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Human-Like Immune Responses in CD46 Transgenic Mice¹

Linda Johansson^2,, Anne Rytkönen^2,*, Hong Wan^¶, Peter Bergman, Laura Plant^¶, Birgitta Agerberth, Tomas Hökfelt and Ann-Beth Jonsson^3,¶

^* Department of Infectious Diseases, Centre for Molecular Microbiology and Infection, Imperial College, London, United Kingdom; Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital, and Departments of Medical Biochemistry and Biophysics and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; and ^¶ Department of Medical Biochemistry and Microbiology, Uppsala University, Biomedical Center, Uppsala, Sweden

Neisseria meningitidis is a major cause of sepsis and/or meningitis. These bacteria normally cause disease only in humans, however, mice expressing human CD46 are susceptible to meningococcal disease. To explain the sensitivity of CD46 transgenic mice to meningococci, we evaluated early immune responses. Stimulation of TNF, IL-6, and IL-10 was stronger in CD46 transgenic mice compared with nontransgenic mice, and resembled human responses. In CD46 transgenic mice, bacterial clearance in blood started at later time points, and neutrophil numbers in blood were lower compared with nontransgenic mice. Further, elevated levels of activated microglia cells and cyclooxygenase-2 were observed in brain of infected CD46 transgenic mice. Intraperitoneal administration of meningococci lead to increased levels of macrophages only in the i.p. cavity of CD46 transgenic mice. Most of the responses were impaired or absent using LPS-deficient meningococci, showing the importance of LPS in the early immune response to meningococcal infection. Taken together, these data demonstrate that responses in mice expressing human CD46 mimic human meningococcal disease in many aspects, and demonstrate novel important links between CD46 and the innate immune system.

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