C5a Enhances Dysregulated Inflammatory and Angiogenic Responses to Malaria In Vitro: Potential Implications for Placental Malaria
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BACKGROUND: Placental malaria (PM) is a leading cause of maternal and infant mortality. Although the accumulation of parasitized erythrocytes (PEs) and monocytes within the placenta is thought to contribute to the pathophysiology of PM, the molecular mechanisms underlying PM remain unclear. Based on the hypothesis that excessive complement activation may contribute to PM, in particular generation of the potent inflammatory peptide C5a, we investigated the role of C5a in the pathogenesis of PM in vitro and in vivo. METHODOLOGY AND PRINCIPAL FINDINGS: Using primary human monocytes, the interaction between C5a and malaria in vitro was assessed. CSA- and CD36-binding PEs induced activation of C5 in the presence of human serum. Plasmodium falciparum GPI (pfGPI) enhanced C5a receptor expression (CD88) on monocytes, and the co-incubation of monocytes with C5a and pfGPI resulted in the synergistic induction of cytokines (IL-6, TNF, IL-1beta, and IL-10), chemokines (IL-8, MCP-1, MIP1alpha, MIP1beta) and the anti-angiogenic factor sFlt-1 in a time and dose-dependent manner. This dysregulated response was abrogated by C5a receptor blockade. To assess the potential role of C5a in PM, C5a plasma levels were measured in malaria-exposed primigravid women in western Kenya. Compared to pregnant women without malaria, C5a levels were significantly elevated in women with PM. CONCLUSIONS AND SIGNIFICANCE: These results suggest that C5a may contribute to the pathogenesis of PM by inducing dysregulated inflammatory and angiogenic responses that impair placental function.
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Some studies concluded that complications during pregnancy and foetal death in P. falciparum placental malaria might be determined by changes in the regulation of apoptosis via Fas/FasL and increased Th1 immune responses in the syncytiotrophoblast.
“Some studies concluded that complications during pregnancy and foetal death observed in P. falciparum placental malaria might be determined by changes in the regulation of apoptosis, via Fas /FasL [9], and increased Th1 immune responses in the syncytiotrophoblast [10,11].”
From Submicroscopic infection of placenta by Plasmodium produces Th1/Th2 cytokine imbalance, inflammation and hypoxia in women from north-west Colombia (2014) · cites this paper as [10]
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- Authors
- Conroy, A., Serghides, L., Finney, C., Owino, S. O., Kumar, S., Gowda, D. C., Liles, W. C., Moore, J. M., & Kain, K. C.
- Affiliations
- University of Toronto (CA)
- University of Georgia (US)
- Pennsylvania State University (US)
- University Health Network (CA)
- Corresponding author
- Kain, Kevin C.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-03-24
- Volume
- 4
- Issue
- 3
- Pages
- e4953
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2655724
- OpenAlex
- W2002561997
- Cited by
- 81
- References
- 71
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 11 · 2014: 4 · 2013: 12 · 2012: 10
- FWCI
- 6.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Genome Canada
- Ontario Genomics
- Ontario Genomics Institute
- Canada Research Chairs (13721)
- National Institutes of Health
- U.S. Public Health Service (R01050240)
- Canadian Institutes of Health Research (13721, MT-13721)
- National Institute of Allergy and Infectious Diseases (R01AI050240)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Keywords
- placental malaria, C5a, complement activation, Plasmodium falciparum, monocytes, soluble fms-like tyrosine kinase-1, angiogenesis, inflammation, cytokines, chemokines, placenta, primigravid women, malaria in pregnancy
- MeSH terms
- Animals, Cells, Cultured, Female, Humans, Inflammation, Kenya, Malaria, Monocytes, Neovascularization, Pathologic, Placenta, Plasmodium falciparum, Pregnancy, Complement C5a
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