Vaccine signatures in humanized mice indicate better understanding of infectious diseases

Infectious diseases kill millions of people each year, but the search for treatments is hindered by the fact that lab mice are not susceptible to certain human viruses, including killers such as the human immunodeficiency virus (HIV). For decades, researchers have turned to mice whose immune systems have been "humanized" to react in the same way as humans.

At present, a team at Princeton University has developed a comprehensive way to assess the extent to which the immune responses of humanized mice compare to those of humans. The research team examined the immune responses of both mice and humans to one of the most potent vaccines known, a yellow fever vaccine called YFV-17D. The comparison of these "vaccine signatures" showed that a newly developed humanized mouse developed at Princeton shares a significant immune system response with humans. The study was published in the journal Nature Communications.

"Understanding immune responses to human pathogens and potential vaccines remains difficult because of differences in the way our human immune system responds to stimuli, for example, in mice, rats, or other conventional animals, for example. said Alexander Ploss, associate professor of biology at Princeton University. "Until now, there was a lack of a rigorous method to test the functionality of the human immune system in such a model.Our study highlights an experimental paradigm to fill this gap."

Humanized mice have been used in infectious disease research since the late 1980s. Yet, without rigorous comparison, researchers do not know how mice accurately predict human responses, such as the production of anti-infectious cells and d & # 39; antibodies.

To address this problem, the researchers exposed the mice to the YFV-17D vaccine, made from a weakened or attenuated yellow fever virus. Vaccines protect against future infections by causing the production of antibodies and immune system cells.

In earlier work, researchers explored the effect of YFV-17D on classical humanized mice. But the researchers found that mice responded only weakly. This led them to develop a mouse with responses more similar to those of humans.

To do this, researchers have introduced additional human genes for components of the immune system, such as molecules that detect foreign invaders and chemical messengers called cytokines, so that the complexity of the human immune system grafted reflects that of the immune system. 39; man. They found that the new mice had YFV-17D responses very similar to those observed in humans. For example, the pattern of gene expression that occurs in response to YFV-17D in mice shared significant similarities with that of humans. This pattern of expression of the signature genes, reflected in the "transcriptome" or the total reading of all genes in the body, has resulted in better control of infection by yellow fever virus and immune responses more specific to yellow fever.

"Many vaccines have been generated empirically without a thorough knowledge of how they induce immunity," Douam said. "The next generation of mouse models, such as the one we introduced in our study, offers unprecedented opportunities to study the fundamental mechanisms that define the protective immunity induced by live attenuation vaccines."

Mice carrying human cells or human tissue can help in research on the treatment of many diseases that infect humans but not other animals, such as, in addition to HIV, the Epstein Barr virus, the human T-cell leukemia and sarcoma associated herpes virus.

"Our study highlights the importance of human biological signatures in guiding the development of mouse models of disease," Ploss said. "It also highlights the way forward to develop better models for human immune responses."

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More information:
Florian Douam et al., Selective expansion of myeloid cells and NK in humanized mice gives vaccine responses similar to those of man. Nature Communications (2018). DOI: 10.1038 / s41467-018-07478-2