Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria

Stephanie I. Studniberg; Lisa J. Ioannidis; Retno A.S. Utami; Leily Trianty; Yang Liao; Waruni Abeysekera; Connie S.N. Li-Wai-Suen; Halina M. Pietrzak; Julie Healer; Agatha M. Puspitasari; Dwi Apriyanti; Farah Coutrier; Jeanne R. Poespoprodjo; Enny Kenangalem; Benediktus Andries; Pak Prayoga; Novita Sariyanti; Gordon K. Smyth; Alan F. Cowman; Ric N. Price; Rintis Noviyanti; Wei Shi; Alexandra L. Garnham; Diana S. Hansen

doi:10.15252/msb.202110824

Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria

Stephanie I. Studniberg, Lisa J. Ioannidis, Retno A.S. Utami, Leily Trianty, Yang Liao, Waruni Abeysekera, Connie S.N. Li-Wai-Suen, Halina M. Pietrzak, Julie Healer, Agatha M. Puspitasari, Dwi Apriyanti, Farah Coutrier, Jeanne R. Poespoprodjo, Enny Kenangalem, Benediktus Andries, Pak Prayoga, Novita Sariyanti, Gordon K. Smyth, Alan F. Cowman, Ric N. PriceRintis Noviyanti, Wei Shi, Alexandra L. Garnham, Diana S. Hansen

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

Clinical immunity to P. falciparum malaria is non-sterilizing, with adults often experiencing asymptomatic infection. Historically, asymptomatic malaria has been viewed as beneficial and required to help maintain clinical immunity. Emerging views suggest that these infections are detrimental and constitute a parasite reservoir that perpetuates transmission. To define the impact of asymptomatic malaria, we pursued a systems approach integrating antibody responses, mass cytometry, and transcriptional profiling of individuals experiencing symptomatic and asymptomatic P. falciparum infection. Defined populations of classical and atypical memory B cells and a T_H2 cell bias were associated with reduced risk of clinical malaria. Despite these protective responses, asymptomatic malaria featured an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T-cell function, and CTLA-4 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA-4 in the development of asymptomatic parasitemia in infection models. The results suggest that asymptomatic malaria is not innocuous and might not support the induction of immune processes to fully control parasitemia or efficiently respond to malaria vaccines.

Original language	English
Article number	e10824
Journal	Molecular Systems Biology
Volume	18
Issue number	4
DOIs	https://doi.org/10.15252/msb.202110824
Publication status	Published - Apr 2022

Bibliographical note

Funding Information:
This work was performed in part at the Materials Characterisation and Fabrication Platform (MCFP) at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility (ANFF). Supported by the Australian Government National Health and Medical Research Council (NHMRC) Independent Medical Research Institutes Infrastructure Support Scheme and Project Grants 1058665 and 1137989; the Australian Academy of Science (DSH), the Victorian State Government Operational Infrastructure Support, and the Ministry of Research and Technology of the Republic of Indonesia. GKS was supported by NHMRC Fellowship 1154970.

Funding Information:
This work was performed in part at the Materials Characterisation and Fabrication Platform (MCFP) at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility (ANFF). Supported by the Australian Government National Health and Medical Research Council (NHMRC) Independent Medical Research Institutes Infrastructure Support Scheme and Project Grants 1058665 and 1137989; the Australian Academy of Science (DSH), the Victorian State Government Operational Infrastructure Support, and the Ministry of Research and Technology of the Republic of Indonesia. GKS was supported by NHMRC Fellowship 1154970.

Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.

