Research Group:	Institute of Immunology
Address:	Freie Universität Berlin, Centre for Infection Medicine, Robert-von-Ostertag-Str. 7-13, 14163 Berlin
Supervisors:	Jun.-Prof. Dr. Friederike Ebner
Doctoral Researcher:	Larissa Oser, Robert Mugo

Project Description 

State of the art:

Domestic pigs are commonly infected with more than one species of helminth parasites. Ascaris suum infections are economically relevant and highly prevalent in intensive pig production systems worldwide. The distribution of Ascaris in swine and human populations is typically overdispersed, meaning, a few individuals harbor the majority of Ascaris worms. In addition, individual hosts appear predisposed to low or high worm burdens. In this context, we aim to study the pig as an outbred host system for Ascaris infections to decipher the role of highly specific, parasite-recognizing T cells on differences in host susceptibility. Parasite-specific T cells are a very rare population of effector T cells that specifically recognizes parasite antigens and orchestrates adaptive immune reactions to control parasite burden. Thus, from all the causal players that might contribute to heterogeneity in Ascaris worm burden such as variability in exposure, host immunity or host and worm genetics, we will concentrate on i) initiation, ii) perpetuation and iii) recall mechanisms of adaptive immune responses on the level of parasite-specific T cells.

Previous own work:

Antigen-specific, CD4⁺ effector T cells orchestrate defense or tolerance against pathogens, but are a very rare population within the larger effector T cell pool and have been, for long time, inaccessible to be studied due to technical limitations. Recently, we have adapted an activation marker (CD40L) from human research that allows us to directly detect rare, pathogen-recognizing T cells in the pig as the natural host for Ascaris parasites and have now developed a magnetic enrichment method that enables us for the first time to follow up parasite-specific T cell responses directly in vivo. We have also contributed to unravel distinct populations of differentiated T helper cells in swine. Because antigen-specificity now allows us to separate T cells recognizing Ascaris from those that recognize other, co-infecting parasites, we can address parasite-specific responses and their interplay within one host at the same time.

Hypotheses and work plan:

1) Heterogeneities in Ascaris infection rates are directly linked to induction, expansion, phenotype and function of parasite-specific CD4⁺ T cells.

2) Individual predisposition is reflected by the ability of the host to generate specific memory and to mount effective, parasite-specific recall responses.

Domestic pigs will be experimentally infected with either single doses of Ascaris suum or trickle inoculations to study helminth-specific CD4⁺ T cells -their induction, expansion, functional heterogeneity and migratory behavior- during larval development until chronic persistence. To decipher whether the host`s disability to generate specific T cell memory is causal for predisposition, we will clear the infection during chronicity and monitor kinetics of circulating, parasite-specific memory T cells before challenging and monitoring individual recall responses and re-infection rates. In parallel, we will sample a pig population from intensive indoor production to assess our findings from experimental to natural infection. Considering that pigs are commonly co-infected with various helminth parasites, we will study species-specific T cell responses in helminth-helminth co-infected hosts to understand the dynamics and helminth-specific differences of acquired immunity.