Scientists working out of Trinity College Dublin, Maynooth University, and Queen Mary University of London have unearthed a potential new preventative option to combat Ascaris roundworm infection. Ascaris lumbricoides is an intestinal parasite that results in severe health consequences, including growth retardation and impaired cognitive development. The infection, which affects an estimated one billion people worldwide, is particularly common in Third World countries and is estimated to be responsible for 60,000 deaths per annum.
Ascaris infection is treatable, but individuals who have overcome the infection naturally -- or with the help of drugs -- do not develop resistance and can be easily re-infected. Susceptibility to Ascaris infection differs between individuals but heavily infected individuals have more severe symptoms and higher morbidity. Therefore, understanding host resistance could lead to the development of better ways to prevent and treat Ascaris infection.
Based on prior work, scientists from Maynooth University, Trinity, and Queen Mary University used a proteomics approach to study the differences between two different mouse strains. They have just published their findings in the international journal, PLOS NTDs.
Mice can be infected with Ascaris eggs, but unlike humans or pigs, they do not support the full life cycle of the parasite (ingested egg to larva to adult which produces a new round of eggs, which leave the host with the feces and start the life cycle again). Ingested Ascaris eggs in mice do hatch and, as larvae, start their normal migration to the liver and lungs, where the larvae do develop further to adults.
Professor of Zoology in the School of Natural Sciences at Trinity, Celia Holland, has spent over a decade developing this mouse model to study Ascaris infection and has previously demonstrated that susceptible mice have more than ten-fold higher larval numbers in the lungs than resistant ones. The difference in susceptibility between the two strains, however, is first visible in the liver of infected mice.
Following infection with identical numbers of Ascaris eggs, mice from the resistant strain show an earlier inflammatory immune response coupled with more rapid tissue repair in the liver compared with susceptible mice. The researchers therefore set out to investigate the differences in the liver proteomes (via a broad analysis of liver proteins) of both uninfected control mice and infected mice, for each strain.
Professor Holland said: “By focusing on the liver we aimed to target the metaphorical front line in this particular host-parasite interaction.”
The proteomic study was conducted in collaboration with former Trinity graduate Dr Jim Carolan, now of Maynooth University, and Dr Joe Colgan (QMU London) utilising the core facilities of the MU Biological Mass Spectrometry Unit including the Science Foundation Ireland-funded ThermoFisher QExactive high resolution mass spectrometer.
The researchers identified and quantified thousands of proteins from highly complex samples and found that hundreds of liver proteins differed substantially between the two strains, even without Ascaris infection. The resistant strain showed generally higher levels of proteins involved in the generation of reactive oxygen species (ROS). Ascaris infection increased the levels of these proteins in both strains, supporting their role in the defense against the parasite and suggesting that resistant mice have a better defense at the earliest stages of infection.
Other proteins were seen only in infected mice; these included proteins involved in a part of the immune response. Two of these proteins were absent from both strains before infection but among the highest expressed proteins in both strains following infection. Interestingly, proteins involved in translation were of lower abundance in all infected mice livers, which suggests either a broad response in the host to the presence of Ascaris or a specific targeting of the protein synthesis machinery by the parasite itself.
Lead author Gwen Deslyper said: “Given our findings and the central role of the liver in the Ascaris migratory pathway, we suggest a potentially novel research direction to develop alternative preventative control strategies for Ascaris. It seems that the key determinant in murine resistance to Ascaris may lie in highly oxidative conditions that presumably restricts and arrests successful larval migration within the hepatic environment – at least of the resistant strain. By manipulating the hepatic ROS levels in the susceptible mouse strain we hope to determine the importance of intrinsic ROS in conferring resistance to Ascaris.”
Professor Holland added: “Significant research is now required to fully understand the determinants of resistance to Ascaris in the murine model, but the findings seem to have at least presented new options in the pursuit of strategies to control a disease that affects around one eighth of our planet’s population.”
The article can be viewed at http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004837.