The Divergent Roles of Neutrophils and Monocytes During Infection with the Bacterium, Listeria monocytogenes

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.