About
Laura Kirkman, M.D., is an Associate Professor of Medicine in Microbiology and Immunology at Weill Cornell Medicine. Her research focuses on the pathogenesis and treatment of malaria and babesiosis, which are vector-borne diseases that have a significant impact on human health. She studies how parasites that infect and live in red blood cells adapt to a hostile host environment, including mechanisms that allow these parasites to cause disease, evade host immune clearance, and persist within their hosts. Her work aims to identify new therapeutic targets to combat these infections, particularly given the high morbidity and mortality associated with malaria in Sub-Saharan Africa.
Research topics
- Biology
- Virology
- Immunology
- Microbiology
- Medicine
- Pharmacology
- Biochemistry
Selected publications
Red Blood Cell Exchange Transfusion for Severe Babesiosis
JAMA Internal Medicine · 2026-03-30
articleOpen accessImportance: Babesiosis is a worldwide emerging tick-borne disease with an expanding geographic range in the US, Europe, and Asia. Red blood cell exchange transfusion (ET) is often used as an adjunctive treatment for severe illness from babesiosis, particularly in patients with high parasitemia, acute organ injury, or severe hemolytic anemia. Data supporting its clinical effectiveness, however, are lacking. Objective: To test whether ET improves clinical outcomes among hospitalized adult patients with severe babesiosis. Design, Settings, and Participants: This target trial emulation used data from a multicenter cohort study of 3233 consecutive adults hospitalized with babesiosis from 2010 to 2024 at 82 sites across the northeastern US. Patients were eligible if they had parasitemia greater than 10%, or 5% to 10% with either acute organ injury or severe hemolytic anemia. Data were analyzed from April to August 2025. Exposure: Treatment with ET in the first 7 days of hospitalization. Main Outcomes and Measures: A composite of in-hospital death or 30-day readmission. Outcomes were compared between patients who received ET within the first 7 days of admission and those who did not. The analysis used logistic regression, with inverse probability of treatment weighting (IPTW) to adjust for potential confounders. Results: The analysis included 629 patients (median [IQR] age, 71 [63-79] years; 446 male [70.9%]), among whom 209 (33.2%) received ET in the first 7 days of hospitalization. Patients treated with ET were more severely ill at baseline than those not treated with ET (median parasitemia, 14.0% vs 7.2%); however, severity of illness characteristics were well balanced after applying IPTW. In the main analysis, the primary end point occurred in 3.6% of patients who received ET and in 9.8% who did not (adjusted odds ratio, 0.22; 95% CI, 0.09-0.51). The benefit of ET was confirmed in multiple sensitivity analyses. Conclusions and Relevance: This multicenter cohort study found that among severely ill adults hospitalized with babesiosis, the adjusted risk of in-hospital death or 30-day readmission was nearly 5-fold lower in those treated with ET vs those not treated with ET. These data support ET for severely ill patients with babesiosis, although the findings may be susceptible to unmeasured confounding. Further research is needed to identify which patients are most likely to benefit.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-07
preprintOpen accessSenior authorCorrespondingAbstract The haploid malaria parasite, Plasmodium falciparum, evolved a unique cohort of DNA repair pathways enabling the parasite to survive in a vertebrate host red blood cell and the mosquito vector. P. falciparum chromosomes are partitioned into a highly conserved core genome and remarkably diverse, largely subtelomeric regions that contain genes encoding important parasite virulence factors. The molecular mechanisms that maintain this chromosomal structure have not been identified. Here, we describe specific DNA repair pathways that differentiate between hypervariable subtelomeric and conserved core regions of the genome. Based on our previous work, we hypothesized that there are potentially important interactions between translesion (TLS) and homologous recombination (HR) pathways for the diversification of multicopy gene families in P. falciparum. Thus, we created knockout parasite lines of the DNA repair enzymes: PfRad51 and the TLS polymerases PfPol ζ and PfRev1 . We identified that irradiation hypersensitivity varied across the cell cycle for TLSΔ parasites and was uniform across the erythrocytic cycle for PfRad51 Δ parasites, highlighting the variable roles of these pathways. However, important interactions between these pathways were found when we studied directed double strand break (DSB) repair, which revealed a difference in the DNA damage response according to chromosomal location. PfRad51 was essential for HR-mediated repair in the core genome. In contrast, we identified a Rad51 independent homology-directed repair in all three of our knockout lines when a DSB was made in the subtelomeric region of the chromosome. We propose that this differential DNA damage response maintains the distinction in diversification across the chromosome.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-23
