scRNA-seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with uncomplicated malaria
Malaria causes significant morbidity and mortality worldwide, disproportionately impacting sub-Saharan Africa. Disease phenotypes associated with Plasmodium falciparum infection can vary widely, from asymptomatic to life-threatening. To date, prevention efforts, particularly those related to vaccine...
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Frontiers Media S.A.
2025-01-01
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| Series: | Experimental Biology and Medicine |
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| Online Access: | https://www.ebm-journal.org/articles/10.3389/ebm.2024.10233/full |
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| author | Collins M. Morang’a Riley S. Drake Riley S. Drake Riley S. Drake Riley S. Drake Vincent N. Miao Vincent N. Miao Vincent N. Miao Vincent N. Miao Nancy K. Nyakoe Dominic S. Y. Amuzu Vincent Appiah Yaw Aniweh Yaw Bediako Saikou Y. Bah Alex K. Shalek Alex K. Shalek Alex K. Shalek Alex K. Shalek Gordon A. Awandare Thomas D. Otto Lucas Amenga-Etego |
| author_facet | Collins M. Morang’a Riley S. Drake Riley S. Drake Riley S. Drake Riley S. Drake Vincent N. Miao Vincent N. Miao Vincent N. Miao Vincent N. Miao Nancy K. Nyakoe Dominic S. Y. Amuzu Vincent Appiah Yaw Aniweh Yaw Bediako Saikou Y. Bah Alex K. Shalek Alex K. Shalek Alex K. Shalek Alex K. Shalek Gordon A. Awandare Thomas D. Otto Lucas Amenga-Etego |
| author_sort | Collins M. Morang’a |
| collection | DOAJ |
| description | Malaria causes significant morbidity and mortality worldwide, disproportionately impacting sub-Saharan Africa. Disease phenotypes associated with Plasmodium falciparum infection can vary widely, from asymptomatic to life-threatening. To date, prevention efforts, particularly those related to vaccine development, have been hindered by an incomplete understanding of which factors impact host immune responses resulting in these divergent outcomes. Here, we conducted a field study of 224 individuals to determine host-parasite factors associated with symptomatic malaria “patients” compared to asymptomatic malaria-positive “controls” at both the community and healthy facility levels. We further performed comprehensive immune profiling to obtain deeper insights into differences in response between the pair. First, we determined the relationship between host age and parasite density in patients (n = 134/224) compared to controls (n = 90/224). Then, we applied single-cell RNA sequencing to compare the immunological phenotypes of 18,176 peripheral blood mononuclear cells isolated from a subset of the participants (n = 11/224), matched on age, sex, and parasite density. Patients had higher parasite densities compared to the controls, although the levels had a negative correlation with age in both groups, suggesting that they are key indicators of disease pathogenesis. On average, patients were characterized by a higher fractional abundance of monocytes and an upregulation of innate immune responses, including those to type I and type II interferons and tumor necrosis factor-alpha signaling via NFκB. Further, in the patients, we identified more putative interactions between antigen-presenting cells and proliferating CD4 T cells, and naïve CD8 T cells driven by MHC-I and MHC-II signaling pathways, respectively. Together, these findings highlight transcriptional differences between immune cell subsets associated with disease phenotypes that may help guide the development of improved malaria vaccines and new therapeutic interventions. |
| format | Article |
| id | doaj-art-5a15cf719f6749f5a0f47bcf9aa0b124 |
| institution | Kabale University |
| issn | 1535-3699 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Experimental Biology and Medicine |
| spelling | doaj-art-5a15cf719f6749f5a0f47bcf9aa0b1242025-01-03T04:11:11ZengFrontiers Media S.A.Experimental Biology and Medicine1535-36992025-01-0124910.3389/ebm.2024.1023310233scRNA-seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with uncomplicated malariaCollins M. Morang’a0Riley S. Drake1Riley S. Drake2Riley S. Drake3Riley S. Drake4Vincent N. Miao5Vincent N. Miao6Vincent N. Miao7Vincent N. Miao8Nancy K. Nyakoe9Dominic S. Y. Amuzu10Vincent Appiah11Yaw Aniweh12Yaw Bediako13Saikou Y. Bah14Alex K. Shalek15Alex K. Shalek16Alex K. Shalek17Alex K. Shalek18Gordon A. Awandare19Thomas D. Otto20Lucas Amenga-Etego21West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, GhanaProgram in Health Sciences and Technology, Harvard Medical School and Massachusetts Institute of Technology, Boston, MA, United StatesInstitute for Medical Engineering and Science (IMES), Department of Chemistry, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, United StatesRagon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesProgram in Health Sciences and Technology, Harvard Medical School and Massachusetts Institute of Technology, Boston, MA, United StatesInstitute for Medical Engineering and Science (IMES), Department