Inbred mice have been instrumental in biomedical research. Essentially clones of one another, they can offer researchers low variability between animals, increasing the power of their studies. Genetic diversity is not necessarily a bad thing though—it can help increase the predictive value of the models for human disease—but until recently it was challenging to control. The development of Collaborative Cross mice, in which multiple lines derived from both inbred and wild-type animals are interbred without losing track of their genotypes, is reintroducing genetic diversity in a controlled manner.

Collaborative Cross mouse lines are important tools in on-going immunogenetics project at the Fred Hutchinson Cancer Research Center to screen for emerging or extreme phenotypes prompted by different viral infections. As part of this effort, researchers working with West Nile Virus have identified a novel phenotype that models chronic infection (PLoS Pathog. 12, e1005996; 2016).

Most immunological work with West Nile Virus has been conducted in C57BL/6J inbred mice. Though infection in these mice is well characterized for acute symptoms, lead author Jessica Graham comments, “at the same time, there's a wide variety of symptoms and outcomes in humans that simply are not being observed in just one inbred strain,” a common problem in classic models. Testing several Collaborative Cross mouse lines, the researchers identified a line in which viral RNA would persist, often with minimal symptoms, in the brain for several months. Looking more closely at immune responses in this model of chronic infection, the team observed changes in Regulatory T cells, responsible “for maintaining that balance of trying to clear the pathogen without doing too much damage and destroying neural tissue that can't be regenerated.” In the chronic model, these cells appear to suppress immune responses enough that the virus can manage to linger on. Because the mice used have been genotyped, future work will look for potential genetic underpinnings as well as parallels to human infections.

The chronic infection discovered using this model is one example of multiple emerging phenotypes identified by the larger screening work, the results of which the researchers hope to share with the immunology community; the data itself is being uploaded to the NIH ImmPORT resource. Rather than having to undertake their own intensive (and expensive) screens, Graham explains, researchers looking for a particular phenotype can take advantage of the database to identify a smaller number of potential lines for testing with their own infectious diseases. All against a diverse but documented genotype, thanks to the Collaborative Cross.