preprintOpen accessSenior authorCorrespondingAbstract The ubiquitin-proteasome system (UPS) is essential for Plasmodium falciparum to maintain protein homeostasis, adapt to proteotoxic stress, and regulate parasite growth and stage transitions. The proteolytic 20S proteasome core is the central component of the UPS, where unfolded protein substrates are degraded into oligopeptides. Mechanisms regulating malaria parasite proteasome activity are poorly understood and have not been thoroughly studied. This knowledge gap is especially critical in the context of artemisinin (ART) resistance, where parasite survival depends on an enhanced stress response, including a greater reliance on the UPS. Here, we profiled proteasome activity and abundance across the parasite intraerythrocytic developmental cycle (IDC) in both ART-sensitive (ART-S) Dd2 and ART-resistant (ART-R) Dd2K13 R539T parasites. We uncovered striking stage-specific regulation: proteasome activity was abundant in the ring stage, decreased in trophozoites, and then peaked in schizonts. Furthermore, ART-R Dd2K13 R539T parasites exhibited higher ring-stage proteasome activity than ART-S Dd2, despite reduced proteasome abundance, suggesting a unique adaptive rewiring of proteasome function. To study proteasome regulation in the parasite, we manipulated proteasome abundance in Dd2 and Dd2K13 R539T by creating a conditional knockdown of PfUMP1, a conserved proteasome maturation factor. PfUMP1 depletion disrupted 20S assembly, decreased proteasome activity, and led to parasite death. These experiments uncovered two key features of proteasome regulation in P. falciparum : (1) the absence of canonical transcriptional regulation of proteasome genes in response to downregulation of proteasome activity, and (2) ART-R parasites exhibit a ring-stage specific increased sensitivity to proteasome downregulation. Together, our findings reveal a previously unrecognized layer of proteasome regulation in malaria parasites and how, as part of their survival adaptations to decreased hemoglobin uptake associated with ART resistance, these parasites alter proteasome function to survive. This work reinforces the therapeutic potential of the proteasome as a stage- and resistance-specific antimalarial target.
Guidance on the Management of Asymptomatic Blood Donors Who Test Positive for <i>Babesia</i>
Clinical Infectious Diseases · 2025-12-24
articleOpen accessDESCRIPTION: Babesiosis is a tick-borne disease that is endemic in the United States (US). The major species, Babesia microti, is readily transmissible via blood transfusion. Since 2019, blood donors in 14 US states and Washington DC have been routinely screened for Babesia infection using highly sensitive and specific nucleic acid testing (NAT). Currently, there are no recommendations regarding the management of asymptomatic blood donors who test positive for Babesia. METHODS: A multidisciplinary expert panel was convened to develop guidance for the management of asymptomatic Babesia-infected blood donors. A survey was distributed through the Infectious Diseases Society of America (IDSA) Emerging Infections Network (EIN) to evaluate how a geographically diverse group of infectious diseases specialists would approach this problem. RESULTS: The expert panel recommends that all Babesia NAT positive blood donors should be referred for clinical evaluation and retested using peripheral blood smear (PBS) and B. microti PCR within two months of blood donation screening. The panel also recommends observation rather than treatment for a reactive molecular test alone. Antimicrobial therapy should be considered for PBS positive cases. Donors should be counseled regarding the typically self-limiting nature of this infection and instructed to seek medical care if symptoms develop. The EIN survey results are consistent with these recommendations. CONCLUSIONS: Several factors support these management recommendations. Blood donors typically comprise healthy, immunocompetent adults in whom most Babesia infections are self-limited based on studies showing that molecular evidence of infection clears in almost all asymptomatic blood donors without intervention.
