The impact of type 2 immunity on haematopoiesis and consequences for host immune function

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Our bone marrow constantly produces new immune cells to fight against infection. These originate from blood stem cells called haematopoietic stem cells (HSC). HSCs can respond to chemical signals (cytokines) that are produced following infection and this stimulates increased production of immune cells to kill the pathogen. This is beneficial against acute infections like certain bacteria and viruses but can also cause tissue damage in long-lasting diseases. Our research is focused on understanding how we respond to a class of pathogen that represent a very different challenge to our immune system - parasitic worms (helminths). Helminth parasites are much larger than bacteria and viruses and so are controlled by a different type of immune response (type 2 immunity). Type 2 immune responses also cause allergic disease. Around one quarter of the global population are infected with a helminth and these are extremely long-lived infections as the parasite can survive for years or even decades in an infected person. We are researching parasitic worms called which causes the disease schistosomiasis. More than 200 million people are infected with schistosomes and at least 800M people are at risk of infection, mostly in sub-Saharan Africa. There is no vaccine to this infection and treatment relies on a single drug (praziquantel) that does not stop people becoming immediately reinfected. Schistosomes are well known for their ability to manipulate our immune system and this allows them to turn-off immune responses that could otherwise kill them. This has spill over effects on other immune responses and these infections have been shown to reduce our response to other infections and even to vaccines. We have found that one way schistosomes can do this is by altering immune cell development in the bone marrow. We have little understanding of how the type 2 immune responses induced by parasitic worms alters bone marrow cells such as HSCs. Importantly, these changes caused by infection seem to even persist after the parasite is killed by drugs. This means that people who have been successfully cured of their worm infection may still respond to other infections or vaccines in a different or less robust manner to people who have never been infected. To better understand this, we will study how schistosome infection alters HSCs and immune cell function in both laboratory mice and by using blood cells from naturally infected people. We will test how infection alters immune cells, how long these effects persist for after parasite clearance, and how these changes alter immune responses to both the worm itself and also vaccines. This research will reveal how changes to bone marrow cells in schistosome infection broadly alter how our immune system functions and is an essential first step in understanding how we can reverse these changes. This has obvious importance for ongoing vaccine programmes against many different diseases, especially as weaker responses could potentially allow pathogens to mutate and becoming resistant to these vaccines.