Oxidation of hemoproteins by Streptococcus pneumoniae collapses the cell cytoskeleton and disrupts mitochondrial respiration leading to the cytotoxicity of human lung cells

Authors

• Anna Scasny, University of Mississippi School of Medicine
• Babek Alibayov, University of Mississippi School of Medicine
• Faidad Khan, University of Mississippi School of Medicine
• Shambavi J. Rao, The Ohio State University College of Medicine
• Landon Murin, University of Mississippi School of Medicine
• Ana G. Jop Vidal, University of Mississippi School of Medicine
• Perriann Smith, University of Southern Mississippi
• Wei Li, Emory University
• Kristin Edwards, University of Mississippi School of Medicine
• Kurt Warncke, Emory University
• Jorge E. Vidal, University of Mississippi School of Medicine

Document Type

Article

Publication Date

1-1-2024

School

Biological, Environmental, and Earth Sciences

Abstract

Streptococcus pneumoniae (Spn) causes pneumonia that kills millions through acute toxicity and invasion of the lung parenchyma. During aerobic respiration, Spn releases hydrogen peroxide (Spn-H2O2) as a by-product of the enzymes pyruvate oxidase and lactate oxidase and causes cell death with signs of both apoptosis and pyroptosis by oxidizing unknown cell targets. Hemoproteins are molecules essential for life and prone to oxidation by H2O2. We recently demonstrated that during infection-mimicking conditions, Spn-H2O2 oxidizes the hemoprotein hemoglobin (Hb), releasing toxic heme. In this study, we investigated details of the molecular mechanism(s) by which the oxidation of hemoproteins by Spn-H2O2 causes human lung cell death. Spn strains, but not H2O2-deficient SpnΔspxBΔlctO strains, caused time-dependent cell cytotoxicity characterized by the rearrangement of the actin cytoskeleton, the loss of the microtubule cytoskeleton, and nuclear contraction. Disruption of the cell cytoskeleton is correlated with the presence of invasive pneumococci and an increase in intracellular reactive oxygen species. In cell culture, the oxidation of Hb or cytochrome c (Cytc) caused DNA degradation and mitochondrial dysfunction from inhibition of complex I-driven respiration, which was cytotoxic to human alveolar cells. Oxidation of hemoproteins resulted in the creation of a radical, which was identified as a protein-derived side chain tyrosyl radical by using electron paramagnetic resonance. Thus, we demonstrate that Spn invades lung cells, releasing H2O2 that oxidizes hemoproteins, including Cytc, catalyzing the formation of a tyrosyl side chain radical on Hb and causing mitochondrial disruption that ultimately leads to the collapse of the cell cytoskeleton.

Publication Title

Microbiology Spectrum

Volume

12

Issue

1

Recommended Citation

Scasny, A., Alibayov, B., Khan, F., Rao, S., Murin, L., Jop Vidal, A., Smith, P., Li, W., Edwards, K., Warncke, K., Vidal, J. (2024). Oxidation of hemoproteins by Streptococcus pneumoniae collapses the cell cytoskeleton and disrupts mitochondrial respiration leading to the cytotoxicity of human lung cells. Microbiology Spectrum, 12(1).
Available at: https://aquila.usm.edu/fac_pubs/22263