Immunology
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21714
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Browsing Immunology by Author "Okunnu, Busola"
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Item Divergent Roles of Extracellular Superoxide Dismutase During Intracellular Bacterial Infection(2016-03-23) Break, Timothy; Okunnu, Busola; Swanta, Naomi; Berg, Rance E.; Witter, AlexandraExtracellular superoxide dismutase (ecSOD) regulates extracellular concentrations of reactive oxygen species (ROS) to protect tissues during infection and inflammation. Using congenic mice with varying levels of ecSOD activity (ecSOD HI, WT and KO), we have previously shown that ecSOD activity enhances neutrophil recruitment to the liver, yet inhibits the innate immune response against Listeria monocytogenes (LM) leading to increased host susceptibility. Additionally, we determined that ecSOD activity protects the extracellular matrix (ECM) from degradation and promotes egress of immature neutrophils out of the bone marrow and into the liver where they are unable to provide protection against LM. Since ecSOD can be produced by cells from the hematopoietic lineage as well as somatic cells, the potential contribution of ecSOD produced by cells from each lineage required further investigation. In order to determine the relative contributions of ecSOD produced from either hematopoietic-derived cells or somatic cells, we generated bone marrow chimera mice using ecSOD KO mice and C57Bl/6 mice. Briefly, host mice were irradiated to eliminate hematopoietic lineage cells and reconstituted with bone marrow cells isolated from donor mice. Control groups consisted of ecSOD KO mice reconstituted with bone marrow from ecSOD KO donors (KO -> KO) or C57Bl/6 mice with bone marrow from C57Bl/6 mice (WT -> WT). Experimental groups consisted of ecSOD KO mice reconstituted with bone marrow from C57Bl/6 mice (WT -> KO) or C57Bl/6 mice with bone marrow from ecSOD KO mice (KO -> WT). All mice were then infected with LM and evaluated for neutrophil recruitment and bacterial burden. We observed that ecSOD produced by hematopoietic cells leads to increased bacterial burden during LM infection, while ecSOD produced from somatic cells is essential for increased neutrophil recruitment. Collectively, our data suggest that ecSOD produced by both hematopoietic cells and somatic cells is involved in our observed phenomena; however, the contribution of ecSOD from each cell lineage is skewed towards either increased neutrophil recruitment or increased susceptibility to LM infection, but not both. These studies highlight the potential therapeutic value of ecSOD inhibitors to enhance immune responses during bacterial infections.Item The Role of ecSOD in Phagosomal Containment of Listeria Monocytogenes(2016-03-23) Witter, Alexandra; Swanta, Naomi; Berg, Rance E.; Okunnu, BusolaExtracellular superoxide dismutase (ecSOD) is a secreted enzyme associated with the extracellular matrix that plays a protective role during reactive oxygen species (ROS) mediated inflammatory responses. Listeria monocytogenes is an intracellular gram positive bacteria that causes listeriosis in infected individuals and animals. EcSOD has been shown to modulate the innate immune response to Listeria infection. With the use of ecSOD congenic mice (ecSOD HI, ecSOD WT, ecSOD KO), we have established that high ecSOD activity leads to decreased bacterial clearance despite an increase in neutrophil recruitment. Whereas, no ecSOD activity results in reduced neutrophil recruitment but effective bacterial clearance. Importantly, neutrophils in the livers of ecSOD KO mice show superior protective capabilities in comparison to neutrophils in ecSOD HI mice. To deduce the mechanism by which ecSOD contributes to neutrophil effector function during Listeria infection, we made use of different strains of GFP expressing Listeria monocytogenes. Neutrophils isolated from both the bone marrow and the liver of the ecSOD congenic mice were able to effectively phagocytose the bacteria. However, we observed that there was more bacterial escape from the phagosome of neutrophils isolated from the bone marrow of ecSOD KO mice in comparison to the ecSOD HI and WT mice. In contrast, there was no observable difference in the ability of neutrophils isolated from the livers of the ecSOD congenic mice to prevent Listeria escape from the phagosome. These data are contradictory to the previously reported protective nature of the ecSOD KO neutrophils and their importance for bacterial clearance from the livers of infected mice. The neutrophils used for the current in vitro studies were isolated from the tissues in the absence of infection. Neutrophils are generally not present in large numbers in tissues in the absence of infection, therefore, we inferred that the isolated neutrophils were not functionally active. In conclusion, our results suggest that our in vitro observations are not supportive of the previous in vivo data regarding the ability of ecSOD to modulate neutrophil function.