Mauel, Katharina: Cellular and molecular dynamics of splenic myeloid cells during blood-stage malaria. - Bonn, 2024. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Melbourne.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-79563
@phdthesis{handle:20.500.11811/12492,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-79563,
author = {{Katharina Mauel}},
title = {Cellular and molecular dynamics of splenic myeloid cells during blood-stage malaria},
school = {{Rheinische Friedrich-Wilhelms-Universität Bonn} and {University of Melbourne}},
year = 2024,
month = oct,

note = {The spleen is a secondary lymphoid organ with the essential function of maintaining blood homeostasis through its function as a filtering system. Aberrant erythrocytes and infectious particles are recognized and eliminated by specialized phagocytes, the splenic macrophages, that reside in the spleen. These splenic macrophages have different specializations and phenotypes dependent on their sub-tissular niche of residence. To date, four different macrophage subtypes have been identified in distinct splenic compartments: red pulp macrophages (RPM), marginal metallophilic macrophages, marginal zone macrophages and white pulp macrophages. The ontogeny and function of these different splenic macrophages is incompletely understood. Here, novel fate-mapping models were developed to discover new biology on the fate and function of the splenic macrophage populations during steady-state and in the context of parasitic or viral infection. With high-dimensional flow cytometry and immunofluorescent imaging, a so far unrecognized CD163+ RPM subpopulation that develops early during embryogenesis was identified. The CD163 receptor is responsible for uptake of free heme and thereby prevents oxidative stress in the tissue. To understand the functional role of the CD163 receptor on RPM, mice were challenged with blood-stage malaria infection, and the dynamics of the splenic macrophage populations studied. As part of the natural course of infection, Plasmodium parasites cause erythrolysis and the release of free heme. Upon challenge with blood-stage malaria, CD163+ RPM disappeared seven days after infection with P. chabaudi, P. bergheii, and P. yoelii, while CD163- RPM were completely replenished by monocyte-derived macrophages. The splenic architecture was disrupted during acute-phase malaria, and the distinct anatomical zones of red and white pulp, which harbor different macrophage subpopulations, were dissolved. However, while the splenic architecture recovered after the resolution of infection, the spatiotemporal myeloid cell dynamics and functions remained altered. Longitudinal studies, including chloroquine treatment to achieve sterile control of infection, revealed that CD163+ RPM did not recover after 90 days, when the tissue largely returned to its homeostatic state. Using single-cell RNA-sequencing, two distinct cluster of RPM were identified with differential expression of CD163 in the steady-state. The annotated CD163+ RPM cluster remained 90 days after P. chabaudi infection, but CD163 expression was at almost absent compared to expression observed in naïve mice, indicating a persistence of this macrophage population per se, but an inability of these cells to express CD163 after parasite exposure. The failure to express CD163 after infection was also observed in viral infection-models and caused a partial loss of the CD163+ RPM population, that does not recover to steady-state numbers long-term. To test the function of the CD163 receptor, CD163-/- mice were infected showing that CD163 had no impact on the control of parasitemia but lead to an abrogated regeneration of the structure of the marginal zone. In contrast, genetic deficiency of marginal zone macrophages resulted in increased parasitemia during the acute phase of the infection. In summary, this study presents a comprehensive ontogenetic and functional map of splenic macrophage populations and provides evidence that the tight interplay of RPM and marginal zone macrophages is important to resolve malaria infection.},
url = {https://hdl.handle.net/20.500.11811/12492}
}

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