A Plasmodium -encoded cytokine suppresses T-cell immunity during malaria
Open accessAbstract
The inability to acquire protective immunity against Plasmodia is the chief obstacle to malaria control, and inadequate T-cell responses may facilitate persistent blood-stage infection. Malaria is characterized by a highly inflammatory cytokine milieu, and the lack of effective protection against infection suggests that memory T cells are not adequately formed or maintained. Using a genetically targeted strain of Plasmodium berghei, we observed that the Plasmodium ortholog of macrophage migration inhibitory factor enhanced inflammatory cytokine production and also induced antigen-experienced CD4 T cells to develop into short-lived effector cells rather than memory precursor cells. The short-lived effector CD4 T cells were more susceptible to Bcl-2–associated apoptosis, resulting in decreased CD4 T-cell recall responses against challenge infections. These findings indicate that Plasmodia actively interfere with the development of immunological memory and may account for the evolutionary conservation of parasite macrophage migration inhibitory factor orthologs.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The Plasmodium-secreted cytokine macrophage migrating inhibitory factor (PMIF) has been shown to prevent T cells from developing long-term memory.
“For example, the Plasmodium-secreted cytokine, macrophage migrating inhibitory factor (PMIF), has been shown to prevent T cells from developing long-term memory191.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [191]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Joshi, N. S., Cui, W., Chandele, A., Lee, H. K., Urso, D. R., Hagman, J., Gapin, L., & Kaech, S. M. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.010 · Cited by 1,861 · see citing works
Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo
Schluns, K. S., Kieper, W. C., Jameson, S. C., & Lefrançois, L. (2000) · Nature Immunology · doi:10.1038/80868 · Cited by 1,619 · see citing works
Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells.
Macatonia, S. E., Hosken, N. A., Litton, M. J., Vieira, P., Hsieh, C., Culpepper, J., Wysocka, M., Trinchieri, G., MURPHY, K. M. M., & O’Garra, A. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.154.10.5071 · Cited by 1,524 · see citing works
Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major
Darrah, P. A., Patel, D. T., Luca, P. M. D., Lindsay, R. W. B., Davey, D. F., Flynn, B. J., Hoff, S. T., Andersen, P. L., Reed, S. G., Morris, S. L., et al. (2007) · Nature Medicine · doi:10.1038/nm1592 · Cited by 1,364 · see citing works
Szabo, S. J., Sullivan, B. M., Stemmann, C., Satoskar, A. R., Sleckman, B. P., & Glimcher, L. H. (2002) · Science · doi:10.1126/science.1065543 · Cited by 1,172 · see citing works
MIF Signal Transduction Initiated by Binding to CD74
Leng, L., Metz, C. N., Fang, Y., Xu, J., Donnelly, S., Baugh, J., Delohery, T., Chen, Y., Mitchell, R. A., & Bucala, R. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030286 · Cited by 1,154 · see citing works
Self-citationCalandra, T., Bernhagen, J., Mitchell, R. A., & Bucala, R. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.179.6.1895 · Cited by 984 · see citing works
Self-citationImmunity to malaria: more questions than answers
Langhorne, J., Ndungu, F. M., Sponaas, A., & Marsh, K. (2008) · Nature Immunology · doi:10.1038/ni.f.205 · Cited by 877 · see citing works
Kwiatkowski, D. P., Sambou, I., Twumasi, P., Greenwood, B. M., Hill, A. V. S., Manogue, K. R., Cerami, A., Castracane, J. M., & Brewster, D. (1990) · The Lancet · doi:10.1016/0140-6736(90)92827-5 · Cited by 870 · see citing works
T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells
Lighvani, A. A., Frucht, D. M., Jankovic, D., Yamane, H., Aliberti, J., Hissong, B. D., Nguyen, B. V., Gadina, M., Sher, A., Paul, W. E., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.261570598 · Cited by 783 · see citing works
γ Interferon, CD8+ T cells and antibodies required for immunity to malaria sporozoites
Schofield, L., Villaquiran, J., Ferreira, A., et al. (1987) · Nature · doi:10.1038/330664a0 · Cited by 713 · see citing works
Molyneux, M. E., Taylor, T. E., Wirima, J. J., & Borgstein, A. (1989) · QJM · doi:10.1093/oxfordjournals.qjmed.a068338 · Cited by 691 · see citing works
CD44 Is the Signaling Component of the Macrophage Migration Inhibitory Factor-CD74 Receptor Complex
