for FL imaging studies due to low autofluorescent background usually generated by fur. Infection studies with a BL strain of B. mallei have also been reported [150,151] with a BL signal detectable in the lung after i.n. challenge from 48 h after infection (p.i.…”

“…This mouse model of B. mallei infection has been further used to investigate the effects of CpG treatment alone, previously shown to provide protection against B. mallei infection when given preexposure to mice [152]. Mott et al (2013) [151] used dual signal imaging to elucidate the role of CpGs on neutrophil activation using a neutrophil-specific fluorescent probe. This cyanine 7-conjugate, PEG modified hexapeptide reagent specifically binds to the formylpeptide receptor of neutrophils [136].…”