Immune modulation by experimental filarial infection and its impact on E. coli-induced sepsis
Immune modulation by experimental filarial infection and its impact on E. coli-induced sepsis
Dokument öffnen (2.2MB)Art der Hochschulschrift
DissertationPrüfungsdatum
20.10.2015Datum der Veröffentlichung
12.11.2015Erstgutachter
Hörauf, AchimZweitgutachter
Schultze, Joachim L.Metadaten
Zur Langanzeige
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Inhalt
Helminths cause so-called neglected tropical diseases in tropical and sub-tropical regions and are prevalent in almost one third of mankind. Thus, co-infections of helminths with other pathogens are common. However, the effects of helminths on outcomes of infections with unrelated pathogens like bacteria are rather poorly understood and underrepresented in biomedical research. In this thesis it was investigated, how chronic filarial infection influences acute bacterial challenge infections. To achieve this, mice chronically infected with the filarial nematode Litomosoides sigmodontis (L.s.) were intraperitoneally challenged with the gram-negative bacterium Escherichia coli. Sepsis severity was determined by survival, development of hypothermia, systemic pro-inflammatory cytokine and chemokine levels. Clearance of bacteria and recruitment of immune cells to the peritoneum were determined 6 hours after bacterial challenge. The role of nematode-induced immune cell populations as regulatory T cells, eosinophils and macrophages and their receptors (e.g. Toll-like receptor 2, IL-4 receptor) were investigated using various gene-deficient mouse strains. In order to further elucidate the protective mechanisms, in vitro studies and adoptive cell transfers were performed.
This thesis demonstrates that chronic infection with the filarial nematode L. sigmodontis provides a significant survival benefit to E. coli-induced sepsis in mice. This was accompanied by attenuated hypothermia and reduced systemic cytokine/chemokine secretion. Chronically L.s.-infected mice displayed an improved bacterial control and increased recruitment of neutrophils and eosinophils, which was accompanied by a reduced activation and apoptosis of peritoneal macrophages. Depletion of macrophages by Clodronate liposomes indicated a protective role of macrophages in the L.s.-mediated protection against E. coli-induced sepsis. L.s. infection induced RELMα expression on peritoneal macrophages in wildtype BALB/c mice following E. coli challenge, indicating a possible switch to an alternatively activated macrophage (AAM) phenotype. However, L.s.-infected IL-4Rα/IL-5-/- and IL-4-/- mice that were devoid of AAM were still protected from E. coli sepsis. These experiments suggest that the presence of macrophages is necessary, but the induction of an AAM phenotype is not required to improve sepsis outcome by L.s. infection.
Most filarial species have endosymbiotic Wolbachia bacteria that activate innate cells and reduce subsequent responses to innate stimuli via Toll-like receptor 2 (TLR2). In vitro stimulation with Wolbachia-containing preparations in wildtype but not TLR2-deficient macrophages reduced TNFα secretion following LPS-restimulation. These macrophages showed enhanced phagocytosis and uptake of bacteria and produced more bactericidal nitric oxide in a TLR2 dependent manner. Accordingly, the protective effect of chronic L.s. infection was lost in TLR2-deficient mice promoting a concept of Wolbachia- and TLR2-mediated immune modulation. Moreover, repeated injections of L.s. and Wolbachia-derived preparations improved sepsis outcome in a TLR2-dependent manner.
Finally, macrophage transfer experiments demonstrated that macrophages from L.s.-infected mice improved sepsis outcome of recipient mice, whereas macrophages from L.s.-infected TLR2-/- mice and naïve BALB/c mice did not significantly improve sepsis outcome in recipient mice.
This thesis provides immunologic insight to the complex interplay of filarial and bacterial co-infection and demonstrates a filariae- and Wolbachia-induced mechanism that protects mice via a dual beneficial effect on phagocytes, which permits improved containment of bacteria and reduced systemic inflammation. This may help to find new therapeutic interventions to prevent severe sepsis also in human patients.
This thesis demonstrates that chronic infection with the filarial nematode L. sigmodontis provides a significant survival benefit to E. coli-induced sepsis in mice. This was accompanied by attenuated hypothermia and reduced systemic cytokine/chemokine secretion. Chronically L.s.-infected mice displayed an improved bacterial control and increased recruitment of neutrophils and eosinophils, which was accompanied by a reduced activation and apoptosis of peritoneal macrophages. Depletion of macrophages by Clodronate liposomes indicated a protective role of macrophages in the L.s.-mediated protection against E. coli-induced sepsis. L.s. infection induced RELMα expression on peritoneal macrophages in wildtype BALB/c mice following E. coli challenge, indicating a possible switch to an alternatively activated macrophage (AAM) phenotype. However, L.s.-infected IL-4Rα/IL-5-/- and IL-4-/- mice that were devoid of AAM were still protected from E. coli sepsis. These experiments suggest that the presence of macrophages is necessary, but the induction of an AAM phenotype is not required to improve sepsis outcome by L.s. infection.