Shi, X., Leng, L., Wang, T., Wang, W., Du, X., Li, J., McDonald, C., Chen, Z., Murphy, J. W., Lolis, E., et al. (2006) · Immunity · doi:10.1016/j.immuni.2006.08.020 · Cited by 679 · see citing works
Self-citationTherapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection
Butler, N. S., Moebius, J., Pewe, L. L., Traoré, B., Doumbo, O. K., Tygrett, L. T., Waldschmidt, T. J., Crompton, P. D., & Harty, J. T. (2011) · Nature Immunology · doi:10.1038/ni.2180 · Cited by 482 · see citing works
Franke-Fayard, B. M. D., Trueman, H. E., Ramesar, J., Mendoza, J., van der Keur, M., van der Linden, R., Sinden, R. E., Waters, A. P., & Janse, C. J. (2004) · Molecular and Biochemical Parasitology · doi:10.1016/j.molbiopara.2004.04.007 · Cited by 476 · see citing works
Self-citationAntigen-driven effector CD8 T cell function regulated by T-bet
Sullivan, B. M., Juedes, A. E., Szabo, S. J., von Herrath, M., & Glimcher, L. H. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2636938100 · Cited by 439 · see citing works
Evasion of innate immunity by parasitic protozoa
Sacks, D. L., & Sher, A. (2002) · Nature Immunology · doi:10.1038/ni1102-1041 · Cited by 432 · see citing works
Interferon γ Is Required for Activation-induced Death of T Lymphocytes
Refaeli, Y., Parijs, L. V., Alexander, S. I., & Abbas, A. K. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020666 · Cited by 415 · see citing works
Scharton‐Kersten, T., Afonso, L., Wysocka, M., Trinchieri, G., & Scott, P. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.154.10.5320 · Cited by 414 · see citing works
Pombo, D., Lawrence, G., Hirunpetcharat, C., Rzepczyk, C. M., Bryden, M., Cloonan, N., Anderson, K., Mahakunkijcharoen, Y., Martin, L. B., Wilson, D. W., et al. (2002) · The Lancet · doi:10.1016/s0140-6736(02)09784-2 · Cited by 403 · see citing works
Agnello, D., Lankford, C. S. R., Bream, J. H., Morinobu, A., Gadina, M., O’Shea, J. J., & Frucht, D. M. (2003) · Journal of Clinical Immunology · doi:10.1023/a:1023381027062 · Cited by 380 · see citing works
The Role of T H 1 and T H 2 Cells in a Rodent Malaria Infection
Taylor-Robinson, A. W., PHILLIPS, R. S., Severn, A., Moncada, S., & Liew, F. Y. (1993) · Science · doi:10.1126/science.8100366 · Cited by 346 · see citing works
Dalton, D. K., Haynes, L., Chu, C., Swain, S. L., & Wittmer, S. T. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.1.117 · Cited by 331 · see citing works
CD8+ T cell contraction is controlled by early inflammation
Badovinac, V. P., Porter, B. B., & Harty, J. T. (2004) · Nature Immunology · doi:10.1038/ni1098 · Cited by 317 · see citing works
Stevenson, M. M., Tam, M. F., Wolf, S. F., & Sher, A. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.5.2545 · Cited by 316 · see citing works
IL-7 Promotes the Transition of CD4 Effectors to Persistent Memory Cells
Li, J., Huston, G. E., & Swain, S. L. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030725 · Cited by 309 · see citing works
Marshall, H. D., Chandele, A., Jung, Y. W., Meng, H., Poholek, A. C., Parish, I. A., Rutishauser, R. L., Cui, W., Kleinstein, S. H., Craft, J. E., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.08.016 · Cited by 299 · see citing works
Population genetics of malaria resistance in humans
Hedrick, P. W. (2011) · Heredity · doi:10.1038/hdy.2011.16 · Cited by 297 · see citing works
Merk, M., Zierow, S., Leng, L., Das, R., Du, X., Schulte, W., Fan, J., Lue, H., Chen, Y., Xiong, H., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102941108 · Cited by 243 · see citing works
Self-citationLuty, A. J. F., Lell, B., Schmidt‐Ott, R., et al. (1999) · The Journal of Infectious Diseases · doi:10.1086/314689 · Cited by 235 · see citing works
Generation of CD8 T Cell Memory Is Regulated by IL-12
Pearce, E. L., & Shen, H. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.4.2074 · Cited by 228 · see citing works
Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis
Wojciechowski, S., Tripathi, P., Bourdeau, T., Acero, L. F., Grimes, H. L., Katz, J. D., Finkelman, F. D., & Hildeman, D. A. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20070618 · Cited by 227 · see citing works
Good, M. F., Xu, H., Wykes, M., & Engwerda, C. R. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115638 · Cited by 194 · see citing works
Profiles of cytokine production in relation with susceptibility to cerebral malaria.