of Chemistry, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, United StatesRagon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesWest African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, GhanaWest African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, GhanaWest African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, GhanaWest African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, GhanaWest African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, GhanaSchool of Infection and Immunity, Medical, Veterinary, and Life Sciences (MVLS), University of Glasgow, Glasgow, United KingdomProgram in Health Sciences and Technology, Harvard Medical School and Massachusetts Institute of Technology, Boston, MA, United StatesInstitute for Medical Engineering and Science (IMES), Department of Chemistry, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA, United StatesRagon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United StatesWest African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, GhanaSchool of Infection and Immunity, Medical, Veterinary, and Life Sciences (MVLS), University of Glasgow, Glasgow, United KingdomWest African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, GhanaMalaria causes significant morbidity and mortality worldwide, disproportionately impacting sub-Saharan Africa. Disease phenotypes associated with Plasmodium falciparum infection can vary widely, from asymptomatic to life-threatening. To date, prevention efforts, particularly those related to vaccine development, have been hindered by an incomplete understanding of which factors impact host immune responses resulting in these divergent outcomes. Here, we conducted a field study of 224 individuals to determine host-parasite factors associated with symptomatic malaria “patients” compared to asymptomatic malaria-positive “controls” at both the community and healthy facility levels. We further performed comprehensive immune profiling to obtain deeper insights into differences in response between the pair. First, we determined the relationship between host age and parasite density in patients (n = 134/224) compared to controls (n = 90/224). Then, we applied single-cell RNA sequencing to compare the immunological phenotypes of 18,176 peripheral blood mononuclear cells isolated from a subset of the participants (n = 11/224), matched on age, sex, and parasite density. Patients had higher parasite densities compared to the controls, although the levels had a negative correlation with age in both groups, suggesting that they are key indicators of disease pathogenesis. On average, patients were characterized by a higher fractional abundance of monocytes and an upregulation of innate immune responses, including those to type I and type II interferons and tumor necrosis factor-alpha signaling via NFκB. Further, in the patients, we identified more putative interactions between antigen-presenting cells and proliferating CD4 T cells, and naïve CD8 T cells driven by MHC-I and MHC-II signaling pathways, respectively. Together, these findings highlight transcriptional differences between immune cell subsets associated with disease phenotypes that may help guide the development of improved malaria vaccines and new therapeutic interventions.https://www.ebm-journal.org/articles/10.3389/ebm.2024.10233/fulluncomplicated malariaPlasmodium falciparumscRNA-Sequencingimmune responsescell-cell interactionsTNF-α signaling via NFκB |
| spellingShingle | Collins M. Morang’a Riley S. Drake Riley S. Drake Riley S. Drake Riley S. Drake Vincent N. Miao Vincent N. Miao Vincent N. Miao Vincent N. Miao Nancy K. Nyakoe Dominic S. Y. Amuzu Vincent Appiah Yaw Aniweh Yaw Bediako Saikou Y. Bah Alex K. Shalek Alex K. Shalek Alex K. Shalek Alex K. Shalek Gordon A. Awandare Thomas D. Otto Lucas Amenga-Etego scRNA-seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with uncomplicated malaria Experimental Biology and Medicine uncomplicated malaria Plasmodium falciparum scRNA-Sequencing immune responses cell-cell interactions TNF-α signaling via NFκB |
| title | scRNA-seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with uncomplicated malaria |
| title_full | scRNA-seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with uncomplicated malaria |
| title_fullStr | scRNA-seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with uncomplicated malaria |
| title_full_unstemmed | scRNA-seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with uncomplicated malaria |
| title_short | scRNA-seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with uncomplicated malaria |
| title_sort | scrna seq reveals elevated interferon responses and tnf α signaling via nfkb in monocytes in children with uncomplicated malaria |
| topic | uncomplicated malaria Plasmodium falciparum scRNA-Sequencing immune responses cell-cell interactions TNF-α signaling via NFκB |
| url | https://www.ebm-journal.org/articles/10.3389/ebm.2024.10233/full |
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