Coxiella co-opts the Glutathione Peroxidase 4 to protect the host cell from oxidative stress-induced cell death

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Loterio, Robson K. ; Thomas, David R. ; Andrade, Warrison ; Lee, Yi Wei ; Santos, Leonardo L. ; Mascarenhas, Danielle P. A. ; Steiner, Thiago M. ; Chiaratto, Jessica ; Fielden, Laura F. ; Lopes, Leticia ; Bird, Lauren E. ; Goldman, Gustavo H. ; Stojanovski, Diana ; Scott, Nichollas E. ; Zamboni, Dario S. ; Newton, Hayley J.

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 120, n. 36, p. 11-pg., 2023-09-05.

Abstract

The causative agent of human Q fever, Coxiella burnetii, is highly adapted to infect alveolar macrophages by inhibiting a range of host responses to infection. Despite the clinical and biological importance of this pathogen, the challenges related to genetic manipulation of both C. burnetii and macrophages have limited our knowledge of the mechanisms by which C. burnetii subverts macrophages functions. Here, we used the related bacterium Legionella pneumophila to perform a comprehensive screen of C. burnetii effectors that interfere with innate immune responses and host death using the greater wax moth Galleria mellonella and mouse bone marrow-derived macrophages. We identified MceF (Mitochondrial Coxiella effector protein F), a C. burnetii effector protein that localizes to mitochondria and contributes to host cell survival. MceF was shown to enhance mitochondrial function, delay membrane damage, and decrease mitochondrial ROS production induced by rotenone. Mechanistically, MceF recruits the host antioxidant protein Glutathione Peroxidase 4 (GPX4) to the mitochondria. The protective functions of MceF were absent in primary macrophages lacking GPX4, while overexpression of MceF in human cells protected against oxidative stress-induced cell death. C. burnetii lacking MceF was replication competent in mammalian cells but induced higher mortality in G. mellonella, indicating that MceF modulates the host response to infection. This study reveals an important C. burnetii strategy to subvert macrophage cell death and host immunity and demonstrates that modulation of the host antioxidant system is a viable strategy to promote the success of intracellular bacteria. (AU)

• FAPESP's process: 19/11342-6 - Mechanisms and consequences of the activation of cytoplasmic receptors by intracellular pathogens
• Grantee: Dario Simões Zamboni
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 14/04684-4 - The inflammasome in the host response against intracellular pathogens and the microbial mechanisms for its evasion
• Grantee: Dario Simões Zamboni
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/07870-9 - The influence of mitogen activated protein kinases (MAPK) on the expression of genetic determinants important for Aspergillus fumigatus virulence
• Grantee: Gustavo Henrique Goldman
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/24275-7 - Identification of Coxiella burnetii proteins involved in the modulation of the inflammasome activasion and in the intracellular signaling pathways in macrophages
• Grantee: Robson Kriiger Loterio
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)