Kossodo, S. D., & Grau, G. E. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.9.4811 · Cited by 175 · see citing works
Pathogen-Induced Inflammatory Environment Controls Effector and Memory CD8+ T Cell Differentiation
Obar, J. J., Jellison, E. R., Sheridan, B. S., Blair, D. A., Pham, Q.-M., Zickovich, J. M., & Lefrançois, L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1102335 · Cited by 169 · see citing works
Gene-targeted mice lacking B cells are unable to eliminate a blood stage malaria infection
von der Weid, T., Honarvar, N., & Langhorne, J. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.156.7.2510 · Cited by 157 · see citing works
The Mechanism and Significance of Deletion of Parasite-specific CD4+T Cells in Malaria Infection
Xu, H., Wipasa, J., Yan, H., et al. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20011174 · Cited by 146 · see citing works
Dendritic cells, pro‐inflammatory responses, and antigen presentation in a rodent malaria infection
Langhorne, J., Albano, F. R., Hensmann, M., et al. (2004) · Immunological Reviews · doi:10.1111/j.0105-2896.2004.00182.x · Cited by 107 · see citing works
Stephens, R., Albano, F. R., Quin, S. J., et al. (2005) · Blood · doi:10.1182/blood-2004-10-4047 · Cited by 106 · see citing works
Cho, Y., Jones, B. F., Vermeire, J. J., Leng, L., Difedele, L. M., Harrison, L. M., Xiong, H., Kwong, Y.-K. A., Chen, Y., Bucala, R., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702950200 · Cited by 102 · see citing works
Self-citationBejon, P., Mwacharo, J. K., Kai, O. K., Todryk, S. M., Keating, S. M., Lowe, B. S., Lang, T. A., Mwangi, T., Gilbert, S. C., Peshu, N. M., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.4193 · Cited by 102 · see citing works
Effector Memory Th1 CD4 T Cells Are Maintained in a Mouse Model of Chronic Malaria
Stephens, R., & Langhorne, J. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1001208 · Cited by 100 · see citing works
A Leishmania Ortholog of Macrophage Migration Inhibitory Factor Modulates Host Macrophage Responses
Kamir, D., Zierow, S., Leng, L., Cho, Y., Díaz, Y. R., Griffith, J. W., McDonald, C., Merk, M., Mitchell, R. A., Trent, J. O., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.12.8250 · Cited by 99 · see citing works
Self-citationOrthologs of macrophage migration inhibitory factor from parasitic nematodes
Vermeire, J. J., Cho, Y., Lolis, E., Bucala, R., & Cappello, M. (2008) · Trends in Parasitology · doi:10.1016/j.pt.2008.04.007 · Cited by 95 · see citing works
Self-citationAntibody-independent immunity to reinfection malaria in B-cell-deficient mice
Grun, J. L., & Weidanz, W. P. (1983) · Infection and Immunity · doi:10.1128/iai.41.3.1197-1204.1983 · Cited by 93 · see citing works
Yoshimoto, T., Takahama, Y., Wang, C., Yoneto, T., Waki, S., & Nariuchi, H. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.11.5500 · Cited by 90 · see citing works
Kumar, S., Good, M. F., Dontfraid, F., et al. (1989) · The Journal of Immunology · doi:10.4049/jimmunol.143.6.2017 · Cited by 90 · see citing works
Lumsden, J. M., Schwenk, R., Rein, L., Moris, P., Janssens, M., Ofori‐Anyinam, O., Cohen, J., Kester, K. E., Heppner, D. G., & Krzych, U. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020775 · Cited by 85 · see citing works
Augustijn, K. D., Kleemann, R., Thompson, J., et al. (2006) · Infection and Immunity · doi:10.1128/iai.00902-06 · Cited by 83 · see citing works
Self-citationColpitts, S. L., Dalton, N. M., & Scott, P. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803450 · Cited by 76 · see citing works
Distinct Clinical and Immunologic Profiles in Severe Malarial Anemia and Cerebral Malaria in Zambia
Thuma, P. E., van Dijk, J., Bucala, R., Debebe, Z., Nekhai, S. A., Kuddo, T., Nouraie, M. S., Weiss, G., & Gordeuk, V. R. (2010) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiq041 · Cited by 76 · see citing works
Self-citationWorld Malaria Day 2009: What Malaria Knows about the Immune System That Immunologists Still Do Not
Pierce, S. K., & Miller, L. H. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0804153 · Cited by 74 · see citing works
Vaccines for Malaria: How Close Are We?
