Abstract
ABSTRACTStudying infectious diseases requires suitable hosts for experimental in vivo infections. Recent years have seen the advent of many alternatives to murine infection models. However, the use of non-mammalian models is still controversial because it is often unclear how well findings from these systems predict virulence potential in humans or other mammals. Here, we compare the commonly used models, fruit fly and mouse (representing invertebrate and mammalian hosts), for their similarities and degree of correlation upon infection with a library of mutants of an important fungal pathogen, the yeast Candida glabrata. Using two indices, for fly survival time and for mouse fungal burden in specific organs, we show a good agreement between the models. We provide a suitable predictive model for estimating the virulence potential of C. glabrata mutants in the mouse from fly survival data. As examples, we found cell wall integrity mutants attenuated in flies, and mutants of a MAP kinase pathway had defective virulence in flies and reduced relative pathogen fitness in mice. In addition, mutants with strongly reduced in vitro growth generally, but not always, had reduced virulence in flies. Overall, we demonstrate that surveying Drosophila survival after infection is a suitable model to predict the outcome of murine infections, especially for severely attenuated C. glabrata mutants. Pre-screening of mutants in an invertebrate Drosophila model can, thus, provide a good estimate of the probability of finding a strain with reduced microbial burden in the mouse host.
Highlights
The selection of suitable models is crucial in infection biology research
To compare the Drosophila melanogaster and Mus musculus microbial infection models, we used a recently created large-scale library of C. glabrata gene-deletion mutants, enriched for processes that are likely to be involved in pathogenesis or transcriptional regulation (Schwarzmüller et al, 2014)
416 individual C. glabrata mutants were first tested in D. melanogaster, and 114 strains were selected to be tested in murine pool infections
Summary
Deciding on the right model system for the biological question at hand requires deliberate weighing of many parameters, such as cost, amount of labor involved, throughput rate, degree of similarity to the human host, and ethical considerations. The use of comparatively simple in vitro models when screening for novel antimicrobial drug candidates and investigating putative virulence factors in microbial pathogens is well established. Using a murine model is considered the gold standard for most infections, due to its comparably high similarity to humans in terms of metabolism, body temperature, and immune system functions. For large-scale screening efforts, for example, with libraries of hundreds or thousands of mutants, the benefits of using these systems are evident: they are generally easier to handle and, in contrast to mice, the use of hundreds of flies or worms for infection experiments is considered ethically acceptable
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