About

Manuel Llinás is the Ernest C. Pollard Professor in Biotechnology, and a Professor of Biochemistry and Molecular Biology and of Chemistry at Penn State University. His research focuses on understanding the molecular mechanisms of gene regulation and metabolism in the malaria parasite Plasmodium falciparum, utilizing functional genomics and metabolomics. His work aims to identify new drug targets to combat malaria, a disease causing over 1.5 million deaths annually, by exploring transcriptional regulation, particularly the role of the ApiAP2 family of DNA-binding proteins, and parasite metabolism. His lab employs tools from molecular biology, biochemistry, computational biology, and high-accuracy mass spectrometry to study the parasite's development stages, especially the red blood cell stage where clinical symptoms manifest. Llinás has contributed to elucidating the transcriptional regulatory network of the parasite, investigating the function of ApiAP2 proteins, and characterizing the unique metabolic pathways of P. falciparum, with the goal of discovering novel therapeutic strategies.

Research topics

• Immunology
• Biology
• Genetics
• Medicine
• Ecology
• Internal medicine
• Computational biology
• Cell biology
• Virology

Selected publications

• Dynamic regulation of long non-coding RNAs across asexual and gametocyte development in <i>Plasmodium falciparum</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-18

  articleOpen access

  Abstract Long non-coding RNAs (lncRNAs) are critical regulators of gene expression in eukaryotes. Short reads from Illumina sequencing, reverse transcriptase artefacts, and incomplete second-strand degradation in strand-specific cDNA libraries hamper genome-wide identification of lncRNAs, especially in gene-dense genomes such as Plasmodium . Here, we integrated long-read Oxford Nanopore Technology direct RNA sequencing, ribosome profiling, and single-cell transcriptomics to generate a robust and stage-specific characterization of P. falciparum lncRNAs. We generated comprehensive annotations of lncRNAs expressed in both asexual and sexual blood stages and confirmed their non-coding nature using ribosome profiling. Most lncRNAs showed pronounced stage-specific expression and appeared to be particularly abundant in mature gametocytes. Single-cell RNA sequencing revealed differential expression of many lncRNAs in female and male gametocytes, suggesting important roles in gametocytogenesis and transmission. Many lncRNAs are located antisense to protein-coding genes and are co-expressed with their sense mRNA, possibly from putative bidirectional promoters, while others overlap mRNA coding sequences or 3’ untranslated regions and showed negatively correlated expression patterns. Overall, our study shows the prevalence of P. falciparum lncRNAs and highlights their possible roles in controlling the regulation of gene expression, particularly during gametocytogenesis.

  PublisherOA PDFDOI

• Natural triterpenic phenolic esters target PfA-M17 in Plasmodium falciparum

  Malaria Journal · 2026-01-02

  articleOpen access

  BACKGROUND: Malaria is a deadly parasitic disease for which innovative treatments are urgently needed. A mixture of eight triterpenic esters (8TTE) was previously identified as important for the antiplasmodial activity of Keetia leucantha twigs, a plant used in traditional medicine in Benin. Despite the reported in vitro and in vivo activity, the targets of 8TTE are unknown. METHODS: The present study investigated the mode of action of 8TTE on Plasmodium falciparum by a multi-scale integrative study from phenotype to metabolome, including: phenotypic analysis, enzymatic tests, molecular docking and metabolomic profiling. RESULTS: This study identified a unique antiplasmodial profile with activity onset in the early-ring stage of the parasite, the inhibition of aminopeptidase PfA-M17 (PlasmoDB PF3D7_1446200) and perturbations in parasite haemoglobin metabolism. CONCLUSIONS: Further structure-activity and medicinal chemistry studies are warranted to elaborate on these findings and the potential for 8TTE-related molecules to serve as future antimalarial drugs.

  PublisherDOI

• Chromatin state dynamics during the Plasmodium falciparum intraerythrocytic development cycle

  BMC Genomics · 2026-01-07

  articleOpen accessCorresponding

  The interdependence of chromatin states and transcription factor (TF) binding in eukaryotic genomes is critical for the proper regulation of gene expression. In this study, we explore the connection between TFs and chromatin states in the human malaria parasite, Plasmodium falciparum, throughout its 48-hour asexual intraerythrocytic developmental cycle (IDC). Most P. falciparum genes are expressed in a periodic manner during the IDC, accompanied by dynamic shifts in histone modifications and chromatin accessibility. Leveraging genome-wide profiles of chromatin accessibility, histone modifications, and Heterochromatin Protein 1 (HP1) occupancy, we characterize chromatin state dynamics during the IDC. Our results indicate that several chromatin states remain stable throughout the lifecycle, while others are dynamic and are linked to gene activation or repression. We further characterize chromatin state dynamics at the genome-wide DNA binding sites for a selection of Plasmodium TFs, allowing us to group TFs according to their chromatin preferences. By correlating changes in chromatin accessibility, histone modifications, and TF binding, we provide a global overview of the chromatin state dynamics that coordinate P. falciparum asexual blood stage development.

