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Human-like immune responses in CD46 transgenic mice
Linda Johansson1, Anne Rytkönen, Hong Wan
1Department of Infectious Diseases, Centre for Molecular Microbiology and Infection, Imperial College, London, United Kingdom.
Abstract:
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.
Insights
Mice expressing human CD46 show immune responses similar to humans when infected with Neisseria meningitidis. This CD46 model reveals key innate immune system links crucial for understanding meningococcal disease.
Area of Science:
- Immunology
- Microbiology
- Genetics
Background:
- Neisseria meningitidis causes sepsis and meningitis, primarily in humans.
- Mice engineered to express human CD46 (CD46 transgenic mice) become susceptible to meningococcal disease.
Purpose of the Study:
- To investigate early immune responses in CD46 transgenic mice infected with Neisseria meningitidis.
- To elucidate the role of CD46 in susceptibility to meningococcal disease and its impact on the innate immune system.
Main Methods:
- Comparison of immune responses (cytokine stimulation, bacterial clearance, immune cell counts) between CD46 transgenic and nontransgenic mice.
- Evaluation of responses using both wild-type and LPS-deficient Neisseria meningitidis.
Main Results:
- CD46 transgenic mice exhibited stronger TNF, IL-6, and IL-10 stimulation, mirroring human responses.
- Delayed bacterial clearance and reduced neutrophil counts were observed in CD46 transgenic mice.
- Increased activated microglia and cyclooxygenase-2 in the brain, and elevated peritoneal macrophages were noted in CD46 transgenic mice.
- LPS-deficient meningococci significantly impaired or abolished most observed immune responses.
Conclusions:
- CD46 transgenic mice serve as a valuable model for human meningococcal disease, recapitulating key aspects of the human immune response.
- The study highlights significant roles for CD46 and lipopolysaccharide (LPS) in the early innate immune response to Neisseria meningitidis infection.