Most filarial species have endosymbiotic Wolbachia bacteria that activate innate cells and reduce subsequent responses to innate stimuli via Toll-like receptor 2 (TLR2). In vitro stimulation with Wolbachia-containing preparations in wildtype but not TLR2-deficient macrophages reduced TNFα secretion following LPS-restimulation. These macrophages showed enhanced phagocytosis and uptake of bacteria and produced more bactericidal nitric oxide in a TLR2 dependent manner. Accordingly, the protective effect of chronic L.s. infection was lost in TLR2-deficient mice promoting a concept of Wolbachia- and TLR2-mediated immune modulation. Moreover, repeated injections of L.s. and Wolbachia-derived preparations improved sepsis outcome in a TLR2-dependent manner.
Finally, macrophage transfer experiments demonstrated that macrophages from L.s.-infected mice improved sepsis outcome of recipient mice, whereas macrophages from L.s.-infected TLR2-/- mice and naïve BALB/c mice did not significantly improve sepsis outcome in recipient mice.
This thesis provides immunologic insight to the complex interplay of filarial and bacterial co-infection and demonstrates a filariae- and Wolbachia-induced mechanism that protects mice via a dual beneficial effect on phagocytes, which permits improved containment of bacteria and reduced systemic inflammation. This may help to find new therapeutic interventions to prevent severe sepsis also in human patients.
Schlagwörter
Filariae, sepsis, macrophages, immunomodulation, inflammation, coinfection, innate immunity, tolerance
Klassifikation (DDC)
570 Biowissenschaften, Biologie 610 Medizin, GesundheitGondorf, Fabian: Immune modulation by experimental filarial infection and its impact on E. coli-induced sepsis. - Bonn, 2015. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-41745
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5n-41745
@phdthesis{handle:20.500.11811/6550,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-41745,
author = {{Fabian Gondorf}},
title = {Immune modulation by experimental filarial infection and its impact on E. coli-induced sepsis},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2015,
month = nov,
note = {Helminths cause so-called neglected tropical diseases in tropical and sub-tropical regions and are prevalent in almost one third of mankind. Thus, co-infections of helminths with other pathogens are common. However, the effects of helminths on outcomes of infections with unrelated pathogens like bacteria are rather poorly understood and underrepresented in biomedical research. In this thesis it was investigated, how chronic filarial infection influences acute bacterial challenge infections. To achieve this, mice chronically infected with the filarial nematode Litomosoides sigmodontis (L.s.) were intraperitoneally challenged with the gram-negative bacterium Escherichia coli. Sepsis severity was determined by survival, development of hypothermia, systemic pro-inflammatory cytokine and chemokine levels. Clearance of bacteria and recruitment of immune cells to the peritoneum were determined 6 hours after bacterial challenge. The role of nematode-induced immune cell populations as regulatory T cells, eosinophils and macrophages and their receptors (e.g. Toll-like receptor 2, IL-4 receptor) were investigated using various gene-deficient mouse strains. In order to further elucidate the protective mechanisms, in vitro studies and adoptive cell transfers were performed.
This thesis demonstrates that chronic infection with the filarial nematode L. sigmodontis provides a significant survival benefit to E. coli-induced sepsis in mice. This was accompanied by attenuated hypothermia and reduced systemic cytokine/chemokine secretion. Chronically L.s.-infected mice displayed an improved bacterial control and increased recruitment of neutrophils and eosinophils, which was accompanied by a reduced activation and apoptosis of peritoneal macrophages. Depletion of macrophages by Clodronate liposomes indicated a protective role of macrophages in the L.s.-mediated protection against E. coli-induced sepsis. L.s. infection induced RELMα expression on peritoneal macrophages in wildtype BALB/c mice following E. coli challenge, indicating a possible switch to an alternatively activated macrophage (AAM) phenotype. However, L.s.-infected IL-4Rα/IL-5-/- and IL-4-/- mice that were devoid of AAM were still protected from E. coli sepsis. These experiments suggest that the presence of macrophages is necessary, but the induction of an AAM phenotype is not required to improve sepsis outcome by L.s. infection.
Most filarial species have endosymbiotic Wolbachia bacteria that activate innate cells and reduce subsequent responses to innate stimuli via Toll-like receptor 2 (TLR2). In vitro stimulation with Wolbachia-containing preparations in wildtype but not TLR2-deficient macrophages reduced TNFα secretion following LPS-restimulation. These macrophages showed enhanced phagocytosis and uptake of bacteria and produced more bactericidal nitric oxide in a TLR2 dependent manner. Accordingly, the protective effect of chronic L.s. infection was lost in TLR2-deficient mice promoting a concept of Wolbachia- and TLR2-mediated immune modulation. Moreover, repeated injections of L.s. and Wolbachia-derived preparations improved sepsis outcome in a TLR2-dependent manner.
