CORDIS - EU research results

Functional Genomics Analysis of Neisseria meningitidis interactions with human dermal blood vessels in vivo

Final Report Summary - HUVASC-SEQ (Functional Genomics Analysis of Neisseria meningitidis interactions with human dermal blood vessels in vivo)

Until recently the use of animal models to study N. meningitidis infection did not accurately reproduce the key features of meningococcal disease. Previous models only permitted the study of prolongation of bacteremia in time, but without showing the development of skin lesions, petechial rashes and purpura. The recent development of the “humanized mouse model” (hMM) for meningococcal infection at the host lab, reproduces the skin and purpuric lesions seen during meningococcal septic shock (Melican et al., 2013).

The hMM introduces human functional dermal micro-vessels by xenografting human skin onto immunodeficient mice (Melican et al., 2013). N. meningitidis injected into the blood circulation migrates to and adheres specifically to the human endothelium present in the skin graft. At the endothelium site N. meningitidis establishes micro-colonies, proliferates and fills the lumen of the vessels in a process that is referred to as “vascular colonization” (Melican and Dumenil, 2012; Melican et al., 2013). The vascular colonization leads to an inflammatory response, tissue damage and formation of purpuric lesions (Melican et al., 2013) mimicking what is seen in humans in acute meningococcemia. Importantly, the vascular colonization process is mediated and dependent on the Type IV pili structure (Melican et al., 2013).

The present project proposed the use of the hMM and the application of studies at genome-wide scale (High throuput Insertion Tracks Sequencing and RNA-seq analysis) and functional assays to gain a better understanding of the mechanisms of vascular colonization and meningococcal disease in vivo. The present project has allowed us to identify new gene candidates important for virulence during the process of vascular colonization. This study is providing new insights in the N. meningitidis pathogenesis and give the potential to develop new therapeutics.