Savannah Lewis

All Publications

• Gravidity-dependent protection against placental malaria is associated with enhanced natural killer cell-mediated antibody-dependent cellular activation: a nested cohort study. EBioMedicine Lewis, S. N., Delmastro, A., Lopez-Perez, M., Presti, S., Kirosingh, A. S., Nankya, F., Musinguzi, K., Kizza, J., Kakuru, A., Ofori, M., Dressman, J., Bendall, S. C., Dorsey, G., Rosenthal, P. J., Kamya, M. R., van der Ploeg, K., Hviid, L., Jagannathan, P. 2026; 131: 106446

  Abstract

  Placental malaria disproportionately affects primigravid women and is a leading cause of morbidity in endemic settings. IgG specific to VAR2CSA, a placenta-binding Plasmodium falciparum protein, accumulates with successive pregnancies, but protective mechanisms remain incompletely understood. We investigated whether natural killer antibody-dependent cellular activation (NK-ADCA) was acquired in a gravidity-dependent manner and associated with improved birth outcomes.We characterised second trimester NK-ADCA and VAR2CSA-specific antibody features among pregnant women in Eastern Uganda (NCT04336189). NK-ADCA (n = 53) against VAR2CSA-expressing P. falciparum-infected erythrocytes was assessed using primary NK cells with autologous or pooled donor plasma with characterised IgG Fc-fucosylation profiles. VAR2CSA-specific IgG abundance and Fc-fucosylation (n = 71) were quantified by ELISA and mass spectrometry. Responses were compared across gravidity and associations with placental malaria and birth weight determined.NK-ADCA increased significantly with gravidity (median 31.0% in multigravida [n = 20] vs. 11.7 in primigravid [n = 18], p = 0.0014) and correlated with reduced placental malaria severity (rs = -0.28, p = 0.043) and higher birth weight (rs = 0.52, p = 1 × 10-4). NK cell phenotypes did not differ across gravidities; instead, gravidity-dependent NK-ADCA was associated with VAR2CSA-specific IgG abundance (rs = 0.50, p = 0.00014) and reduced Fc-fucosylation (rs = -0.69, p = 1.2 × 10-8). Depletion of VAR2CSA-specific antibodies reduced NK-ADCA in multigravid but not primigravid plasma. A CD56neg adaptive-like NK subset (CD85j+FcεRIγ-NKG2C-) mediated most NK-ADCA and was preferentially activated by Fc-afucosylated antibodies.Gravidity-dependent protection against placental malaria was associated with enhanced NK-ADCA driven by accumulation of Fc-afucosylated VAR2CSA-specific antibodies, identifying NK-ADCA as a potentially important component of protective immunity to placental malaria.This work was supported by the National Institutes of Health, the Blavatnik Family Foundation, the Stanford University Office of the Vice Provost for Graduate Education, the Stanford Maternal and Child Health Research Institute, and the Danish Research Council for Development Research.

  View details for DOI 10.1016/j.ebiom.2026.106446

  View details for PubMedID 42660020

• CXCR6+CD127- Tr1 cells balance immunity and persistence in Plasmodium falciparum infection. The Journal of clinical investigation Nideffer, J., Bach, F., Strubbe, S., Lopez, L., Zedi, M., Nankya, F., Briggs, J., van der Ploeg, K., Musinguzi, K., Kim, S., Garcia Romero, A., Keya, A., Camanag, K., Lewis, S., Abdelbasset, M., Wang, B., Boss, A., Nansubuga, E., Nankabirwa, J. I., Arinaitwe, E., Takahashi, S., Dorsey, G., Greenhouse, B., Rodriguez-Barraquer, I., Kamya, M. R., Bacchetta, R., Ssewanyana, I., Haque, A., Roncarolo, M. G., Jagannathan, P. 2026

  Abstract

  Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells capable of long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical knowledge gap, we first performed scRNA-seq on gated cell populations and validated CXCR6+ CD127- as new phenotypic markers to enrich for bona-fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127- Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFNγ during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFNγ, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127- Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.

  View details for DOI 10.1172/JCI200628

  View details for PubMedID 42084919

• CXCR6+ CD127- Tr1 Cells Balance Immunity and Persistence in Plasmodium falciparum Infection. bioRxiv : the preprint server for biology Nideffer, J., Bach, F., Strubbe, S., Lopez, L., Zedi, M., Nankya, F., Briggs, J., van der Ploeg, K., Musinguzi, K., Kim, S., Romero, A. G., Keya, A., Camanag, K., Lewis, S., Abdelbasset, M., Wang, B., Boss, A., Nansubuga, E., Nankabirwa, J. I., Arinaitwe, E., Takahashi, S., Dorsey, G., Greenhouse, B., Rodriguez-Barraquer, I., Kamya, M. R., Bacchetta, R., Ssewanyana, I., Haque, A., Roncarolo, M. G., Jagannathan, P. 2025

  Abstract

  Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells with a capacity for long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical gap in knowledge, we first performed scRNAseq on gated cell populations to validate CXCR6+ CD127- as new phenotypic markers to enrich for bona-fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127- Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFNg during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFNg, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127- Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.

