Immune responses to malaria - Across early life, chronic exposure, and acute malaria
Mortazavi, Susanne LU
(2026)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Malaria caused by Plasmodium falciparum (P. falciparum) remains a major cause of morbidity and mortality, particularly in sub-Saharan Africa. Immunity develops gradually after repeated exposure and is largely mediated by antibodies, yet the mechanisms regulating the development and function of humoral immunity, including the roles of B-cell subsets and inflammatory mediators, remain incompletely understood. This thesis therefore investigates humoral immune responses to P. falciparum, focusing on antibody function, B-cell differentiation, and immune regulatory pathways across different exposure contexts.
In a longitudinal Ugandan mother-infant cohort (Paper I), C1q-fixing antibodies against P. falciparum merozoites were high in infants... (More) - Malaria caused by Plasmodium falciparum (P. falciparum) remains a major cause of morbidity and mortality, particularly in sub-Saharan Africa. Immunity develops gradually after repeated exposure and is largely mediated by antibodies, yet the mechanisms regulating the development and function of humoral immunity, including the roles of B-cell subsets and inflammatory mediators, remain incompletely understood. This thesis therefore investigates humoral immune responses to P. falciparum, focusing on antibody function, B-cell differentiation, and immune regulatory pathways across different exposure contexts.
In a longitudinal Ugandan mother-infant cohort (Paper I), C1q-fixing antibodies against P. falciparum merozoites were high in infants at birth and comparable to maternal levels, consistent with effective placental transfer. Levels declined during early infancy and increased as endogenous responses developed. C1q-fixing antibodies correlated with schizont-specific IgG and atypical memory B cells, linking functional antibodies to parasite exposure. In the same cohort (Paper II), the immunomodulatory protein osteopontin (OPN) was highest in early infancy and exceeded maternal levels. OPN correlated positively with naïve B cells and B-cell activating factor, and negatively with atypical and IgG memory B cells. No direct effect on parasite growth was observed in vitro. These results suggest a role for OPN in immune regulation during early B-cell development rather than direct antiparasitic activity. During acute malaria (Paper III), OPN levels were elevated in children in Uganda and in adults with imported malaria, and correlated with parasitemia. In contrast, adults living in endemic settings showed lower OPN responses. Elevated levels were also observed in non-malarial febrile illness, indicating that OPN reflects general inflammatory activation rather than malaria-specific responses. Finally, PD-1 expression across B-cell subsets (Paper IV) was influenced by both exposure history and infection status. Chronic malaria exposure was associated with expansion of atypical and activated memory B cells. Increased PD-1 expression was observed specifically in individuals with acute malaria and prior exposure, with broad upregulation across B-cell subsets. PD-1 expression was also enriched among P. falciparum-binding B cells. Together, these findings suggest a role for PD-1 in longer-term immune regulation.
This thesis provides insight into how antibodies, B cells, and immunomodulatory signals develop and are regulated across different stages of life and infection. Future studies should determine how these immune features influence parasite-specific B-cell responses and functional antibody activity, which are important for understanding the development of naturally acquired immunity to malaria and may inform the design of more effective and durable malaria vaccines. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/26675e8a-2c97-4287-8369-a196f6920b9d
- author
- Mortazavi, Susanne
LU
- supervisor
- opponent
-
- Associate Research Professor Moncunill, Gemma, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain
- organization
- publishing date
- 2026
- type
- Thesis
- publication status
- published
- subject
- keywords
- Malaria, Immunity, Complement, Osteopontin, PD-1
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2026:80
- pages
- 106 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/61828028972
- defense date
- 2026-05-22 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-878-8
- language
- English
- LU publication?
- yes
- id
- 26675e8a-2c97-4287-8369-a196f6920b9d
- date added to LUP
- 2026-04-27 09:30:11
- date last changed
- 2026-04-30 08:20:21
@phdthesis{26675e8a-2c97-4287-8369-a196f6920b9d,
abstract = {{Malaria caused by Plasmodium falciparum (P. falciparum) remains a major cause of morbidity and mortality, particularly in sub-Saharan Africa. Immunity develops gradually after repeated exposure and is largely mediated by antibodies, yet the mechanisms regulating the development and function of humoral immunity, including the roles of B-cell subsets and inflammatory mediators, remain incompletely understood. This thesis therefore investigates humoral immune responses to P. falciparum, focusing on antibody function, B-cell differentiation, and immune regulatory pathways across different exposure contexts.<br/>In a longitudinal Ugandan mother-infant cohort (Paper I), C1q-fixing antibodies against P. falciparum merozoites were high in infants at birth and comparable to maternal levels, consistent with effective placental transfer. Levels declined during early infancy and increased as endogenous responses developed. C1q-fixing antibodies correlated with schizont-specific IgG and atypical memory B cells, linking functional antibodies to parasite exposure. In the same cohort (Paper II), the immunomodulatory protein osteopontin (OPN) was highest in early infancy and exceeded maternal levels. OPN correlated positively with naïve B cells and B-cell activating factor, and negatively with atypical and IgG memory B cells. No direct effect on parasite growth was observed in vitro. These results suggest a role for OPN in immune regulation during early B-cell development rather than direct antiparasitic activity. During acute malaria (Paper III), OPN levels were elevated in children in Uganda and in adults with imported malaria, and correlated with parasitemia. In contrast, adults living in endemic settings showed lower OPN responses. Elevated levels were also observed in non-malarial febrile illness, indicating that OPN reflects general inflammatory activation rather than malaria-specific responses. Finally, PD-1 expression across B-cell subsets (Paper IV) was influenced by both exposure history and infection status. Chronic malaria exposure was associated with expansion of atypical and activated memory B cells. Increased PD-1 expression was observed specifically in individuals with acute malaria and prior exposure, with broad upregulation across B-cell subsets. PD-1 expression was also enriched among P. falciparum-binding B cells. Together, these findings suggest a role for PD-1 in longer-term immune regulation.<br/><br/>This thesis provides insight into how antibodies, B cells, and immunomodulatory signals develop and are regulated across different stages of life and infection. Future studies should determine how these immune features influence parasite-specific B-cell responses and functional antibody activity, which are important for understanding the development of naturally acquired immunity to malaria and may inform the design of more effective and durable malaria vaccines.}},
author = {{Mortazavi, Susanne}},
isbn = {{978-91-8021-878-8}},
issn = {{1652-8220}},
keywords = {{Malaria; Immunity; Complement; Osteopontin; PD-1}},
language = {{eng}},
number = {{2026:80}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Immune responses to malaria - Across early life, chronic exposure, and acute malaria}},
url = {{https://lup.lub.lu.se/search/files/248585782/Susanne_Mortazavi_-_WEBB.pdf}},
year = {{2026}},
}