Dual Role of Hydrogen Peroxide as an Oxidant in Pneumococcal Pneumonia

Abstract

Significance:Streptococcus pneumoniae (Spn), a facultative anaerobic Gram-positive human pathogen with increasing rates of penicillin and macrolide resistance, is a major cause of lower respiratory tract infections worldwide. Pneumococci are a primary agent of severe pneumonia in children younger than 5 years and of community-acquired pneumonia in adults. A major defense mechanism toward Spn is the generation of reactive oxygen species, including hydrogen peroxide (H₂O₂), during the oxidative burst of neutrophils and macrophages. Paradoxically, Spn produces high endogenous levels of H₂O₂ as a strategy to promote colonization. Recent Advances: Pneumococci, which express neither catalase nor common regulators of peroxide stress resistance, have developed unique mechanisms to protect themselves from H₂O₂. Spn generates high levels of H₂O₂ as a strategy to promote colonization. Production of H₂O₂ moreover constitutes an important virulence phenotype and its cellular activities overlap and complement those of other virulence factors, such as pneumolysin, in modulating host immune responses and promoting organ injury. Critical Issues: This review examines the dual role of H₂O₂ in pneumococcal pneumonia, from the viewpoint of both the pathogen (defense mechanisms, lytic activity toward competing pathogens, and virulence) and the resulting host-response (inflammasome activation, endoplasmic reticulum stress, and damage to the alveolar-capillary barrier in the lungs). Future Directions: An understanding of the complexity of H₂O₂-mediated host-pathogen interactions is necessary to develop novel strategies that target these processes to enhance lung function during severe pneumonia.

Keywords: ARDS; hydrogen peroxide; pneumococci; pneumonia; pyruvate oxidase; virulence factor.

FIG. 1.

Mechanisms of pneumococcal defense against H₂O₂. Schematic overview of the three defense mechanisms involved in the resistance against H₂O₂: (i) defense enzymes that directly or indirectly degrade H₂O₂, (ii) repair mechanisms, and (iii) regulators linked to H₂O₂ stress response. H₂O₂, hydrogen peroxide. Color images are available online.

FIG. 2.

Actions of Spn-derived H₂O₂ on the UPR in host cells. Infection with Spn induces the activation of the UPR. Secretion of Spn-derived H₂O₂ leads to activation of PERK, ATF-6, and IRE1. Dimerization and phosphorylation of activated PERK induce phosphorylation of eIF2α leading to inhibition of protein translation and ATF4 modulating expression of target genes. Activated ATF-6 translocates to the Golgi, where it is cleaved by S1P and S2P. The processed ATF-6 enters the nucleus acting as a transcription factor of target genes. Activation of IRE1 leads to splicing of xbp1 mRNA, which acts as transcription factor of target genes. IRE1 activation can also lead to RIDD of mRNA or JNK signaling activation. ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; eIF2α, eukaryotic translation initiation factor 2α; ER, endoplasmic reticulum; IRE1, inositol-requiring enzyme 1; JNK, c-Jun N-terminal kinase; PERK, protein kinase R (PKR)-like ER kinase; RIDD, regulated IRE1-dependend decay; S1P, site-1-protease; S2P, site-1-protease; Spn, Streptococcus pneumonia; UPR, unfolded protein response; xbp1, X-box-binding protein 1. Color images are available online.

FIG. 3.

H₂O₂-induced responses in the host cell. Spn produces large amounts of H₂O₂, which induce a plethora of host cell responses. This includes oxidative and ER stress (red), activation of all three MAPK subfamilies (green), translocation of NF-κB-complex into the nucleus (violet), and inflammasome inhibition (blue). Oxidative stress leads to production of mtROS and release of mtDNA and subsequent STING-dependent type I IFN (IFN-β) expression. Translocation of NF-κB-complex into the nucleus leads to expression of proinflammatory chemokines and cytokines (such as IL-8 and IL23a) and H₂O₂-dependent production of Nrf-2, which induces expression of HO-1. HO-1, heme oxygenase 1; IFN, interferon; IL, interleukin; MAPK, mitogen-activated protein kinase; mtDNA, mitochondrial DNA; mtROS, mitochondrial reactive oxygen species; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; STING, stimulator of interferon genes. Color images are available online.

FIG. 4.

The complex actions of H₂O₂ in alveoli during pneumococcal pneumonia. Spn will migrate into the lower respiratory tract, and since it lacks catalase will generate millimolar levels of H₂O₂, through the actions of pyruvate oxidase (SpxB) and lactate oxidase (LctO), which will diffuse into the alveolar space (1). Moreover, an early neutrophil-mediated and a later macrophage-derived generation and secretion of μmolar levels of H₂O₂ will occur (2, 3). High ROS levels in the alveolar space will promote alveolar endothelial barrier function (4) and will impair AFC (5), which is mainly mediated through vectorial sodium transport, involving the apically expressed ENaC and the basolateral Na⁺-K⁺ pump in type II pneumocytes. AFC, alveolar fluid clearance; ENaC, epithelial sodium channel; ROS, reactive oxygen species. Color images are available online.

FIG. 5.

Overview of positive (green) and negative (red) actions of endogenous and secreted H₂O₂ in the pathogen and in the host lung during pneumococcal pneumonia. In Spn, endogenous H₂O₂ promotes nucleotide, glycolytic, and capsule biosynthesis and increases Ply secretion. Secreted H₂O₂ kills competing pathogens in the respiratory tract and serves as a virulence factor, since it reduces NLRP3 inflammasome activation in the host. In the alveolar space, Spn-secreted H₂O₂ can induce activation of the UPR and cause DNA damage, which can precede apoptosis. Moreover, H₂O₂ can impair the alveolar–capillary barrier, induce inflammation, and blunt vectorial Na⁺ transport, crucial for AFC in pneumocytes. All of these actions of H₂O₂ on the host lung cells can promote the development of pulmonary edema during pneumococcal pneumonia. Ply, pneumolysin. Color images are available online.