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Studniberg, S. I., Ioannidis, L. J., Utami, R. A. S., Trianty, L., Liao, Y., Abeysekera, W., Li-Wai-Suen, C. S. N., Pietrzak, H. M., Healer, J., Puspitasari, A. M., Apriyanti, D., Coutrier, F., Poespoprodjo, J. R., Kenangalem, E., Andries, B., Prayoga, P., Sariyanti, N., Smyth, G. K., Cowman, A. F., ... Hansen, D. S. (2022). Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria. Molecular Systems Biology, 18(4), Article e10824. https://doi.org/10.15252/msb.202110824

@article{18f70fb42a7d458cbe9ac5910939c49e,

title = "Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria",

abstract = "Clinical immunity to P. falciparum malaria is non-sterilizing, with adults often experiencing asymptomatic infection. Historically, asymptomatic malaria has been viewed as beneficial and required to help maintain clinical immunity. Emerging views suggest that these infections are detrimental and constitute a parasite reservoir that perpetuates transmission. To define the impact of asymptomatic malaria, we pursued a systems approach integrating antibody responses, mass cytometry, and transcriptional profiling of individuals experiencing symptomatic and asymptomatic P. falciparum infection. Defined populations of classical and atypical memory B cells and a TH2 cell bias were associated with reduced risk of clinical malaria. Despite these protective responses, asymptomatic malaria featured an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T-cell function, and CTLA-4 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA-4 in the development of asymptomatic parasitemia in infection models. The results suggest that asymptomatic malaria is not innocuous and might not support the induction of immune processes to fully control parasitemia or efficiently respond to malaria vaccines.",

keywords = "asymptomatic infection, immunity, immunosuppression, malaria, P. falciparum",

author = "Studniberg, {Stephanie I.} and Ioannidis, {Lisa J.} and Utami, {Retno A.S.} and Leily Trianty and Yang Liao and Waruni Abeysekera and Li-Wai-Suen, {Connie S.N.} and Pietrzak, {Halina M.} and Julie Healer and Puspitasari, {Agatha M.} and Dwi Apriyanti and Farah Coutrier and Poespoprodjo, {Jeanne R.} and Enny Kenangalem and Benediktus Andries and Pak Prayoga and Novita Sariyanti and Smyth, {Gordon K.} and Cowman, {Alan F.} and Price, {Ric N.} and Rintis Noviyanti and Wei Shi and Garnham, {Alexandra L.} and Hansen, {Diana S.}",

note = "Funding Information: This work was performed in part at the Materials Characterisation and Fabrication Platform (MCFP) at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility (ANFF). Supported by the Australian Government National Health and Medical Research Council (NHMRC) Independent Medical Research Institutes Infrastructure Support Scheme and Project Grants 1058665 and 1137989; the Australian Academy of Science (DSH), the Victorian State Government Operational Infrastructure Support, and the Ministry of Research and Technology of the Republic of Indonesia. GKS was supported by NHMRC Fellowship 1154970. Funding Information: This work was performed in part at the Materials Characterisation and Fabrication Platform (MCFP) at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility (ANFF). Supported by the Australian Government National Health and Medical Research Council (NHMRC) Independent Medical Research Institutes Infrastructure Support Scheme and Project Grants 1058665 and 1137989; the Australian Academy of Science (DSH), the Victorian State Government Operational Infrastructure Support, and the Ministry of Research and Technology of the Republic of Indonesia. GKS was supported by NHMRC Fellowship 1154970. Publisher Copyright: {\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",

year = "2022",

month = apr,

doi = "10.15252/msb.202110824",

language = "English",

volume = "18",

journal = "Molecular Systems Biology",

issn = "1744-4292",

publisher = "Wiley-Blackwell",

number = "4",

}

Studniberg, SI, Ioannidis, LJ, Utami, RAS, Trianty, L, Liao, Y, Abeysekera, W, Li-Wai-Suen, CSN, Pietrzak, HM, Healer, J, Puspitasari, AM, Apriyanti, D, Coutrier, F, Poespoprodjo, JR, Kenangalem, E, Andries, B, Prayoga, P, Sariyanti, N, Smyth, GK, Cowman, AF, Price, RN, Noviyanti, R, Shi, W, Garnham, AL & Hansen, DS 2022, 'Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria', Molecular Systems Biology, vol. 18, no. 4, e10824. https://doi.org/10.15252/msb.202110824

TY - JOUR

T1 - Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria

AU - Studniberg, Stephanie I.

AU - Ioannidis, Lisa J.

AU - Utami, Retno A.S.

AU - Trianty, Leily

AU - Liao, Yang

AU - Abeysekera, Waruni

AU - Li-Wai-Suen, Connie S.N.

