Browsing by Author "Obimbo, Moses"

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    PublicationOpen Access
    Placental malaria is associated with a TLR–Endothelin-3–oxidative damage response in 1 human placenta tissues
    (medRxiv and bioRxiv, 2024-04-20) Chenge, Samuel; Mbalitsi, Melvin; Ngure, Harrison; Obimbo, Moses; Singoei, Mercy; Kangogo, Mourine; Kanoi1, Bernard N; Gitaka, Jesse; Kobia, Francis M.
    Placental malaria, which is mainly caused by the sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, is an important driver of poor pregnancy outcomes, including fetal growth restriction, preterm birth, and stillbirth. However, the mechanisms underlying its adverse outcomes are unclear. Mouse models have previously shown that placental malaria (PM) triggers a proinflammatory response in the placenta, which is accompanied by a fetal Toll-like receptor (TLR)4-mediated innate immune response associated with improved fetal outcomes. Here, we used hematoxylin and eosin staining to identify PM-positive and negative samples in our biobank of placentas donated by women living in a malaria-endemic region of Kenya and assessed the impact of PM on the expression of TLRs, Endothelins, and oxidative damage. RT-qPCR analysis revealed that PM was associated with an upregulation of TLR4, TLR7, and Endothelin-3. Moreover, immunohistochemistry showed that PM was associated with elevated expression levels of the oxidative DNA damage marker, 8-hydroxy-2’-deoxyguanosine, while RT-qPCR revealed that this was accompanied by an upregulation of p21, an inhibitor of cell cycle progression and marker of cellular response to DNA damage. These findings allude to a novel mechanism of PM pathogenesis driven by a TLR–Endothelin-3–oxidative DNA damage signaling axis.
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    PublicationOpen Access
    Potential pharmacologic interventions targeting TLR signaling in placental malaria
    (Cell press, 2022-05) Obimbo, Moses; Gitaka , Jesse; Smith, Roger; Kobia, Francis M.; Maiti, Kaushik
    In P. falciparum malaria endemic regions, expectant women are at high risk of placental malaria due to P. falciparum sequestration in the placenta, which adversely affects pregnancy outcomes. Placental malaria persists even when the peripheral parasite has been cleared from maternal circulation or is undetectable, and is detectable only by placental histological analysis. There are no interventions for clearing P. falciparum from the placenta or reversing associated placental injury. Poor placental malaria outcomes are attributed to maternal innate immune reactions to P. falciparum sequestration in the placenta. Studies show that fetal innate immune responses counter maternal responses, improving placental malaria outcomes. Evidence suggests that pharmacologically targeting fetal–maternal innate immune interactions during placental malaria may improve pregnancy outcomes. Complications from placental malaria cause poor pregnancy outcomes, including low birthweight, preterm delivery, and stillbirths. Many of these complications are driven by maternal innate proinflammatory responses to the sequestration of Plasmodium falciparum in the placenta. However, recent studies show that, in reaction to maternal innate immune responses that are detrimental to the fetus, the fetus mounts innate immune counter-responses that ameliorate pregnancy outcomes. Such fetal–maternal conflict in placental malaria has potential for pharmacologic modulation for better pregnancy outcomes. Here, we discuss placental malaria pathogenesis, its complications, and the role of innate immunity and fetal–maternal innate immune conflict in placental malaria. Finally, we discuss pharmacologic immunomodulatory strategies and agents with the potential to improve placental malaria outcomes.