25 S. Grand Ave, 1020 ML
University of Iowa
Iowa City, IA 52242
2015 B.S. Microbiology, The University of Alabama, Tuscaloosa, AL
There are no effective, readily deployable vaccines for malaria, a devastating mosquito-borne disease responsible for hundreds of thousands of deaths annually. Vaccine efforts targeting the liver- or blood stages of the causative parasite Plasmodium suffer from either lack of long-term efficacy in endemic areas or field delivery constraints. Anti-malarial drugs may be compromised due to emerging parasite resistance. Additionally, humans repeatedly infected with malaria never develop sterilizing immunity, defined as the ability to control infection at the liver-stage without blood-stage parasitemia. The inability of humans in malaria endemic regions to efficiently develop sterilizing anti-malarial immunity through either vaccination or natural exposure is not understood. We use mouse models to study liver-stage immunity because there are well developed tools to promote discovery, and because the human liver is ethically inaccessible.
After mosquito bite, sporozoites traffic to the liver and infect hepatocytes. During liver-stage malaria, lasting two days in mice and seven in humans, some infected hepatocytes die. Antigen presenting cells (APCs) capture pre-erythrocytic-stage (sporozoite and liver-stage) malaria antigens from dying hepatocytes, migrate to the liver draining lymph nodes (LdLN), and prime protective liver resident memory (Trm) and effector memory (Tem) CD8 T cells in mice. Memory CD8 T cells are also primed in the spleen and skin dLN. Some infected hepatocytes generate erythrocyte-infecting blood-stage merozoites, which are eventually cleared via humoral immunity if the host survives. During subsequent liver infection, infected hepatocytes present pre-erythrocytic-stage antigens via major histocompatibility complex I (MHC-I), allowing memory CD8 T cells to eliminate hepatocytes via cytotoxic effector molecules. High numbers of pre-erythrocytic-stage-specific memory CD8 T cells in vaccinated mice mediate sterilizing immunity to liver-stage malaria. Circulating pre-erythrocytic- stage-specific memory CD8 T cell responses exist in malaria-experienced humans, however, repeated malaria infection does not induce sterilizing immunity.
Whole parasite vaccination is frequently used to study memory CD8 T cell responses. Intravenous (i.v.) or mosquito delivered immunization of humans or mice with radiation attenuated sporozoites (RAS), which cause an abortive liver infection, can induce sterilizing anti-malarial immunity by generating pre-erythrocytic stage-specific non-recirculating liver Trm cells. RAS immunization in mice also primes circulating memory CD8 T cells (Tcirc), including effector Tem and central (Tcm) memory in the blood, spleen, and LdLN. Tcirc cell frequencies correlate with sterilizing immunity in mice. In this regard, my research focuses on (1) memory CD8 T cell contributions to protection against liver-stage malaria and (2) effects of blood-stage malaria infection on memory CD8 T cell biology.
- Lefebvre MN, Harty JT. γδ T cells burst malaria's bubble. Nat Immunol. 2021 Feb 5. doi: 10.1038/s41590-021-00879-4. Epub ahead of print. PMID: 33547458.
- Lefebvre MN and JT Harty. 2020. You Shall Not Pass: Memory CD8 T Cells in Liver-Stage Malaria. Trends in Parasitology. 36(2):147-157. [PubMed]
- Jensen IJ, McGonagill PW, Lefebvre MN, Griffith TS, Harty JT, and Badovinac VP. 2020. Worry and FRET: ROS Production Leads to Fluorochrome Tandem Degradation and impairs Interpretation of Flow Cytometric Results. Immunity. 52(3):419-421. [PubMed]
- Martin MD, Ishizuka AS, Jensen IJ, Lefebvre MN, Harty JT, Seder RA, Badovinac VP. 2019. Bystander responses impact accurate detection of antigen specific CD8 T cells in mice and humans. J Clin Invest. 129(9):3894-3908. [PubMed]