AU - Pietrzak, Halina M.

AU - Healer, Julie

AU - Puspitasari, Agatha M.

AU - Apriyanti, Dwi

AU - Coutrier, Farah

AU - Poespoprodjo, Jeanne R.

AU - Kenangalem, Enny

AU - Andries, Benediktus

AU - Prayoga, Pak

AU - Sariyanti, Novita

AU - Smyth, Gordon K.

AU - Cowman, Alan F.

AU - Price, Ric N.

AU - Noviyanti, Rintis

AU - Shi, Wei

AU - Garnham, Alexandra L.

AU - Hansen, Diana S.

N1 - Funding Information: This work was performed in part at the Materials Characterisation and Fabrication Platform (MCFP) at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility (ANFF). Supported by the Australian Government National Health and Medical Research Council (NHMRC) Independent Medical Research Institutes Infrastructure Support Scheme and Project Grants 1058665 and 1137989; the Australian Academy of Science (DSH), the Victorian State Government Operational Infrastructure Support, and the Ministry of Research and Technology of the Republic of Indonesia. GKS was supported by NHMRC Fellowship 1154970. Funding Information: This work was performed in part at the Materials Characterisation and Fabrication Platform (MCFP) at the University of Melbourne and the Victorian Node of the Australian National Fabrication Facility (ANFF). Supported by the Australian Government National Health and Medical Research Council (NHMRC) Independent Medical Research Institutes Infrastructure Support Scheme and Project Grants 1058665 and 1137989; the Australian Academy of Science (DSH), the Victorian State Government Operational Infrastructure Support, and the Ministry of Research and Technology of the Republic of Indonesia. GKS was supported by NHMRC Fellowship 1154970. Publisher Copyright: © 2022 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2022/4

Y1 - 2022/4

N2 - Clinical immunity to P. falciparum malaria is non-sterilizing, with adults often experiencing asymptomatic infection. Historically, asymptomatic malaria has been viewed as beneficial and required to help maintain clinical immunity. Emerging views suggest that these infections are detrimental and constitute a parasite reservoir that perpetuates transmission. To define the impact of asymptomatic malaria, we pursued a systems approach integrating antibody responses, mass cytometry, and transcriptional profiling of individuals experiencing symptomatic and asymptomatic P. falciparum infection. Defined populations of classical and atypical memory B cells and a TH2 cell bias were associated with reduced risk of clinical malaria. Despite these protective responses, asymptomatic malaria featured an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T-cell function, and CTLA-4 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA-4 in the development of asymptomatic parasitemia in infection models. The results suggest that asymptomatic malaria is not innocuous and might not support the induction of immune processes to fully control parasitemia or efficiently respond to malaria vaccines.

AB - Clinical immunity to P. falciparum malaria is non-sterilizing, with adults often experiencing asymptomatic infection. Historically, asymptomatic malaria has been viewed as beneficial and required to help maintain clinical immunity. Emerging views suggest that these infections are detrimental and constitute a parasite reservoir that perpetuates transmission. To define the impact of asymptomatic malaria, we pursued a systems approach integrating antibody responses, mass cytometry, and transcriptional profiling of individuals experiencing symptomatic and asymptomatic P. falciparum infection. Defined populations of classical and atypical memory B cells and a TH2 cell bias were associated with reduced risk of clinical malaria. Despite these protective responses, asymptomatic malaria featured an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T-cell function, and CTLA-4 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA-4 in the development of asymptomatic parasitemia in infection models. The results suggest that asymptomatic malaria is not innocuous and might not support the induction of immune processes to fully control parasitemia or efficiently respond to malaria vaccines.

KW - asymptomatic infection

KW - immunity

KW - immunosuppression

KW - malaria

KW - P. falciparum

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U2 - 10.15252/msb.202110824

DO - 10.15252/msb.202110824

M3 - Article

C2 - 35475529

AN - SCOPUS:85128883119

SN - 1744-4292

VL - 18

JO - Molecular Systems Biology

JF - Molecular Systems Biology

IS - 4

M1 - e10824

ER -

Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria

Abstract

Bibliographical note

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