Thera, M., & Plowe, C. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-022411-192402 · Cited by 66 · see citing works
Griffith, J. W., O’Connor, C. L., Bernard, K., et al. (2007) · The Journal of Infectious Diseases · doi:10.1086/522865 · Cited by 64 · see citing works
Self-citationQuantitative Plasmodium sporozoite neutralization assay (TSNA)
Kumar, K. A., Oliveira, G. A., Edelman, R., et al. (2004) · Journal of Immunological Methods · doi:10.1016/j.jim.2004.06.017 · Cited by 61 · see citing works
The immunological challenge to developing a vaccine to the blood stages of malaria parasites
Good, M. F., Stanisic, D. I., Xu, H., Elliott, S. R., & Wykes, M. (2004) · Immunological Reviews · doi:10.1111/j.0105-2896.2004.00178.x · Cited by 58 · see citing works
Characterization of aPlasmodium falciparumMacrophage‐Migration Inhibitory Factor Homologue
Cordery, D. V., Kishore, U., Kyes, S., et al. (2007) · The Journal of Infectious Diseases · doi:10.1086/511309 · Cited by 56 · see citing works
Chandele, A., Mukerjee, P., Das, G., Ahmed, R., & Chauhan, V. S. (2010) · Immunology · doi:10.1111/j.1365-2567.2010.03363.x · Cited by 51 · see citing works
Taylor, J. J., & Jenkins, M. K. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.03.010 · Cited by 51 · see citing works
Miller, J. L., Harupa, A., Kappe, S. H. I., & Mikolajczak, S. A. (2012) · Infection and Immunity · doi:10.1128/iai.05861-11 · Cited by 51 · see citing works
Villegas-Méndez, A., de Souza, J. B., Murungi, L., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100241 · Cited by 47 · see citing works
Dobson, S. E., Augustijn, K. D., Brannigan, J. A., et al. (2009) · Protein Science · doi:10.1002/pro.263 · Cited by 32 · see citing works
Self-citationMultiple functions of human T cells generated by experimental malaria challenge
Todryk, S. M., Walther, M. R., Bejon, P., Hutchings, C. L., Thompson, F. M., Urban, B. C., Porter, D. W., & Hill, A. V. S. (2009) · European Journal of Immunology · doi:10.1002/eji.200939434 · Cited by 30 · see citing works
Thorat, S., Daly, T. M., Bergman, L. W., et al. (2010) · Infection and Immunity · doi:10.1128/iai.00277-10 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
mRNA vaccines for infectious diseases: principles, delivery and clinical translation
Chaudhary, N., Weissman, D., & Whitehead, K. A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00283-5 · Cited by 1,555 · see citing works
Baeza Garcia, A., Siu, E., Sun, T., Exler, V., Brito, L., Hekele, A., Otten, G., Augustijn, K., Janse, C. J., Ulmer, J. B., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05041-7 · Cited by 97 · see citing works
Self-citationParasite-Produced MIF Cytokine: Role in Immune Evasion, Invasion, and Pathogenesis
Ghosh, S., Jiang, N., Farr, L., Ngobeni, R., & Moonah, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01995 · Cited by 62 · see citing works
- Authors
- Sun, T., Holowka, T., Song, Y., Zierow, S., Leng, L., Chen, Y., Xiong, H., Griffith, J., Nouraie, M., Thuma, P. E., Lolis, E., Janse, C. J., Gordeuk, V. R., Augustijn, K., & Bucala, R.
- Affiliations
- Yale University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Howard University (US)
- Malaria Institute at Macha, Choma, Zambia; and
- Leiden University Medical Center (NL)
- Corresponding author
- Bucala, Richard
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-07-09
- Volume
- 109
- Issue
- 31
- Pages
- E2117-26
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3411961
- OpenAlex
- W2160891320
- Cited by
- 75
- References
- 64
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 12 · 2020: 5 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 1 · 2014: 7 · 2013: 6 · 2012: 2
- FWCI
- 4.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Howard (Howard University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- National Science Foundation
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (816.02.001)
- National Institutes of Health
- U.S. Public Health Service (5732A1007404-20)
- National Institute of Allergy and Infectious Diseases (R01AI110452, AI 2R01-042310-12, T32AI007404, AI 5R01-51306-05, R01AI042310)
- National Center for Research Resources (G12RR003048)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- Plasmodium, malaria, macrophage migration inhibitory factor, cytokine inhibition, T cell immunity, CD4+ T cells, memory T cells, short-lived effector cells, immunological memory, Plasmodium berghei, blood-stage infection, parasite evasion
- MeSH terms
- Animals, Humans, Immunologic Memory, Mice, Inbred BALB C, Plasmodium berghei, Plasmodium falciparum, CD4-Positive T-Lymphocytes, Protozoan Proteins, Cytokines, Malaria, Falciparum, Apoptosis, Evolution, Molecular, Proto-Oncogene Proteins c-bcl-2, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
