Research indicates that a bacterial protein has the potential to maintain the well-being of human cells.




In a joint effort between the University of Sao Paulo (USP) in Brazil and Australian collaborators, scientists have identified an extraordinary bacterial protein. This protein demonstrates the ability to sustain the health of human cells, even under severe bacterial contamination. This breakthrough holds promising implications for the development of novel treatments targeting various disorders associated with mitochondrial dysfunction, such as cancer and autoimmune conditions.

Through a collaborative initiative involving the University of Sao Paulo (USP) in Brazil and researchers from Australia, scientists have pinpointed an exceptional bacterial protein. This protein showcases the capacity to uphold the well-being of human cells, even in the face of substantial bacterial contamination. The significance of this discovery extends to the potential development of innovative treatments for a spectrum of disorders linked to mitochondrial dysfunction, encompassing conditions like cancer and autoimmune diseases.

Upon infiltrating host cells, C. burnetii discharges a previously unidentified protein, termed mitochondrial coxiella effector F (MceF). This protein engages with glutathione peroxidase 4 (GPX4), an antioxidant enzyme situated in the mitochondria. The interaction enhances mitochondrial functionality by fostering an antioxidative effect, preventing cell damage and potential death that can arise during the replication of pathogens within mammalian cells.

Coxiella burnetii



Professor Dario Zamboni, affiliated with the Ribeirao Preto Medical School (FMRP-USP) and one of the co-authors of the article, expressed, "C.. burnetii employs diverse strategies to impede cell death and thrive within invaded cells. One such strategy involves the modulation of GPX4 by MceF, a mechanism that our research has unveiled and detailed in this article. The repositioning of these proteins within cellular mitochondria prolongs the lifespan of mammalian cells, even under the strain of a substantial bacterial load."

The research was carried out at the Center for Research on Inflammatory Diseases (CRID), a Research, Innovation, and Dissemination Center (RIDC) supported by FAPESP, in collaboration with Professor Hayley Newton from Monash University in Australia. Financial support was also provided by FAPESP through a project overseen by Zamboni.

In the words of Robson Kriiger Loterio, the first author of the article stemming from his PhD research, "Essentially, we uncovered a strategy employed by C. burnetii to promote prolonged cellular health during intense replication. Our discovery reveals that the protein MceF redirects GPX4 to the mitochondria, where it serves as a potent antioxidant, detoxifying the infected cell. This process prevents cellular components from aging, facilitating bacterial replication."

C. burnetii, the pathogenic agent responsible for Q fever, induces a severe infection that is a frequently overlooked zoonosis. The authors highlight that agricultural outbreaks pose a growing economic and public health challenge.

This bacterium triggers atypical pneumonia in humans and coxiellosis in certain animals, including cattle, sheep, and goats. Zamboni elucidated that C. burnetii is remarkably adept at invading and regulating macrophages and monocytes, key white blood cells constituting the frontline defense of the organism. This capability inhibits the host's immune responses to the infection.

"The intriguing facet of undertaking a thorough examination of this bacterium resides in its precise ability to manipulate cellular functions. In contrast to other bacteria that induce disease only upon reaching substantial numbers through multiplication, a lone C. burnetii is sufficient to afflict a healthy individual. It efficiently acts to regulate the cells it infiltrates. We playfully dub it a 'brilliant cell biologist' due to its adeptness at modulating various aspects within host cells," remarked Zamboni.

He further noted another intriguing facet of C. burnetii – its replication period within cells spans about a week. By comparison, Salmonella, a bacterium causing severe food poisoning, leads to the demise of host cells in less than 24 hours.

"Studying Coxiella burnetii provides valuable insights into cellular functions. In this particular investigation, it enhanced our understanding of treating mitochondrial dysfunction and offered perspectives on programmed cell death in humans," he remarked.

To assess the bacterium's ability to manipulate macrophages and directly impact mitochondria, the researchers conducted in vitro assays and experiments involving larvae of the Greater wax moth (Galleria mellonella). In the initial phase of the study, they explored over 80 novel proteins from C. burnetii with the potential to interact with host cells and disrupt their functions. "We ultimately narrowed our focus to MceF because of its direct impact on mitochondria, a pivotal player in the cell death process," explained Zamboni.

The research team will proceed on two fronts: one delving deeper into the exploration of additional proteins of interest, and the other involving biochemical studies to unravel the intricacies of how MceF impacts GPX4.

"What's fascinating about this research is that by studying this bacterium, we're gaining substantial insights into cell signaling, cell death, and innovative approaches to counteracting mitochondrial dysfunction. There's no need to devise a new technique; the process naturally unfolds during the bacterium's interaction with host cells," he emphasized.