Scientists recently found two genes that make certain mice susceptible to methicillin-resistant Staphylococcus aureus (MRSA) infections. The NIAID-funded research, which was led by Vance Fowler, M.D., M.H.S., of Duke University, was published in the journal PLoS Pathogens in September 2010.
S. aureus is one of the most common causes of bacterial infection in the world, resulting in roughly 292,000 hospitalizations annually in the United States. It has been known for some time that genetic factors are important in determining susceptibility to S. aureus infection, but the specific genes involved are so far largely unknown. MRSA, which is actually resistant to a wide variety of antibiotics, is most often acquired in community or healthcare settings and usually causes a skin infection.
The study suggests a new approach to treating S. aureus infection. “Currently, we develop drugs to weaken or kill the bacteria or other pathogen. This study opens up the idea of host-directed treatment, in which the treatment has the potential to strengthen the host against the bacteria,” says NIAID Project Officer Clayton Huntley, Ph.D. With the rise in S. aureus strains that are resistant to available antibiotics, such as MRSA, research into new treatment possibilities is especially timely.
Although the research took place in mice, it provides scientists with clues as to what happens in the human genome. This is especially true in this case because the two genes that were found have direct counterparts in humans.
Using a mouse model can be an efficient way of investigating these questions, for many reasons: mice breed abundantly and quickly, with short gestation periods. Genetic sequencing data is also available for a number of different laboratory strains. “For research in general immunology,” explains Dr. Huntley, “mice are quite useful; they’re the best animal model we have.”
Previous research found that among laboratory mouse strains, the strain A/J was highly susceptible to infection by S. aureus, while the strain C57BL/6J was not. The researchers compared the two strains to learn more about which genes contribute to S. aureus susceptibility.
Researchers used a multi-step process to find the two genes. Starting with the whole genome, they used chromosome substitution strains (CSS) of mice, which were genetically engineered so that each strain had one chromosome pair from the susceptible A/J genome and the remaining 19 from the C57BL/6J genome. By measuring susceptibility of each CSS to S. aureus, the researchers found that mice that contained A/J chromosomes 8, 11, or 18 were significantly more susceptible than the other CSS strains. About 4,200 genes are located on these three chromosomes.
The researchers then challenged the mice with S. aureus and compared gene expression of the two strains. This yielded 191 genes that were differentially expressed between the strains. Focusing their search on chromosome 18 for this study, they then found two relevant quantitative trait loci (QTL), or stretches of DNA found to be closely linked to the trait in question. Ten genes were contained in these two QTLs. By analyzing the expression of proteins called cytokines after exposure to S. aureus, they found that two of those ten genes, Tnfaip8 and Seh1, appear to influence susceptibility to infection.
As a next step, the researchers measured bacterial burden in the two strains and found a correlation to S. aureus susceptibility. This suggests that the genes involved in susceptibility are associated with a relative inability to control infection.
“One really interesting thing about this study is the [set of] genetic tools used, particularly the CSS strains,” says Dr. Fowler. “Having the background of available CSS strains being susceptible and inbred strains being resistant was a lucky break,” he adds.
However, the study had some limitations. For example, because not all genes act independently of one another, there may be additional genes that contribute to S. aureus susceptibility only in conjunction with others. Also, because the researchers’ strategy used levels of RNA – not protein – to measure gene expression, their approach could miss any genes that affect protein accumulation or modulate the expression of other genes.
Future directions of research include exploring additional genes on chromosome 18, as well as those on chromosomes 8 and 11. “Ultimately, the importance of the identified candidate genes or their human homologs will need to be evaluated in patients with S. aureus infections,” the authors write. Funded by the same NIH grant, Fowler and his team are aiming to do just that. They have just conducted a genome-wide association study of humans with S. aureus bacteremia in order to determine if the genes found to be associated with susceptibility in mice are also identified in the human cohort.
Ahn S-H, Deshmukh H, Johnson N, Cowell LG, Rude TH, Scott WK, Nelson CL, Zaas AK, Marchuk DA, Keum S, Lamlertthon S, Sharma-Kuinkel BK, Sempowski GD, Fowler VG. Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and quantitative trait locus (QTL) analyses. PLoS Pathogens. 2010.
Last Updated October 12, 2011