Immunomodulation of vaccine-induced CD8+ T cell responses through early life exposure to chronic maternal schistosomiasis

• Applicant: Professorin Dr. Clarissa Prazeres da Costa
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440551290

With 221 million infected people worldwide, schistosomiasis is one of the most common infectious diseases in LMIC (low and middle income countries) alongside malaria, and the transmission of the pathogen by water contact has significantly hampered previous measures to combat the disease. An estimated 40 million women are infected during pregnancy and maternal infection - in addition to low birth weight and anemia - has been associated with changes in allergic phenotypes (e.g. eczema) of offspring. In fact, we have been able to show in the mouse model that offspring of infected female mice are protected from allergic airway inflammation (AAI) and retain this altered immunophenotype into adulthood. However, recent preliminary work shows that the changes in these offspring go beyond modified AAI and are not limited to CD4+ T cell responses. Different vaccination models showed marked differences in the reactivity of CD8+ T-cells: modern vaccines based on viral vectors (MVA) may have a decisive advantage over classically adjuvanted vaccines in these offspring. The former play an increasingly important role for an effective and protective immunity against viruses but also against protozoa such as plasmodia, the malaria pathogen, which may be central in view of the coendemicity with helminth diseases in the respective countries. Because this modified immunological phenotype persists into adulthood, we suspect that "immunological training" in utero is influenced by infection-related maternal inflammatory status. The main factors may be the induction of modified regulatory networks, which ultimately inhibit the ability of antigen-presenting cells to effectively prime CD8+ T-cells by classical, for example alum-based vaccines in offspring, but which can be overcome by modern vector-based vaccines. In order to further clarify the mechanisms involved in this process, we will use different vaccine models to differentiate changes in phenotype and functionality of antigen-presenting cells as a central switch point in the induction and regulation of CD8+ T-cell priming as compared to CD8+ T cell intrinsic developmental and reactivity changes e.g. by transcriptome, subpopulation frequency and stimulation analysis. The results of these investigations will make an important contribution to the understanding of the interplay between maternal inflammatory status and the development of the child's immune system and ultimately to the development of adapted vaccination strategies in helminth-endemic areas.

• DFG Programme: Research Grants