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Human blood vessels infected by meningococcus

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Mouse model of meningococcal infection

Neisseria Meningitides (NM) is a bacterium that can cause meningitis and other forms of meningococcal disease. Understanding how the pathogen behaves inside the organism is crucial for the development of new drug targets.

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Meningococcal sepsis is a rapidly progressing disease, which occurs when the bacterial pathogen NM gains access to the blood stream. The human specificity of the pathogen has hampered the use of animal models to study this infection. The EU-funded 'Human blood vessels infected by meningococcus' (HUVIM) project aimed to develop and implement a humanised mouse model for the study of meningococcal septicaemia. Their objective was to introduce human dermal microvessels into a mouse model through grafting of human skin onto immunocompromised mice. The human skin was sourced primarily from plastic surgery procedures. The grafting procedure proved to be replicable and stable, with a very high (>90 %) graft success rate. Researchers found that NM adhered rapidly and exclusively to the human vessels in the skin graft when introduced intravenously into the model. The bacteria adhered both as individuals and eventually as micro colonies of various sizes. By using a library of mutants it was shown that this binding relied on the Type IV pili of the bacteria. The pathology of the human skin graft following infection mimicked that seen in human patients. Researchers were able to identify human cytokine signalling following infection of the model. Using a cytometric bead array, they differentiated between inflammatory signalling from the human endothelium versus the circulating mouse cells. Human IL-6 and IL-8 were both shown to be significantly upregulated within 24h of infection. The project resulted in four published papers. The success enabled the extension of the project into such areas as coagulation and immune cell responses to the infection. This is the first animal model to mimic the development of dermal lesions following infection with NM. The hope is that this work would lead to better treatment strategies and therefore outcomes for patients with meningococcal sepsis.

Keywords

Neisseria Meningitides, humanised mouse model, meningococcal septicaemia, immunocompromised mice, skin graft, cytokine signalling, inflammatory

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