image: Ascaris larva is in liver histological section stained with Hemotoxylin and Eosin. view more
Credit: C. Dold and C. Holland
Approximately one billion people worldwide are estimated to be infected with the roundworm Ascaris lumbricoides, an intestinal parasite of humans. Some of them, especially children who carry high parasite loads, suffer from severe health consequences, including growth retardation and impaired cognitive development. A study published in PLOS NTDs examines the difference between mice that are susceptible to Ascaris infection and those that are resistant.
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. That said, there is evidence that susceptibility to Ascaris infection differs between individuals and heavily infected individuals have more severe symptoms. The same appears to be true for infection in pigs with a close relative of A. lumbricoides called A. suum. Understanding host resistance could lead to the development of better ways to prevent and treat Ascaris infection, but neither humans nor pigs are the most suitable participants in such studies.
Based on earlier work, which showed a difference in susceptibility to A. suum between two different mouse strains, Jim Carolan, from Maynooth University, Ireland, Celia Holland, from Trinity College Dublin, Ireland and, and colleagues decided to use a proteomics approach to study the differences between the two strains. Mice can be infected with Ascaris eggs, but unlike human or pig hosts, 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, but the larvae do develop further to adults.
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 A. suum eggs, mice from the resistant strain show an earlier inflammatory immune response coupled with a more rapid tissue repair in the liver compared with susceptible mice. The researchers therefore set out to investigate the differences in the liver proteomes (i.e., a broad analysis of liver proteins) of both uninfected control mice and mice infected with A. suum for each strain.
They used high throughput quantitative mass spectrometry, which can identify and quantify thousands of proteins from highly complex samples and found that hundreds of liver proteins differed substantially between the two strains, even without Ascaris infection. For example, 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 called the complement system. Two of these proteins were absent from both strains before infection but among the highest expressed proteins in both strains following infection, supporting a role of the complement system in the defense against Ascaris larvae, but probably not one that distinguishes the two strains. Proteins involved in translation were less abundant in livers of infected mice from both strains compared with uninfected mice, 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.
"Given our findings and the central role of the liver in the Ascaris migratory pathway", the researchers say, "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 [of the resistant strain]". "Through the manipulation of hepatic ROS levels in the susceptible mouse strain", they hope to "determine the importance of intrinsic ROS in conferring resistance to Ascaris".
They conclude that "although significant research is required to fully understand the determinants of resistance to Ascaris in our murine model, it does seem that we have at least been presented with new options in our pursuit of strategies to control a disease that affects an estimated one eighth of our planet's population".
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Journal
PLoS Neglected Tropical Diseases