Bacterial protein keeps cells healthy for longer – 09/11/2023 – Science

Researchers from the University of São Paulo (USP) and collaborators from Australia have identified a bacterial protein capable of keeping human cells healthy for longer.

The discovery could lead to new treatments for a wide variety of diseases related to mitochondrial dysfunction (that is, the malfunction of mitochondria, the cell’s energy-producing organelle), such as cancer and autoimmune diseases.

In the study, published in the journal PNAS, researchers identified that among the more than 130 proteins released by the bacteria Coxiella burnetii When invading the host cell, at least one has the ability to extend cell longevity through direct action on the mitochondria.

After invasion of the host cell, the W. burnetii releases a previously unknown protein, which the authors named MceF (an acronym in English for mitochondrial coxiella effector F).

The molecule interacts with GPX4 (glutathione peroxidase 4), an enzyme located in the mitochondria. In this way, the bacteria promotes the survival of the cell in which it is hosted, as MceF improves mitochondrial function by promoting an antioxidant effect and delaying cell damage and death – which can occur when pathogens replicate inside mammalian cells.

“A W. burnetii it uses different strategies so that the invaded cell does not die and, thus, manages to replicate within it. One of them is the modulation of the GPX4 protein by MceF – a mechanism that we discovered in this work. The relocation of these proteins in the cellular mitochondria allows mammalian cells to live longer even when infected and with a very high bacterial load”, explains Dario Zamboni, professor at the Faculty of Medicine of Ribeirão Preto (FMRP-USP) and one of the authors corresponding to the article.

The study was carried out within the scope of the Center for Research in Inflammatory Diseases (CRID) – a Center for Research, Innovation and Dissemination (CEPID) at FAPESP –, in collaboration with professor Hayley Newton, from Monash University, in Australia. The investigation also received funding through a project coordinated by Zamboni.

“Basically, we found a strategy used by W. burnetii to keep the cell healthy for longer while it replicates intensely. We observed that the bacteria redirects – through the MceF protein – the host cell’s own enzyme [GPX4] to the mitochondria, in order to act as a potent antioxidant for the infected cell, which prevents the aging of cellular components”, explains Robson Kriiger Loterio, first author of the study, which is the result of his doctorate.

Cellular biologist

A C. burnetii It is the cause of the so-called Q fever, a relatively common but little diagnosed zoonosis. The bacteria causes atypical pneumonia in humans, as well as coxiellosis in several animals. Zamboni explains that this pathogen is highly adapted to infect macrophages and monocytes (white blood cells that act on the front line of the immune response), inhibiting a series of host responses against infection.

“The interest in studying this bacterium in more depth lies precisely in the fact that it subverts the cell’s functions. Unlike other bacteria, which only cause diseases when they are already present in large numbers in individuals, just one W. burnetii It’s enough to make a healthy person sick. It then acts efficiently to modulate the invaded cells. We joke that she is a born cellular biologist, capable of modulating everything in host cells”, says Zamboni.

Another interesting aspect of C. burnetii, according to the researcher, is that it spends around a week replicating inside the cell. By way of comparison, Salmonella (which causes serious food poisoning) causes the death of host cells in less than 24 hours.

“Watch them [as Coxiellas] It’s a great way to learn about cellular functioning. In the case of this study, it helped us understand how to improve mitochondrial dysfunctions and gave us insights into the programmed death of human cells,” says the researcher.

In the work, the researchers analyzed the bacteria’s ability to subvert macrophages and act directly on cellular mitochondria based on in vitro and in vivo studies, using larvae of a species of moth called Galleria mellonella.

In this first phase of the study, they investigated more than 80 new Coxiella proteins that have the potential to interact with the host cell and subvert its functioning.

“We focused our investigation on MceF because it acts directly on the mitochondria, an organelle that is very important for regulating the cell death process”, explains Zamboni.

The group now intends to work on two new fronts: deepening the understanding of other proteins of interest and carrying out more biochemical studies to understand how MceF influences the cellular protein GPX4.

“The beautiful thing about this work is that, from studies with a bacterium, we can learn more about signaling, cell death and new ways to reverse mitochondrial dysfunction. There is no need to invent a new technique, the process already occurs during the interaction between these bacteria with the cells”, he says.

The article Coxiella co-opts the Glutathione Peroxidase 4 to protect the host cell from oxidative stress–induced cell death can be read here.