Community Research and Development Information Service - CORDIS

Final Report Summary - PSMS-IN-INFLAMMATION (Imaging Innate Immunity of Staphylococcal Infections)

This study was designed to dissect the role of Staphylococcal phenol soluble modulins (PSMs) in
bacterial pathogenesis and visualize how Staphylococcus aureus modulate host immunology in vivo.
Dr. Surewaard has approached this research project by learning cutting-edge real-time in vivo imaging techniques such as Spinning-disk confocal intravital microscopy (SDIVM) and Multi photon IVM (MPIVM), but also made use of standard multidisciplinary methodologies in: microbiology, histopathology, immunology and biochemistry. These techniques were also applied to study a number of serous pathogens including Streptococcus pneumonia, Pseudomonas aeruginosa and Escherichia coli

Surewaard has learned and gained extensive experience in intravital microscopy to study bacterial
pathogenesis in experimental animal models. He has developed various fluorescent reporter strains in clinical important pathogenic bacterial strains. The applicant gained experience in Immunohistochemistry to determine in which cellular compartment Staphylococcus aureus is able to replicate and confirmed this data using electron microscopy. Using high resolution Z-stack images and newly developed replication reporter strains surewaard could show that Staphylococcus aureus replicates and forms intracellular micro-colonies of up to 80 bacteria inside Kupffer cells. In addition newly developed antibiotics were able to target this intracellular reservoir in Kupffer cells and this result was later published in the Journal of Experimental Medicine. In addition Surewaard and Z. Zeng have discovered the mechanism how Gram-positive bacteria a captured by Kupffer cells. Kupffer cells express Crig, however unlike previously thought this receptor does not recognize complement but it recognizes Lipoteichoic acid in the cell wall from Gram-positive bacteria. This new mechanism of bacterial clearance was published in Cell Host and Microbes. In addition collaborations have been established with the pharmaceutical company Medimmune to address the mechanism of action of bi-specific antibodies that work against intracellular virulence factors that high potency in generating new therapeutics for diseases of the bacteria Pseudomonas aeruginosa and Staphylococcus aureus. This data was published last year in the high ranking Journal of Clinical investigation.

The data generated by this study are currently accepted for publication high ranking biomedical
research journals; Journal of Experimental Medicine, Cell Host and Microbes and Journal of clinical investigations. By publishing in this data many scientist in the field of Infectious disease, immunology and microbiology will have access to it. Furthermore we identified a clinical problem that Methicillin-resistant Staphylococcus aureus (MRSA) actually thrives intracellularly. The pathogen survives and grows inside Kupffer cells and ultimately escapes to colonize other tissues. Based on these findings, a simple, inexpensive and rational way to target and eradicate the pathogen was further uncovered. This
immunotherapeutic approach could help treat patients with MRSA bacteremia by increasing
effectiveness of antibiotics and decreasing the length of administration. Following these publications we were approached by the Centre of Drug Research and Development (CDRD) based in Vancouver to translating our work into novel therapeutics and I will collaborate extensively the CDRD.

Reported by

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Netherlands

Subjects

Life Sciences
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