Browsing by Subject "innate immunity"
Now showing 1 - 3 of 3
- Results Per Page
- Sort Options
Item EXTRACELLULAR SUPEROXIDE DISMUTASE ENHANCES NEUTROPHIL RECRUITMENT WHILE DECREASING THEIR FUNCTION(2013-04-12) Break, TimothyPurpose: Listeria monocytogenes (LM) causes spontaneous abortions in pregnant females and septicemia and meningitis in immunocompromised individuals, and results in ~25% mortality rate in infected individuals. Extracellular superoxide dismutase (ecSOD) converts superoxide into hydrogen peroxide in the extracellular milieu and protects against oxidative stress. The use of mice with varying levels of ecSOD serves as a novel approach to determine how an extracellular enzyme can impact immunity against an intracellular pathogen. Methods: Congenic mice with high ecSOD activity (ecSOD HI), wild type ecSOD activity (ecSOD WT), or lacking ecSOD (ecSOD KO), on the C57Bl/6 background, were infected with LM. Colony forming units (CFUs) were counted to determine bacterial load. Percentages of different cell types, cell-surface markers, and intracellular molecules (including ROS and proteins) were determined by flow cytometry. Neutrophil depletions were performed by i.p. injection of anti-Ly6G or isotype control antibody. Cytokine and chemokine concentrations were measured by ELISA. Results: EcSOD HI mice were more susceptible to LM infection than ecSOD WT and ecSOD KO mice. Interestingly, ecSOD HI mice have higher percentages of neutrophils in the liver compared to ecSOD KO mice, which was at least partially mediated by increased ecSOD-induced neutrophil-attracting chemokine production. Neutrophil depletions were performed, and ecSOD WT and KO livers had increased CFUs, while ecSOD HI mice showed slightly decreased CFUs, compared to isotype-treated mice. Furthermore, TNF-ɑ, which is important for clearance of LM, was highest in ecSOD KO mice. Interestingly, ecSOD activity decreased the ability of neutrophils to undergo oxidative burst, a mechanism to kill LM, and increased the amount of LM inside neutrophils. Lastly, ecSOD activity increased the percentage of myeloid-derived suppressor cells, which suppress immune responses. Conclusions: Our data show that ecSOD is detrimental during the early response to LM infection. An increased percentage of neutrophils in ecSOD HI livers, but no concurrent decrease in CFUs, suggests that ecSOD can impair the function of neutrophils. One way this may occur is through the internalization of ecSOD during phagocytosis, which decreases oxidative burst, allowing for LM to survive inside neutrophils. Furthermore, an increase in myeloid-derived suppressor cells in the ecSOD HI livers helps explain why these mice are more susceptible to infection.Item The Divergent Roles of Neutrophils and Monocytes During Infection with the Bacterium, Listeria monocytogenes(2020-05) Okunnu, Busola; Berg, Rance E.; Hodge, Lisa M.; Su, Dong-Ming; Fudala, Rafal; Uteshev, Victor V.Neutrophils are polymorphonuclear phagocytic cells that can play both protective and damaging roles during innate immune responses to infection and disease. Therefore, gaining a complete understanding of the functions and capabilities of neutrophils is vital. Our studies on neutrophil function were focused on their role during bacterial infections and were conducted using a Listeria monocytogenes (Lm) mouse infection model. Lm is an intracellular bacterium that causes diseases such as gastroenteritis, spontaneous abortion and meningitis. Lm infection in mice is commonly used as a model to study cell mediated immune responses and previous studies have demonstrated that neutrophils are essential for host protection against the bacteria. A major function attributed to neutrophils is the killing of pathogens via the generation of Reactive Oxygen Species (ROS). The unintentional damage to host cells by ROS is mitigated by antioxidants such as superoxide dismutases (SODs) which convert superoxide into hydrogen peroxide. Our studies focused on how one of the SODs, extracellular superoxide dismutase (ecSOD), modulates the function of neutrophils during Lm infection. Congenic mice with differing activities of ecSOD: high (ecSOD HI), normal (ecSOD WT), and no activity (ecSOD KO) were used for these studies. Previous studies from our lab have shown that the ecSOD HI mice are more susceptible to Lm infection in comparison to ecSOD KO mice, though the ecSOD HI mice have a higher percentage of neutrophils recruited to the sites of infection. Therefore, the purpose of these studies was to determine how ecSOD activity modifies functions such as phagocytosis, phagosomal containment and killing of Lm by neutrophils. EcSOD activity correlated with increased presence of extracellular bacteria in the spleen after three days of infection. High activity of ecSOD was also observed to decrease neutrophil phagocytosis of Lm. However, surprisingly, ecSOD activity had no effect on phagosomal containment or killing of Lm by neutrophils. As a result, ecSOD activity appears to primarily modify Lm uptake by neutrophils during infection. Another class of innate immune phagocytes that have also been demonstrated to be necessary for protection during Lm infection are monocytes. Previous studies also indicate that monocytes play important roles during infection and disease, similarly to neutrophils. Although specific functions have generally been assigned to each of the cells, similarities and differences in functions necessary for Lm clearance have not previously been investigated. In the present study, phagocytosis, phagosomal containment, bacterial killing and cytokine production by neutrophils and monocytes during Lm infection were studied. Data obtained via in vitro studies show that neutrophils are more effective at Lm uptake, phagosomal containment, and killing than monocytes. However, monocytes were found to be more effective at cytokine production during Lm infection, in vivo. Additionally, the data demonstrated that neutrophils and monocytes are also capable of producing IL-1α, a cytokine that does not yet have a clearly defined role during infection with Lm. Furthermore, a population of monocytes capable of producing both TNF-α and IL-1α, concurrently, were identified. Collectively, these studies highlight the impact of ecSOD activity on neutrophils, as well as the multi-functional capabilities of neutrophils and monocytes, further adding to our knowledge of these innate immune cells.Item The Many Faces of Innate Immunity in SARS-CoV-2 Infection(MDPI, 2021-06-04) Hanan, Nicholas; Doud, Ronnie L., Jr.; Park, In-Woo; Jones, Harlan P.; Mathew, Stephen O.The innate immune system is important for initial antiviral response. SARS-CoV-2 can result in overactivity or suppression of the innate immune system. A dysregulated immune response is associated with poor outcomes; with patients having significant Neutrophil-to-Lymphocyte ratios (NLR) due to neutrophilia alongside lymphopenia. Elevated interleukin (IL)-6 and IL-8 leads to overactivity and is a prominent feature of severe COVID-19 patients. IL-6 can result in lymphopenia; where COVID-19 patients typically have significantly altered lymphocyte subsets. IL-8 attracts neutrophils; which may play a significant role in lung tissue damage with the formation of neutrophil extracellular traps leading to cytokine storm or acute respiratory distress syndrome. Several factors like pre-existing co-morbidities, genetic risks, viral pathogenicity, and therapeutic efficacy act as important modifiers of SARS-CoV-2 risks for disease through an interplay with innate host inflammatory responses. In this review, we discuss the role of the innate immune system at play with other important modifiers in SARS-CoV-2 infection.