Evaluating the impact of pre-existing humoral immunity on hepatocyte death

SUMMARY Malaria remains a critical global health concern, with increasing deaths world-wide since 2020, now estimated at greater than half a million individuals. A complex network of interactions between the parasite, infected cell, and host immune system dictates success or failure for the Plasmodium parasite, and major efforts have sought to interrogate the mechanisms of host-parasite interactions that underlie infection and immunity. Unfortunately, most studies of host-parasite interactions occur in a laboratory vacuum, disconnected from the reality of re-infections in the field. Over the last two decades, several high-profile vaccine candidates have shown great promise in pre-clinical development and have achieved high levels of sterilizing immunity in human clinical trials in malaria naïve western populations. However, as candidates advance to field trials, where subjects have prior exposure to malaria, trials have achieved dramatically reduced sterilizing efficacy, or no efficacy at all. In this proposal, we explore the possibility that preexisting immunity to malaria alters the Plasmodium-host interactions in a way that dampens inflammatory responses and curtails subsequent immunity. This work is based on two novel findings that might explain the apparent disconnect between protection in malaria-naïve westerners and malaria-exposed populations. We have demonstrated that (1) live parasites vaccines elicit decreased protection in apoptosis-component mice when compared to mice without the capacity for hepatocyte apoptosis and (2) that exposure to non-neutralizing antibodies, which bind the parasite but do not alter infection, lead to elevated levels of apoptosis in Plasmodium-infected hepatocytes. In this proposal, we will test the hypothesis that non-neutralizing antibodies that bind Plasmodium sporozoites promote hepatocyte apoptosis and subsequently decrease protective immunity. We will test this hypothesis in two independent, but complementary aims. The first aim will evaluate infected hepatocyte signaling and the promotion and prevention of hepatocyte death in the presence of a panel of non-neutralizing antibodies. In the second aim, we will evaluate how the presence of nnAbs, in the presence or absence of hepatocyte apoptosis, alters parasite immunogenicity and immunity. Taken together, our work, if substantiated, could explain why robust sterilizing protection is difficult to achieve in malaria-endemic areas where pre-existing immunity exists.