Role of innate lymphoid cells in type 1-dominated experimental Plasmodium berghei ANKA and type 2-dominated Litomosoides sigmodontis infection
Role of innate lymphoid cells in type 1-dominated experimental Plasmodium berghei ANKA and type 2-dominated Litomosoides sigmodontis infection
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DissertationDate of Exam
13.10.2021Date of Publication
27.10.2021Advisor
Hörauf, AchimCo-Referee
Burgdorf, SvenMetadata
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Abstract
Malaria and filariasis remain among the biggest health problems in the tropics and subtropics, especially in Africa, and in the case of malaria among the ten most frequent causes of death. The parasites that cause malaria and filariasis, plasmodia and helminths, respectively, trigger completely differently directed immune responses in their host. Plasmodium infection can lead to considerable complications as a result of a strong systemic inflammation including cerebral malaria, which is a life-threatening condition. Helminths regulate the immune system of their host to achieve an immune tolerance that ensures their survival and limits morbidities. Recently, a new cell population within the innate immune system has been characterized: innate lymphoid cells (ILCs). Involvement of ILCs in various infectious diseases has already been demonstrated. However, for cerebral malaria and filariasis no studies have yet assessed the influence of these cells on infection. To investigate the role and function of ILCs in these diseases, the experimental infection mouse models with Plasmodium berghei ANKA and the rodent filarial nematode Litomosoides sigmodontis were used.
Establishment of staining procedures for flow cytometry was followed by experiments with P. berghei ANKA (PbA)-infected wild-type (WT) C57BL/6 mice, which develop experimental cerebral malaria (ECM) after infection, and PbA-infected Ifnar1-/- mice, which are protected from ECM. These experiments provided evidence for the involvement of ILC1s and NK cells in the immune response to PbA, since these cells increased in numbers during infection and infiltrated the brain. NK cells isolated from the spleens of ECM-protected Ifnar1-/- mice were significantly less activated and produced fewer effector molecules than those isolated from WT mice. This suggested that in ECM-protected mice the NK cells might have an influence on the protective mechanism. However, depletion of NK cells still led to ECM development in WT mice, which precludes a dominant role of NK cells in the development of ECM, and did not affect the protection of Ifnar1-/- mice. Thus, a direct role of NK cells and ILC1s in the protection from ECM was excluded, although those cells are important mediators in the immune response to PbA in general and infiltrate the brain of ECM-positive mice. Interestingly, infected Ifnar1-/- mice further showed a strong regulatory and type 2 immune response characterized by an increase of eosinophils and increased IL-13 levels in the spleen. Depletion of eosinophils led to ECM development in Ifnar1-/- mice, suggesting a protective role of eosinophils from PbA-induced ECM.
In addition, experiments were performed with L. sigmodontis-infected animals, comparing WT BALB/c mice that develop a chronic infection and WT C57BL/6 mice that eliminate the infection right after the molting into adult worms. Kinetics were performed to analyze the occurrence of ILC populations during the course of infection in both strains. A significantly higher number of ILC2s in the pleural cavity in infected C57BL/6 mice was found compared to BALB/c animals and a strong type 2 immune response was observed with very high IL-5 levels in infected WT C57BL/6 mice. ILC2s were the main producers of IL-5. In the absence of T cells (Rag2-/- mice), ILC2s remained one of the dominant sources of IL-5, together with eosinophils. Depletion of ILC2s in T and B cell-deficient and susceptible Rag2-/- mice did not lead to an increase in adult worm burden, but significantly increased the numbers of the filarial progeny, the microfilariae. Thus, ILC2s do not have a decisive impact on the adult worm burden, but do control the microfilarial load in the absence of T and B cells in C57BL/6 mice.
In summary, this thesis makes a decisive contribution to the detailed characterization of ILCs in the immune response to parasitic infections. By using two immunologically different models, it was shown that depending on the model, different ILC populations are involved. The data underline the heterogeneity of ILCs subsets and their contribution, despite their small proportion among all immune cells, to protective immune responses.
Establishment of staining procedures for flow cytometry was followed by experiments with P. berghei ANKA (PbA)-infected wild-type (WT) C57BL/6 mice, which develop experimental cerebral malaria (ECM) after infection, and PbA-infected Ifnar1-/- mice, which are protected from ECM. These experiments provided evidence for the involvement of ILC1s and NK cells in the immune response to PbA, since these cells increased in numbers during infection and infiltrated the brain. NK cells isolated from the spleens of ECM-protected Ifnar1-/- mice were significantly less activated and produced fewer effector molecules than those isolated from WT mice. This suggested that in ECM-protected mice the NK cells might have an influence on the protective mechanism. However, depletion of NK cells still led to ECM development in WT mice, which precludes a dominant role of NK cells in the development of ECM, and did not affect the protection of Ifnar1-/- mice. Thus, a direct role of NK cells and ILC1s in the protection from ECM was excluded, although those cells are important mediators in the immune response to PbA in general and infiltrate the brain of ECM-positive mice. Interestingly, infected Ifnar1-/- mice further showed a strong regulatory and type 2 immune response characterized by an increase of eosinophils and increased IL-13 levels in the spleen. Depletion of eosinophils led to ECM development in Ifnar1-/- mice, suggesting a protective role of eosinophils from PbA-induced ECM.