  View details for DOI 10.1101/2025.09.16.676649

  View details for PubMedID 41000872

  View details for PubMedCentralID PMC12458128

• ANTIBODY FC GLYCOSYLATION MODULATES NATURAL KILLER CELL-MEDIATED ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY (ADCC) IN MALARIA-EXPOSED PREGNANT WOMEN Lewis, S. N., Kirosingh, A. S., van der Ploeg, K., Press, K. D., Nankya, F., Musinguzi, K., Nansubuga, E., Tukwasibwe, S., Lopez-Perez, M., Kamya, M. R., Rosenthal, P., Dorsey, G., Hviid, L., Jagannathan, P. AMER SOC TROP MED & HYGIENE. 2025

  View details for Web of Science ID 001698542200190

• Natural killer cell antibody-dependent cellular cytotoxicity to Plasmodium falciparum is impacted by cellular phenotypes, erythrocyte polymorphisms, parasite diversity and intensity of transmission. Clinical & translational immunology Tukwasibwe, S., Lewis, S. N., Taremwa, Y., van der Ploeg, K., Press, K. D., Ty, M., Namirimu Nankya, F., Musinguzi, K., Nansubuga, E., Bach, F., Chamai, M., Okitwi, M., Tumusiime, G., Nakimuli, A., Colucci, F., Kamya, M. R., Nankabirwa, J. I., Arinaitwe, E., Greenhouse, B., Dorsey, G., Rosenthal, P. J., Ssewanyana, I., Jagannathan, P. 2024; 13 (11): e70005

  Abstract

  Natural killer (NK) cells make important contributions to anti-malarial immunity through antibody-dependent cellular cytotoxicity (ADCC), but the role of different components of this pathway in promoting NK cell activation remains unclear.We compared the functions and phenotypes of NK cells from malaria-exposed and malaria-naive donors, and then varied the erythrocyte genetic background, Plasmodium falciparum strain and opsonising plasma used in ADCC to observe their impacts on NK cell degranulation as measured by CD107a mobilisation.Natural killer cells from malaria-exposed adult Ugandan donors had enhanced ADCC, but an impaired pro-inflammatory response to cytokine stimulation, compared to NK cells obtained from malaria-naive adult North American donors. Cellular phenotypes from malaria-exposed donors reflected this specialisation for ADCC, with a compartment-wide downregulation of the Fc receptor γ-chain and enrichment of highly differentiated CD56dim and CD56neg populations. NK cell degranulation was enhanced in response to opsonised P. falciparum schizonts cultured in sickle cell heterozygous erythrocytes relative to wild-type erythrocytes, and when using opsonising plasma collected from donors living in a high transmission area compared to a lower transmission area despite similar levels of 3D7 schizont-specific IgG levels. However, degranulation was lowered in response to opsonised field isolate P. falciparum schizonts isolated from clinical malaria infections, compared to the 3D7 laboratory strain typically used in these assays.This work highlights important host and parasite factors that contribute to ADCC efficacy that should be considered in the design of ADCC assays.

  View details for DOI 10.1002/cti2.70005

  View details for PubMedID 39493859

  View details for PubMedCentralID PMC11528551

• Natural killer cells and antibodies versus malaria. Nature microbiology Lewis, S. N., Guiton, P. S. 2023; 8 (6): 1001

  View details for DOI 10.1038/s41564-023-01399-7

  View details for PubMedID 37268775

• Malaria-driven expansion of adaptive-like functional CD56-negative NK cells correlates with clinical immunity to malaria. Science translational medicine Ty, M., Sun, S., Callaway, P. C., Rek, J., Press, K. D., van der Ploeg, K., Nideffer, J., Hu, Z., Klemm, S., Greenleaf, W., Donato, M., Tukwasibwe, S., Arinaitwe, E., Nankya, F., Musinguzi, K., Andrew, D., de la Parte, L., Mori, D. M., Lewis, S. N., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Blish, C., Utz, P. J., Khatri, P., Dorsey, G., Kamya, M., Boyle, M., Feeney, M., Ssewanyana, I., Jagannathan, P. 2023; 15 (680): eadd9012

  Abstract

  Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56neg NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56dim NK cells. Higher frequencies of CD56neg NK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparum is required to maintain this modified, adaptive-like NK cell subset.

  View details for DOI 10.1126/scitranslmed.add9012

  View details for PubMedID 36696483