Plasmodium species, the etiologic agents of malaria, kill nearly 1 million people annually. They initially infect the liver as sporozoites, then they replicate as liver stages within hepatocytes to generate exoerythrocytic merozoites that initiate symptomatic blood stage infection. These preerythrocytic stages of infection are clinically silent and were thought to not provoke a significant innate immune response. Yet, recent findings from our group and collaborators have shown that preerythrocytic stages induce a pronounced innate immune response in the liver. The mechanisms by which these complex parasites induce an innate immune response and the downstream effects of these responses on parasite infection remain poorly defined. Understanding the innate immune response to this eukaryotic, intracellular pathogen is important in its own right but also a critical missing piece in the puzzl to understand the development of sterilizing adaptive immunity engendered by whole parasite immunizations. Therefore, we propose to identify which innate immune responses are activated by wild-type and attenuated Plasmodium preerythrocytic parasites and to determine how these innate immune responses influence protective adaptive immune responses. Using gene expression analysis and functional assays, we have shown that liver stage infection induces an innate immune response mediated by type I and type II interferon (IFN) signaling pathways. We have also shown that lymphocytes infiltrate the liver within days following infection and that this infiltration is strongly dependent on type I IFN (IFN-1) signaling. Furthermore, this innate response reduces the initial infection. These results indicate a link between IFN-1, lymphocyte recruitment, and subsequent innate parasite elimination. Our preliminary data also shows that this IFN-1 driven innate response shapes the adaptive immune response that is engendered by whole parasite immunizations. This we demonstrate with mice deficient in key IFN-1 signaling molecules, which surprisingly, are better protected by whole parasite immunizations. In this proposal, we intend to further delineate the generation and consequences of an IFN-mediated innate immune response to Plasmodium liver infection.
In Aim 1 we will identify the host-parasite interactions that initiate this IFN-mediated innate immune response and identify the cell types in the liver that respond to IFN.
In Aim 2 we will characterize cell-specific responses withi the liver following infection and identify cytokine and chemokine receptors that are necessary for innate lymphocyte infiltration. Additionally, we will evaluate the cellular mechanisms by which these innate cells eliminate liver stage parasites. Finally, in Aim 3, we will investigate how IFN-1-mediated signaling influences the development of adaptive immune responses engendered by whole parasite immunizations. Understanding the nature of the early innate immune response will reveal how a complex eukaryotic parasite engages early host immune defenses. Equally important, it will also identify innate molecular pathways to target for improvement of adaptive immune responses after vaccination that aims to protect against malaria infection.

Public Health Relevance

Malaria remains a devastating disease with global impact and an effective vaccine to prevent malaria is urgently needed. Immunizations with whole attenuated parasites that target the liver stage of development are effective at preventing subsequent infection, however the innate immune responses generated to parasites at this stage of infection remain unknown. This proposal seeks to identify and delineate the innate immune responses generated against malaria parasite liver stage infection, and will assess how these innate responses shape the adaptive immune response during whole parasite immunization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
6R01AI114699-05
Application #
9590595
Study Section
Immunity and Host Defense (IHD)
Program Officer
MO, Annie X Y
Project Start
2014-11-01
Project End
2019-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98101
Arredondo, Silvia A; Kappe, Stefan H I (2017) The s48/45 six-cysteine proteins: mediators of interaction throughout the Plasmodium life cycle. Int J Parasitol 47:409-423