Neutralization of Mitochondrial Superoxide by Superoxide Dismutase 2 Promotes Bacterial Clearance and Regulates Phagocyte Numbers in Zebrafish

Abstract

T he roles that mitochondria play in antiviral signaling, via mitochondrial antiviral-signaling protein and promotion of inflammation and apoptosis, are well established (1-3); however, their importance in innate immunity is only now becoming clear. While mitochondria can promote inflammation via NF-B signaling and NLRP3 inflammasome formation, inflammation can lead to mitochondrial dysfunction, which can compound the severity of exaggerated inflammatory conditions such as sepsis (4-10). As the site of the electron transport chain within cells, mitochondria are a major source of reactive oxygen species (ROS) (mainly superoxide anions). ROS play diverse roles in cellular and organismal health, especially in innate immunity and inflammation. While the use of ROS to clear infections is beneficial to the host, inappropriate ROS production or lack of ROS neutralization can damage host DNA, proteins, and cell membranes. ROS-induced cellular damage can contribute to the undesired side effects of infectious and inflammatory diseases. Mechanisms are in place in hosts, and even some pathogens, to chemically convert ROS into less toxic compounds; however, overproduction of ROS can overwhelm host antioxidants. Thus, a better understanding of the impact of mitochondria, ROS, and mechanisms for neutralization of ROS on innate immunity could lead to improved treatments for infectious diseases and inflammatory disorders.The cellular mechanisms to neutralize ROS include the glutathione system, catalases, and the superoxide dismutase (SOD) family of enzymes. As superoxide producers, mitochondria are equipped with nuclear-encoded, mitochondrially localized SODs (SOD2, MnSOD) that convert superoxide into hydrogen peroxide. The deleterious effects of mitochondrial superoxide are demonstrated by mutations in SOD2 being implicated in idiopathic cardiomyopathy, age-related macular degeneration, aberrant brain morphology, motor neuron disease, vascular complications of diabetes, and cancer, whereas overexpression of SOD2 increases the Drosophila life span (11,(69)(70)(71)(72). Despite the importance of SOD2 and the regulation of ROS for health, surprisingly little is known about the role of SOD2 in immunity. Numerous studies have implicated SOD2 in the immune response, but few have defined functional roles for SOD2 in immunity. SOD2 is upregulated in response to lipopolysaccharide (LPS), poly(I·C), beta-glucan, and numerous pathogens in multiple cell types and organisms (12-17). Functionally, SOD2 was found to be necessary for the phorbol myristate acetate-induced respiratory burst response and cell survival upon poly(I·C) exposure in vitro (16,17). In a mouse model with SOD2 deleted specifically from thymocytes, the animals did not mount an effective adaptive immune response to influenza virus infection because of disrupted T-cell

Mitochondria-Derived Vesicles Deliver Antimicrobial Reactive Oxygen Species to Control Phagosome-Localized Staphylococcus aureus

“…As a consequence, Sod2-deficient macrophages (Sod2 KD) failed to efficiently kill MRSA. Although we were not able to successfully generate live Sod2-deficient mice, studies of Sod2 knockdown in zebrafish demonstrate a protective role for Sod2 during infection by Pseudomonas aeruginosa (Peterman et al, 2015). Our studies have identified MDVs as a delivery mechanism by which antimicrobial effectors can be trafficked into the macrophage phagosome.…”

Insights into host–pathogen interactions from state‐of‐the‐art animal models of respiratory Pseudomonas aeruginosa infections

“…The versatility of the zebrafish as an infection model was most impressively demonstrated by Peterman et al . . They were interested in the role of the mitochondrial superoxide dismutase (SOD2) under infectious conditions.…”

“…SOD2 detoxifies ROS within the mitochondria. By infecting zebrafish with P. aeruginosa , it could be shown that SOD2 is upregulated in hematopoietic and myelopoietic organs . By deleting SOD2 and infecting the larvae early in development when only macrophages are present, they could show that ROS needs to be detoxified in such cells.…”

Mitochondria-derived vesicles deliver antimicrobial payload to control phagosomal bacteria

“…As a consequence, Sod2-deficient macrophages (Sod2 KD) failed to kill MRSA. Although we were not able to successfully generate live Sod2-deficient mice, studies of Sod2 knockdown in zebrafish demonstrate a protective role for Sod2 during infection by Pseudomonas aeruginosa (Peterman et al, 2015). Our studies have identified MDVs as a new delivery mechanism by which antimicrobial effectors can be trafficked into the macrophage phagosome.…”