  PublisherDOI

• A single valine to leucine switch disrupts <i>Plasmodium falciparum</i> AP2-G DNA binding and reveals GDV1’s role in <i>ap2-g</i> activation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-23

  preprintOpen access

  Abstract Sexual commitment in Plasmodium parasites is essential for malaria transmission, yet much remains unknown about the underlying signaling events initiating sexual conversion in a subpopulation of parasites. We discovered a single valine (V 2163 ) to leucine (L 2163 ) mutation in an Apetala 2 (AP2) transcription factor required for P. falciparum gametocytogenesis, ap2-g that abrogates sexual differentiation and confirmed this with forward and reverse mutation editing. Mutated AP2-G.L 2163 does not bind the ap2-g consensus motif, GnGTAC, or stimulate AP2-G-dependent gene transcription including autoregulation. We then used AP2-G.L 2163 parasite lines as tools to demonstrate the critical role of GDV1 in the initial activation of the silent ap2-g locus during the trophozoite to schizont transition in the absence of functional AP2-G and its autoregulation. Additionally, we show that AP2-G.V is required for MSRP1 expression, which can be used to distinguish early and late sexually committed schizonts. Together this work demonstrates that valine 2163 in AP2-G plays a critical role in DNA binding, highlighting the functional importance of this specific region for malaria transmission as well as the critical role of GDV1 in the initial activation of ap2-g expression and induction of sexual differentiation. The reporter lines generated allow further study of signaling pathways or screening of factors regulating sexual commitment.

  PublisherOA PDFDOI

• Metabolite profiling of Artemisia afra and Artemisia annua extracts reveals divergent effects on Plasmodium falciparum

  Phytomedicine · 2025-01-01 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance

  Research Square · 2025-10-09

  preprintOpen access
  PublisherOA PDFDOI

• Degradation of ribosomal RNA during <i>Plasmodium falciparum</i> gametocytogenesis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-13

  preprintOpen access

  Abstract The life cycle of Plasmodium falciparum is characterized by complex regulatory changes that allow adaptation of the parasites to different environmental conditions, which are especially pronounced during transmission between the mammalian host and the insect vector. Previous studies have shown that P. falciparum uses three types of ribosomal RNAs (rRNA A-, S1- and S2-types) at different stages of its life cycle. We used Oxford Nanopore Technologies (ONT) direct RNA sequencing to investigate the dynamics of rRNA usage throughout the parasite’s intraerythrocytic development, as well as in salivary gland sporozoites. Our study revealed a preponderance of A-type rRNAs during the intraerythrocytic cycle and gametocytogenesis, while S-type rRNAs slowly increase in abundance in mosquito stages starting three days post infection. Salivary gland sporozoites showed an even proportion of all rRNA types. By examining the length distributions of rRNA molecules, we detected an extensive and specific degradation of rRNAs during gametocytogenesis, starting in stage II gametocytes and continuing until the final stages of gametocyte development. We hypothesize that rRNA degradation may be linked to the global translational repression and metabolic quiescence described in stage V gametocytes, similar to mechanisms observed in bacterial and eukaryotic stress responses.

  PublisherOA PDFDOI

• Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages

  PLoS Pathogens · 2025-07-03 · 2 citations

  articleOpen access

  UDP-N-acetylglucosamine (UDP-GlcNAc) is a crucial sugar nucleotide for glycan synthesis in eukaryotes. In the malaria parasite Plasmodium falciparum, UDP-GlcNAc is synthesized via the hexosamine biosynthetic pathway (HBP) and is essential for glycosylphosphatidylinositol (GPI) anchor production, the most prominent form of protein glycosylation in the parasite. In this study, we explore a conditional knockout of glucosamine-6-phosphate N-acetyltransferase (PfGNA1), a key HBP enzyme. PfGNA1 depletion led to significant disruptions in HBP metabolites, impairing GPI biosynthesis and causing mislocalization of the merozoite surface protein 1 (MSP1), the most abundant GPI-anchored protein in the parasite. Furthermore, parasites were arrested at the schizont stage, exhibiting severe segmentation defects and an incomplete rupture of the parasitophorous vacuole membrane (PVM), preventing egress from host red blood cells. Our findings demonstrate the critical role of HBP and GPI biosynthesis in P. falciparum asexual blood stage development and underscore the potential of targeting these pathways as a therapeutic strategy against malaria.

