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Publications of the Week

Innate Immunity Limits Protective Adaptive Immune Responses against Pre-Erythrocytic Malaria Parasites

By September 19, 2019No Comments

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This week we profile a recent publication in Nature Communications from the laboratory of
Dr. Stefan Kappe (pictured) at Seattle Children’s Research Institute and UW.

Can you provide a brief overview of your lab’s current research focus?

My laboratory studies the complex biology of malaria parasites and the immune responses generated after infection. This is critical to the design novel interventions that will help eradicate this deadly global infectious disease, which sickens 200 million people and kills 400,000 people every year. Malaria infection in the host starts when mosquito-transmitted parasite stages enter the skin and migrate to the liver, where they infect hepatocytes. Here, the parasite multiplies asymptomatically and then moves on to infect red blood cells, where cyclical invasion and destruction of these cells leads to malaria-associated disease and death. Interventions that block the complete development of the asymptomatic stages will prevent symptomatic blood stage infection and onward transmission. An attractive way to block the development of the skin and liver stages is to immunize hosts with experimental vaccines that target these stages. We have pioneered the use of live, genetically attenuated malaria parasites that can infect and develop in the liver but are unable to cause blood stage infection, as a novel vaccine regimen. These vaccine types confer high levels of protection in animal models and also humans.

What is the significance of the findings in this publication?

While these experimental vaccines provide great protection against malaria infection, their further improvement requires a detailed understanding of the immune responses generated by them. We had previously shown that the body’s first line of defense, innate immunity, is turned on during the asymptomatic liver stage of infection and also during vaccination with live-attenuated parasites. However, whether this innate immune response helps to educate the adaptive immune response that protects from malaria infection after vaccination was not known. Given that adjuvants that boost innate immunity have been used to increase vaccine efficacy in other systems, we expected that this liver stage innate immune response would be necessary for optimal vaccine efficacy. To address this, a scientist in my group, Dr. Nana Minkah, examined vaccine efficacy in immunized mice in the presence or absence of competent innate immunity. To our great surprise, immunized mice lacking the ability to induce innate immune responses were better protected against malaria. Moreover, these mice generated greater numbers of protective T cells and exhibited evidence of higher qualitative T cell responses. Thus, to generate an even more highly efficacious malaria vaccine, it would be advantageous to dampen the innate immune response during vaccination.

What are the next steps for this research? 

This study was carried out in a murine model of malaria vaccination and so we aim to examine whether a similar observation of detrimental roles for innate immunity in vaccine efficacy exists in human subjects receiving experimental malaria vaccines. We also only studied a few specific markers of memory T cell quality and therefore, in subsequent studies we aim to identify the extent to which CD8 T cell memory is compromised by Plasmodium engendered innate immunity. Lastly, we will determine what is truly distinctive about the Plasmodium-engendered innate immune response that leads to sub-optimal vaccine efficacy. We are especially interested in the different cell types recruited to the liver and activated in the presence or absence of competent innate immunity. The long-term hope is to use the information generated from these studies to make a great vaccine even better!

This work was funded by:

This work was funded by the US National Institutes of health grant 1 R01AI114699-01.


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