In addition, experiments were performed with L. sigmodontis-infected animals, comparing WT BALB/c mice that develop a chronic infection and WT C57BL/6 mice that eliminate the infection right after the molting into adult worms. Kinetics were performed to analyze the occurrence of ILC populations during the course of infection in both strains. A significantly higher number of ILC2s in the pleural cavity in infected C57BL/6 mice was found compared to BALB/c animals and a strong type 2 immune response was observed with very high IL-5 levels in infected WT C57BL/6 mice. ILC2s were the main producers of IL-5. In the absence of T cells (Rag2-/- mice), ILC2s remained one of the dominant sources of IL-5, together with eosinophils. Depletion of ILC2s in T and B cell-deficient and susceptible Rag2-/- mice did not lead to an increase in adult worm burden, but significantly increased the numbers of the filarial progeny, the microfilariae. Thus, ILC2s do not have a decisive impact on the adult worm burden, but do control the microfilarial load in the absence of T and B cells in C57BL/6 mice.
In summary, this thesis makes a decisive contribution to the detailed characterization of ILCs in the immune response to parasitic infections. By using two immunologically different models, it was shown that depending on the model, different ILC populations are involved. The data underline the heterogeneity of ILCs subsets and their contribution, despite their small proportion among all immune cells, to protective immune responses.
Subjects
Innate lymphoid cells, ILC1s, NK cells, ILC2s, experimental cerebral malaria, Plasmodium berghei ANKA, Ifnar1-/- mice, filariae, Litomosoides sigmodontis, microfilariae, type 2 immune response, IL-5, Rag2-/- mice, protective immune responses, filariasis, malaria
Classification (DDC)
570 Biowissenschaften, Biologie 610 Medizin, GesundheitReichwald, Julia Jennifer: Role of innate lymphoid cells in type 1-dominated experimental Plasmodium berghei ANKA and type 2-dominated Litomosoides sigmodontis infection. - Bonn, 2021. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-64159
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-64159
@phdthesis{handle:20.500.11811/9382,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-64159,
author = {{Julia Jennifer Reichwald}},
title = {Role of innate lymphoid cells in type 1-dominated experimental Plasmodium berghei ANKA and type 2-dominated Litomosoides sigmodontis infection},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2021,
month = oct,
note = {Malaria and filariasis remain among the biggest health problems in the tropics and subtropics, especially in Africa, and in the case of malaria among the ten most frequent causes of death. The parasites that cause malaria and filariasis, plasmodia and helminths, respectively, trigger completely differently directed immune responses in their host. Plasmodium infection can lead to considerable complications as a result of a strong systemic inflammation including cerebral malaria, which is a life-threatening condition. Helminths regulate the immune system of their host to achieve an immune tolerance that ensures their survival and limits morbidities. Recently, a new cell population within the innate immune system has been characterized: innate lymphoid cells (ILCs). Involvement of ILCs in various infectious diseases has already been demonstrated. However, for cerebral malaria and filariasis no studies have yet assessed the influence of these cells on infection. To investigate the role and function of ILCs in these diseases, the experimental infection mouse models with Plasmodium berghei ANKA and the rodent filarial nematode Litomosoides sigmodontis were used.
Establishment of staining procedures for flow cytometry was followed by experiments with P. berghei ANKA (PbA)-infected wild-type (WT) C57BL/6 mice, which develop experimental cerebral malaria (ECM) after infection, and PbA-infected Ifnar1-/- mice, which are protected from ECM. These experiments provided evidence for the involvement of ILC1s and NK cells in the immune response to PbA, since these cells increased in numbers during infection and infiltrated the brain. NK cells isolated from the spleens of ECM-protected Ifnar1-/- mice were significantly less activated and produced fewer effector molecules than those isolated from WT mice. This suggested that in ECM-protected mice the NK cells might have an influence on the protective mechanism. However, depletion of NK cells still led to ECM development in WT mice, which precludes a dominant role of NK cells in the development of ECM, and did not affect the protection of Ifnar1-/- mice. Thus, a direct role of NK cells and ILC1s in the protection from ECM was excluded, although those cells are important mediators in the immune response to PbA in general and infiltrate the brain of ECM-positive mice. Interestingly, infected Ifnar1-/- mice further showed a strong regulatory and type 2 immune response characterized by an increase of eosinophils and increased IL-13 levels in the spleen. Depletion of eosinophils led to ECM development in Ifnar1-/- mice, suggesting a protective role of eosinophils from PbA-induced ECM.