Nucleic Acids Research · 2025-11-13
articleOpen accessSenior authorThe human malaria parasite, Plasmodium falciparum, faces unique DNA repair challenges; it is haploid, undergoes asynchronous mitosis termed schizogony, and lacks canonical non-homologous end joining (C-NHEJ). Yet, it has adapted DNA repair pathways that enable survival in distinct environments, including human erythrocytes and hepatocytes, as well as the mosquito vector. Plasmodium falciparum chromosomes are partitioned into a conserved core genome and highly diverse subtelomeric regions containing hypervariable, multicopy gene families, including var, which encodes a critical parasite virulence factor. The molecular mechanisms maintaining this chromosomal structure remain unclear. Here, we describe specific DNA repair pathways that distinguish hypervariable subtelomeric regions from the conserved core genome. By disrupting the DNA repair enzyme PfRad51 and TLS polymerases PfPolζ and PfRev1, we identified differential irradiation hypersensitivity across the cell cycle for TLSΔ parasites and uniform hypersensitivity for PfRad51Δ parasites, highlighting variable roles for these repair pathways. Repair of targeted double-strand breaks demonstrated that PfRad51 is essential for HR-mediated repair in the core genome, whereas a Rad51-independent, homology-directed repair pathway was observed in subtelomeric regions. This previously unidentified alternative repair pathway was independent of TLS polymerases. We propose that these differential DNA repair responses maintain the unique structure that defines P. falciparum chromosomes.
Recurrent Plasmodium falciparum Malaria in U.S. Travelers Treated with Artemether–Lumefantrine
American Journal of Tropical Medicine and Hygiene · 2025-01-07 · 1 citations
articleOpen accessWe report two cases of recurrent malaria in U.S. travelers returning from Africa (Ghana and Central African Republic) despite a full course of artemether-lumefantrine (AL). Both patients presented to New York City hospitals, received AL treatment, and clinically improved. Within 2 weeks, they presented with recurrent Plasmodium falciparum malaria. Parasite isolates were sequenced, and P. falciparum kelch 13 propeller domain mutations that are validated or candidate markers of artemisinin partial resistance were not identified. Parasites had mutations within the P. falciparum multidrug resistance protein 1 gene. It is crucial to remain vigilant for recurrent malaria in travelers, even from African regions where partial resistance to artemisinin-based combination therapy has only rarely been reported.
Cell chemical biology · 2025-05-23 · 3 citations
articleOpen accessSpreading resistance to front-line treatments necessitate the search for new classes of antimalarials. Limitations of standard screening conditions lead us to develop an assay using culture media that more closely reflects nutrient levels in human serum to reveal new therapeutically relevant parasite pathways. Our approach was validated by testing 22k compounds followed by a full 750k compound screen and identified 29 chemotypes with higher activity in nutrient restricted media that were further characterized. Through a combination of chemo-genomics and innovative photocatalytic proximity labeling proteomics, we identified the target of two compounds as the CLAG3 component of the plasmodial surface anion channel (PSAC). Strikingly, every one of the other 29 chemotypes selected was also found to block PSAC activity, highlighting the importance of this nutrient channel for parasite survival under physiological conditions. The effect of PSAC inhibitors in the in vivo humanized mouse model was confirmed.
Zizyphus mauritiana as a Source of Tannins with Antibacterial and Antiplasmodial Activities
2025-12-04
book-chapterBackground: In Africa and other countries where malaria is endemic, traditional medicinal plants are frequently used to treat or cure malaria. Ziziphus mauritiana, a tropical fruit tree species belonging to the family Rhamnaceae, is used in African traditional medicine against different symptoms and diseases. Aim: This study was designed to evaluate tannins extracted from Ziziphus mauritiana as a source of potential antimalarial and antimicrobial agents in Mali. Methodology: The collection of plant materials, tannins extraction, antibacterial activity evaluation were done at the University of Sciences, Techniques and Technologies of Bamako, Mali and antiplasmodial activity assessment at Department of Microbiology and Immunology, Weill Cornell Medicine, New York, United States of America, between September 2013 and February 2014. The tannins were extracted from leaves of Z. mauritiana collected around Bamako, Mali. Antiplasmodial activity was evaluated against 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant) strains of Plasmodium falciparum using the fluorescence-based SYBR® green I method. Antibacterial activity of tannins was evaluated by the disc diffusion method against strains of Escherichia coli, Salmonella Typhi, Streptococcus and Staphylococcus aureus donated by the National Research Institute in Public Health in Mali and collected from infected patients suffering from different diseases. The Kruskal–Wallis