Finally, macrophage transfer experiments demonstrated that macrophages from L.s.-infected mice improved sepsis outcome of recipient mice, whereas macrophages from L.s.-infected TLR2-/- mice and naïve BALB/c mice did not significantly improve sepsis outcome in recipient mice.
This thesis provides immunologic insight to the complex interplay of filarial and bacterial co-infection and demonstrates a filariae- and Wolbachia-induced mechanism that protects mice via a dual beneficial effect on phagocytes, which permits improved containment of bacteria and reduced systemic inflammation. This may help to find new therapeutic interventions to prevent severe sepsis also in human patients.},
url = {https://hdl.handle.net/20.500.11811/6550}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5n-41745,
author = {{Fabian Gondorf}},
title = {Immune modulation by experimental filarial infection and its impact on E. coli-induced sepsis},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2015,
month = nov,
note = {Helminths cause so-called neglected tropical diseases in tropical and sub-tropical regions and are prevalent in almost one third of mankind. Thus, co-infections of helminths with other pathogens are common. However, the effects of helminths on outcomes of infections with unrelated pathogens like bacteria are rather poorly understood and underrepresented in biomedical research. In this thesis it was investigated, how chronic filarial infection influences acute bacterial challenge infections. To achieve this, mice chronically infected with the filarial nematode Litomosoides sigmodontis (L.s.) were intraperitoneally challenged with the gram-negative bacterium Escherichia coli. Sepsis severity was determined by survival, development of hypothermia, systemic pro-inflammatory cytokine and chemokine levels. Clearance of bacteria and recruitment of immune cells to the peritoneum were determined 6 hours after bacterial challenge. The role of nematode-induced immune cell populations as regulatory T cells, eosinophils and macrophages and their receptors (e.g. Toll-like receptor 2, IL-4 receptor) were investigated using various gene-deficient mouse strains. In order to further elucidate the protective mechanisms, in vitro studies and adoptive cell transfers were performed.
This thesis demonstrates that chronic infection with the filarial nematode L. sigmodontis provides a significant survival benefit to E. coli-induced sepsis in mice. This was accompanied by attenuated hypothermia and reduced systemic cytokine/chemokine secretion. Chronically L.s.-infected mice displayed an improved bacterial control and increased recruitment of neutrophils and eosinophils, which was accompanied by a reduced activation and apoptosis of peritoneal macrophages. Depletion of macrophages by Clodronate liposomes indicated a protective role of macrophages in the L.s.-mediated protection against E. coli-induced sepsis. L.s. infection induced RELMα expression on peritoneal macrophages in wildtype BALB/c mice following E. coli challenge, indicating a possible switch to an alternatively activated macrophage (AAM) phenotype. However, L.s.-infected IL-4Rα/IL-5-/- and IL-4-/- mice that were devoid of AAM were still protected from E. coli sepsis. These experiments suggest that the presence of macrophages is necessary, but the induction of an AAM phenotype is not required to improve sepsis outcome by L.s. infection.
Most filarial species have endosymbiotic Wolbachia bacteria that activate innate cells and reduce subsequent responses to innate stimuli via Toll-like receptor 2 (TLR2). In vitro stimulation with Wolbachia-containing preparations in wildtype but not TLR2-deficient macrophages reduced TNFα secretion following LPS-restimulation. These macrophages showed enhanced phagocytosis and uptake of bacteria and produced more bactericidal nitric oxide in a TLR2 dependent manner. Accordingly, the protective effect of chronic L.s. infection was lost in TLR2-deficient mice promoting a concept of Wolbachia- and TLR2-mediated immune modulation. Moreover, repeated injections of L.s. and Wolbachia-derived preparations improved sepsis outcome in a TLR2-dependent manner.
Finally, macrophage transfer experiments demonstrated that macrophages from L.s.-infected mice improved sepsis outcome of recipient mice, whereas macrophages from L.s.-infected TLR2-/- mice and naïve BALB/c mice did not significantly improve sepsis outcome in recipient mice.
This thesis provides immunologic insight to the complex interplay of filarial and bacterial co-infection and demonstrates a filariae- and Wolbachia-induced mechanism that protects mice via a dual beneficial effect on phagocytes, which permits improved containment of bacteria and reduced systemic inflammation. This may help to find new therapeutic interventions to prevent severe sepsis also in human patients.},
url = {https://hdl.handle.net/20.500.11811/6550}
}
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