In addition, experiments were performed with L. sigmodontis-infected animals, comparing WT BALB/c mice that develop a chronic infection and WT C57BL/6 mice that eliminate the infection right after the molting into adult worms. Kinetics were performed to analyze the occurrence of ILC populations during the course of infection in both strains. A significantly higher number of ILC2s in the pleural cavity in infected C57BL/6 mice was found compared to BALB/c animals and a strong type 2 immune response was observed with very high IL-5 levels in infected WT C57BL/6 mice. ILC2s were the main producers of IL-5. In the absence of T cells (Rag2-/- mice), ILC2s remained one of the dominant sources of IL-5, together with eosinophils. Depletion of ILC2s in T and B cell-deficient and susceptible Rag2-/- mice did not lead to an increase in adult worm burden, but significantly increased the numbers of the filarial progeny, the microfilariae. Thus, ILC2s do not have a decisive impact on the adult worm burden, but do control the microfilarial load in the absence of T and B cells in C57BL/6 mice.
In summary, this thesis makes a decisive contribution to the detailed characterization of ILCs in the immune response to parasitic infections. By using two immunologically different models, it was shown that depending on the model, different ILC populations are involved. The data underline the heterogeneity of ILCs subsets and their contribution, despite their small proportion among all immune cells, to protective immune responses.},
url = {https://hdl.handle.net/20.500.11811/9382}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-64159,
author = {{Julia Jennifer Reichwald}},
title = {Role of innate lymphoid cells in type 1-dominated experimental Plasmodium berghei ANKA and type 2-dominated Litomosoides sigmodontis infection},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2021,
month = oct,
note = {Malaria and filariasis remain among the biggest health problems in the tropics and subtropics, especially in Africa, and in the case of malaria among the ten most frequent causes of death. The parasites that cause malaria and filariasis, plasmodia and helminths, respectively, trigger completely differently directed immune responses in their host. Plasmodium infection can lead to considerable complications as a result of a strong systemic inflammation including cerebral malaria, which is a life-threatening condition. Helminths regulate the immune system of their host to achieve an immune tolerance that ensures their survival and limits morbidities. Recently, a new cell population within the innate immune system has been characterized: innate lymphoid cells (ILCs). Involvement of ILCs in various infectious diseases has already been demonstrated. However, for cerebral malaria and filariasis no studies have yet assessed the influence of these cells on infection. To investigate the role and function of ILCs in these diseases, the experimental infection mouse models with Plasmodium berghei ANKA and the rodent filarial nematode Litomosoides sigmodontis were used.
Establishment of staining procedures for flow cytometry was followed by experiments with P. berghei ANKA (PbA)-infected wild-type (WT) C57BL/6 mice, which develop experimental cerebral malaria (ECM) after infection, and PbA-infected Ifnar1-/- mice, which are protected from ECM. These experiments provided evidence for the involvement of ILC1s and NK cells in the immune response to PbA, since these cells increased in numbers during infection and infiltrated the brain. NK cells isolated from the spleens of ECM-protected Ifnar1-/- mice were significantly less activated and produced fewer effector molecules than those isolated from WT mice. This suggested that in ECM-protected mice the NK cells might have an influence on the protective mechanism. However, depletion of NK cells still led to ECM development in WT mice, which precludes a dominant role of NK cells in the development of ECM, and did not affect the protection of Ifnar1-/- mice. Thus, a direct role of NK cells and ILC1s in the protection from ECM was excluded, although those cells are important mediators in the immune response to PbA in general and infiltrate the brain of ECM-positive mice. Interestingly, infected Ifnar1-/- mice further showed a strong regulatory and type 2 immune response characterized by an increase of eosinophils and increased IL-13 levels in the spleen. Depletion of eosinophils led to ECM development in Ifnar1-/- mice, suggesting a protective role of eosinophils from PbA-induced ECM.
In addition, experiments were performed with L. sigmodontis-infected animals, comparing WT BALB/c mice that develop a chronic infection and WT C57BL/6 mice that eliminate the infection right after the molting into adult worms. Kinetics were performed to analyze the occurrence of ILC populations during the course of infection in both strains. A significantly higher number of ILC2s in the pleural cavity in infected C57BL/6 mice was found compared to BALB/c animals and a strong type 2 immune response was observed with very high IL-5 levels in infected WT C57BL/6 mice. ILC2s were the main producers of IL-5. In the absence of T cells (Rag2-/- mice), ILC2s remained one of the dominant sources of IL-5, together with eosinophils. Depletion of ILC2s in T and B cell-deficient and susceptible Rag2-/- mice did not lead to an increase in adult worm burden, but significantly increased the numbers of the filarial progeny, the microfilariae. Thus, ILC2s do not have a decisive impact on the adult worm burden, but do control the microfilarial load in the absence of T and B cells in C57BL/6 mice.
In summary, this thesis makes a decisive contribution to the detailed characterization of ILCs in the immune response to parasitic infections. By using two immunologically different models, it was shown that depending on the model, different ILC populations are involved. The data underline the heterogeneity of ILCs subsets and their contribution, despite their small proportion among all immune cells, to protective immune responses.},
url = {https://hdl.handle.net/20.500.11811/9382}
}
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