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Zawartość zarchiwizowana w dniu 2024-06-16

Cues for parasitic nematode development: immunology meets evolutionary biology

Final Activity Report Summary - FILDEV (Cues for parasitic nematode development: immunology meets evolutionary biology)

Parasitic nematodes infect over a third of the world's population with filarial nematodes, causing debilitating diseases such as river blindness and elephantiasis for an estimated 120 million people worldwide. Though drug treatment is available, there is so far no preventive treatment that confers long-term protection to the one billion people living in endemic areas.

A fascinating feature of free-living nematodes is their ability to alter their development according to environmental cues. This is best characterised by the arrested development of caenorhabditis elegans in response to starvation or overcrowding, and the regulation of the resistant 'dauer' stage under the control of genes daf-9 and daf-12. Parasitic nematodes are known to similarly respond to their own environment, namely the host. For example, haemonchus contortus, a gastrointestinal nematode of sheep, will arrest its development in the host until the onset of the rainy season. Data from murine models of schistosomiasis suggest that developmental cues can be immunological since schistosomes require specific host immune cells to develop properly. Our previous studies suggested that nematodes may be able to do the same.

This fellowship took a more multidisciplinary approach to filariasis than any previous study by combining immuno-parasitology, genomics and evolutionary biology to ask specific questions about the host-parasite interface. This was only now possible as we had an ideal experimental model of filariasis to address these questions successfully, namely litomosoides sigmodontis. To explore both the mechanisms and evolutionary implications of these host-parasite interactions, two objectives were outlined.

It was firstly aimed to determine how filarial parasites altered their developmental pathways in the face of an immunological challenge. We determined that filarial nematodes were able to detect and respond to immunological cues provided by their host. We identified which component of the immune system was responsible and how filarial nematodes altered their developmental pathways in the face of immunological challenges. Indeed, our data showed that when faced with a stronger immune response infective larvae accelerated their development. This was intriguing, as one would expect the immune response to stunt the larvae.

Moreover, we identified the element of the immune response that the larvae responded to, which was a major factor involved in their killing, namely the polynuclear eosinophil. We determined that the simultaneous injection of infective larvae and the cytokine that regulated the activation and recruitment of eosinophils, IL-5, induced a more rapid larval growth only when eosinophils could be recruited to the site of infection. Interestingly, eosinophils and IL-5 were essential for vaccine-induced protection and for resolution of a primary infection.

We secondly aimed to determine whether accelerated development was an evolutionary trade-off allowing the parasite to reach patency in the face of an anti-worm immune response, and if so, if it had an evolutionary cost. The ability of filarial nematodes to react to the presence of a major element of their hosts' attacks spurred us to ask whether this ability was a result of their adaptation to their host which gave them a better chance of reproducing in the face of a strong immune response. As an indicator of their fitness, we let the infection run its full course and measured the timing and quantity of their offspring in the blood of their hosts throughout patency.

We found that, indeed, filariae that encountered more IL-5 and eosinophils were able to produce microfilariae earlier. However, we still had little evidence of any cost that a faster development may incur, which led us to envisage other hypotheses, e.g. that eosinophils could provide optimal conditions for filarial development. Our findings could therefore have important implications for the pursuit of a vaccine against filariasis.