  PublisherDOI

• The ATM Kinase Inhibitor AZD0156 Is a Potent Inhibitor of <i>Plasmodium</i> Phosphatidylinositol 4‐Kinase (PI4Kβ) and Is an Attractive Candidate for Medicinal Chemistry Optimization Against Malaria

  Angewandte Chemie International Edition · 2025-05-03 · 6 citations

  articleOpen access

  Abstract New compounds targeting human malaria parasites are critical for effective malaria control and elimination. Here, we pursued the imidazoquinolinone AZD0156 (MMV1580483), a human ataxia‐telangiectasia mutated (ATM) kinase inhibitor that completed Phase I clinical trials as an anticancer agent. We validated its in vitro activity against the two main forms of the Plasmodium falciparum parasite in the human host, viz. the asexual blood (symptomatic) stage and sexual gametocyte (transmission) stage. Resistance selection, cross‐resistance, biochemical, and conditional knockdown studies revealed that AZD0156 inhibits P. falciparum phosphatidylinositol 4‐kinase type III beta ( Pf PI4Kβ), a clinically‐validated target for the treatment of malaria. Metabolic perturbations, fixed‐ratio isobolograms, killing kinetics and morphological evaluation correlated AZD0156 inhibition with other known PI4Kβ inhibitors. The compound showed favorable in vivo pharmacokinetic properties and 81% antimalarial efficacy (4 × 50 mg kg −1 ) in a P. berghei mouse malaria infection model. Importantly, a cleaner biochemical profile was measured against human kinases (MAP4K4, MINK1) implicated in embryofoetal developmental toxicity associated with the Pf PI4Kβ inhibitor MMV390048. This improved kinase selectivity profile and structural differentiation from other PI4Kβ inhibitors, together with its multistage antiplasmodial activity and favorable pharmacokinetic properties, makes AZD0156 an attractive candidate for target‐based drug repositioning against malaria via a medicinal chemistry optimization approach.

  PublisherOA PDFDOI

• The ATM Kinase Inhibitor AZD0156 Is a Potent Inhibitor of <i>Plasmodium</i> Phosphatidylinositol 4‐Kinase (PI4Kβ) and Is an Attractive Candidate for Medicinal Chemistry Optimization Against Malaria

  Angewandte Chemie · 2025-05-03

  articleOpen access

  Abstract New compounds targeting human malaria parasites are critical for effective malaria control and elimination. Here, we pursued the imidazoquinolinone AZD0156 (MMV1580483), a human ataxia‐telangiectasia mutated (ATM) kinase inhibitor that completed Phase I clinical trials as an anticancer agent. We validated its in vitro activity against the two main forms of the Plasmodium falciparum parasite in the human host, viz. the asexual blood (symptomatic) stage and sexual gametocyte (transmission) stage. Resistance selection, cross‐resistance, biochemical, and conditional knockdown studies revealed that AZD0156 inhibits P. falciparum phosphatidylinositol 4‐kinase type III beta ( Pf PI4Kβ), a clinically‐validated target for the treatment of malaria. Metabolic perturbations, fixed‐ratio isobolograms, killing kinetics and morphological evaluation correlated AZD0156 inhibition with other known PI4Kβ inhibitors. The compound showed favorable in vivo pharmacokinetic properties and 81% antimalarial efficacy (4 × 50 mg kg −1 ) in a P. berghei mouse malaria infection model. Importantly, a cleaner biochemical profile was measured against human kinases (MAP4K4, MINK1) implicated in embryofoetal developmental toxicity associated with the Pf PI4Kβ inhibitor MMV390048. This improved kinase selectivity profile and structural differentiation from other PI4Kβ inhibitors, together with its multistage antiplasmodial activity and favorable pharmacokinetic properties, makes AZD0156 an attractive candidate for target‐based drug repositioning against malaria via a medicinal chemistry optimization approach.

  PublisherDOI

Recent grants

• NIH Grant DP2OD00131501

  NIH · $2.4M · 2012

• NIH Grant R56AI076276

  NIH · $390k · 2009

• Structure of Malaria Parasite RNA polymerase

  NIH · $435k · 2022–2024

• Dissecting the role of ApiAP2 proteins in transcriptional regulation during Plasmodium falciparum development

  NIH · $1.9M · 2016–2022

• NIH Grant R21AI133379

  NIH · $421k · 2019

Frequent coauthors

• Lindsey Orchard

  Pennsylvania State University

  72 shared

• Timothy J. Russell

  Massachusetts Institute of Technology

  48 shared

• Philipp Ross

  University of Chicago

  43 shared

• Thomas D. Otto

  University of Glasgow

  43 shared

• Matthew Berriman

  University of Glasgow

  40 shared

• Heather J. Painter

  Center for Biologics Evaluation and Research

  38 shared

• Julian C. Rayner

  University of Cambridge

  38 shared

• Lia Chappell

  Wellcome Sanger Institute

  37 shared

Labs

• Department of Biochemistry and Molecular BiologyPI

Education

• Ph.D., Molecular and Cell Biology

  University of California Berkeley

  1999

• BS, Chemistry

  Carnegie Mellon University

  1992

Awards & honors

• Fellow of the American Association for the Advancement of Sc…
• Fellow of the American Society of Tropical Medicine & Hygien…
• Penn State Faculty Scholar Medal in the Life & Health Scienc…