H test for data of zone of inhibition was used with the Statistical Package for the Medical Sciences version 17.0. Results: The tannin extracts from leaves of Z. mauritiana demonstrated moderate antibacterial activity (average 7-9 mm diameter of inhibition zone) on tested strains. Tannins extracted from leaves of Z. mauritiana showed moderate antiplasmodial activity against 3D7 P. falciparum (46.9±1.12 μg/mL) and against Dd2 P. falciparum strains (67.8±2.39 μg/mL). They also showed an antibacterial activity on different bacterial strains, showing important inhibition zones. Especially, they were more active on Streptococcus than Escherichia coli, Salmonella typhi, and Staphylococcus aureus. Conclusion: Tannins extracted from Z. mauritiana demonstrated good antiplasmodial and antibacterial activities. It could be regarded as effective and studied for further consideration as a complementary medicine source of antimicrobials against most multidrug-resistant bacteria and other parasites. These data confirm the potential use of tannins as a key element in antimalarial and antibacterial drug development.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-14 · 2 citations
preprintOpen accessAbstract The Plasmodium falciparum 20S proteasome (Pf20S) has emerged as a promising antimalarial target. Development of therapeutics to this target has previously relied on native purifications of Pf20S, which is challenging and has limited the scope of previous efforts. Here, we report an effective recombinant Pf20S platform to facilitate drug discovery. Proteasome assembly was carried out in insect cells by co-expressing all fourteen subunits along with the essential chaperone homolog, Ump1. Unexpectedly, the isolated proteins consisted of both a mature and an immature complex. Cryo-EM analysis of the immature complexes revealed structural insights detailing how Ump1 and the propeptides of the β2 and β5 subunits coordinate β-ring assembly, which differ from human and yeast homologs. Biochemical validation confirmed that β1, β2, and β5 subunits of the mature proteasome were catalytically active. Clinical proteasome inhibitors, bortezomib, carfilzomib and marizomib were potent but lacked Pf20S selectivity. However, the tripeptide-epoxyketone J-80 inhibited Pf20S β5 with an IC 50 of 22.4 nM and 90-fold selectivity over human β5. Structural studies using cryo-EM elucidated the basis for the selective binding of J-80. Further evaluation of novel Pf20S-selective inhibitors such as the reversible TDI-8304 and irreversible analogs, 8304-vinyl sulfone and 8304-epoxyketone, confirmed their potency and selectivity over the human constitutive proteasome. This recombinant Pf20S platform facilitates detailed biochemical and structural studies, accelerating the development of selective antimalarial therapeutics.
STAR Protocols · 2024-02-15
articleOpen accessCorrespondingArtezomibs (ATZs), dual-pharmacophore molecules comprising of artemisinin and a parasite proteasome inhibitor, hijack parasite ubiquitin proteasome system to transform into new proteasome inhibitors following the activation of artemisinin by heme. 1 Here, we present a protocol for using a fluorescent activity-based broad-spectrum proteasome inhibitor probe to study intracellular conversion of ATZ molecules into new proteasome inhibitors in malaria parasites. We describe steps for drug treatment and washout, parasite lysis, proteasome labeling, and visualization. For complete details on the use and execution of this protocol, please refer to Zhan et al. 1 • An assay for assessing intracellular artezomib conversion to novel 20S inhibitors • Detailed steps of removing free compound from both media and cells • In-gel fluorescence scanning to visualize 20S active subunit labeling Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics. Artezomibs (ATZs), dual-pharmacophore molecules comprising of artemisinin and a parasite proteasome inhibitor, hijack parasite ubiquitin proteasome system to transform into new proteasome inhibitors following the activation of artemisinin by heme. Here, we present a protocol for using a fluorescent activity-based broad-spectrum proteasome inhibitor probe to study intracellular conversion of ATZ molecules into new proteasome inhibitors in malaria parasites. We describe steps for drug treatment and washout, parasite lysis, proteasome labeling, and visualization.
Recent grants
Novel Inhibitors of Malaria Proteasome
NIH · $466k · 2017–2020
Genetic diversity in virulence genes of Plasmodium falciparum
NIH · $655k · 2008–2012
Role of Translesional Polymerases in Genome Diversification of the Malaria Parasite
NIH · $3.1M · 2019–2025
Frequent coauthors
- 64 shared
Ananías A. Escalante
Temple University
- 64 shared
Macarthur Charles
Center for Global Health
- 64 shared
Rodney Destiné
- 64 shared
Jean W. Pape
Weill Cornell Medicine
- 64 shared
Sanchita Das
National Institutes of Health Clinical Center
- 64 shared
Kristi Shigyo
Harbor–UCLA Medical Center
- 64 shared
Glavdia G. Delva
Massachusetts Institute of Technology
- 64 shared
Linnie M. Golightly
Weill Cornell Medicine
Education
MD, Medicine
Albert Einstein College of Medicine
BA, Biology
Swarthmore College
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