Understanding and exploiting weaknesses in malaria transmission.
Malaria parasites (Plasmodium spp.) must move between two very different hosts: a mammal and a mosquito. Each transmission event is a bottleneck that only a small fraction of parasites survive, which makes these events some of the parasite’s most vulnerable points.
Our lab couples molecular parasitology, proteomics, sequencing, and structural biology to learn how Plasmodium prepares for and survives these transitions. We work primarily with Plasmodium yoelii, a mouse-infectious species that lets us study the complete life cycle in-house, supported by our Anopheles stephensi insectary. Finally, we translate our findings to identify how they apply to the human-infectious P. falciparum.
Research Theme 1 — Translational Control During Transmission
Transmission-stage parasites plan ahead. Gametocytes in the blood and sporozoites in the mosquito make many of the mRNAs they will need later, then hold them in a translationally repressed state until the parasite senses that it has reached its next host. This lets them act quickly after transmission to productively infect the new mammal or mosquito.
We study the RNA-binding proteins and protein/RNA complexes that impose this repression and later release it. We found that sporozoites mature through two distinct waves of translational repression, and that repression is released broadly across the host-to-vector transition. We have also shown that the CAF1/CCR4/NOT deadenylation machinery, including a Plasmodium-specific NOT1 paralogue (NOT1-G), is essential for sexual-stage development and transmission.
A new R21 award from NIAID, with Kristian Swearingen at the Institute for Systems Biology, now asks how specific repressed mRNAs are selected for release at the right moment.
Key papers:
Lindner, Swearingen et al., Nature Communications 2019 (https://doi.org/10.1038/s41467-019-12936-6)
Rios et al., PLOS Pathogens 2025 (https://doi.org/10.1371/journal.ppat.1012823)
Hart et al., PLOS Biology 2021 (https://doi.org/10.1371/journal.pbio.3001434)
Hart et al., PLoS Pathogens 2019 (https://doi.org/10.1371/journal.ppat.1007164)
Research Theme 2 — Specialized Ribosomes
Unlike most organisms, Plasmodium makes distinct ribosomes at different life-cycle stages using only 4-5 rDNA genes: A-type ribosomes predominate in the mammalian host, while S-type ribosomes appear in the mosquito. Whether these ribosomes do different jobs has been an open question for decades.
We are testing whether S-type ribosomes are specialized for transmission, using parasite genetics, sequencing, and cryo-EM. Our recent work indicates that S-type ribosomes of P. yoelii enhance host-to-vector transmission.
Key papers:
McGee et al., bioRxiv 2024 (preprint) (https://doi.org/10.1101/2024.11.14.623520)
McGee, Armache & Lindner, PLoS Pathogens 2023 (https://doi.org/10.1371/journal.ppat.1011267)
Research Theme 3 — Parasite Cell Division in the Mosquito
Inside a single oocyst associated with the mosquito midgut, one parasite divides to produce thousands of sporozoites. This depends on the basal complex, a contractile ring that pinches daughter cells apart.
With Jeffrey Dvorin (Boston Children’s Hospital / Harvard Medical School) and NIAID support, we use Ultrastructure Expansion Microscopy (U-ExM) and proteomics to define how the basal complex is built and how it drives segmentation during sporogony.
Key papers:
Clements et al., PNAS 2022 (https://doi.org/10.1073/pnas.2204167119)
Research Theme 4 — Tools and Resources for the Community
We build methods that make Plasmodium research faster for everyone. These include ribozyme-guided multiplex CRISPR editing and CRISPR interference (CRISPRi) in P. yoelii; a long-read genome assembly with comprehensive gene annotations for P. yoelii 17XNL; a catalog of constitutive and stage-enriched promoters; and surface proteomes of sporozoites. Our mosquito rearing and dissection videos are on the Lindner Lab YouTube channel (https://www.youtube.com/channel/UCZV1SMJtZBEXgE3hb9dMF5g/).
Key papers:
Walker & Lindner, JBC 2019 (https://doi.org/10.1074/jbc.RA118.007121)
Godin, Sebastian et al., JBC 2023 (https://doi.org/10.1016/j.jbc.2023.104871)
Bowman, Finger et al., Malaria Journal 2020 (https://doi.org/10.1186/s12936-020-03498-2)
Swearingen, Lindner et al., PLoS Pathogens 2016 (https://doi.org/10.1371/journal.ppat.1005606)
Research Theme 5 — Collaborative Science
Our tools and expertise support partner labs studying host immunity to malaria, including B-cell and T-cell responses and liver-stage interferon signaling. Beyond our work with malaria parasites, we have contributed protein biochemistry and vaccine-platform work to studies of SARS-CoV-2 and influenza.
Key papers:
Caloba et al., Cell Reports 2025 (https://doi.org/10.1016/j.celrep.2025.115528)
Marques-da-Silva et al., Cell Reports 2022 (https://doi.org/10.1016/j.celrep.2022.111098)
Restori et al., Science Translational Medicine 2025 (https://doi.org/10.1126/scitranslmed.adw4856)
Patel et al., Microbiology Spectrum 2024 (https://doi.org/10.1128/spectrum.04998-22)
Funding
Our research is supported by the National Institutes of Health (NIAID, NIGMS), the Department of Defense/War, Coefficient Giving, and Penn State’s Huck Institutes of the Life Sciences and Eberly College of Science.
