A new study published online in January 2020 in the journal Nature Communications shows that a rare genetic mutation that gives rise to a variant of the TP53 gene called P47S causes several linked biological processes, including a lower response to the malarial toxin.
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Why is the TP53 gene important?
The TP53 gene is often-mutated, and the most commonly mutated in human cancer. It is not only a tumor suppressor gene for most forms of cancer but is a key protein for a host of cellular pathways that are affected in cancer.
Found within the nucleus, the p53 protein binds to the DNA in all cells. It is instrumental in designating DNA damage due to ultraviolet exposure, for instance, as being reparable or irreparable, in which case it prevents further replication of the damaged genome, and instead signals the cell to enter the apoptosis pathway.
If it can be repaired, the p53 protein triggers the repair pathway instead. Thus, it is crucial in preventing tumor development, and has been called “the guardian of the genome”.
The P475 gene variant
It comes in several forms, some common and some rare. One of these is the P475 variant, found in Africans. This has descended to their descendants in America, the African-Americans.
An earlier study by the scientists at the same institute showed that this gene variant is linked to a higher risk of cancer in this population, because of a cell process called ferroptosis. This term refers to a mode of cell death triggered by iron, and is hence related to iron overload.
Iron overload and bacterial infection
The current study in mice carrying the P475 gene variant reports another adverse effect caused by excessive iron. Macrophages in these animals show a build-up of iron within their cells, which makes them less efficient at mounting an inflammatory reaction when exposed to bacterial infection. This means the mice carrying this gene are more easily infected.
“The flip side of diminished inflammation is that these mice have a more favorable response to malaria toxin hemozoin, which is responsible for most of the lethal symptoms in the acute phase of malaria.” Farokh Dotiwala
The researchers found that this variant was much more frequently found in African Americans, using data from the Hemochromatosis and Iron Overload Screening (HEIRS) study. They then switched to a mouse model engineered to carry the human variant P475.
They found macrophages filled with iron, which were unable to counter the proliferation of various bacterial species in culture. This, in turn, led to a more rapid phase of an increase in bacterial numbers and a poorer outcome.
How does P475 increase macrophage iron?
The scientists now set out to find the mechanisms underlying the accumulation of iron in the macrophages. They resorted to proteomics study, which looks at the changes in the protein levels within the macrophages.
They found that in the presence of excessive iron, several proteins that take part in the immune response to bacteria were less abundant. These proteins are key to the metabolic reactions, including the arginine pathway, that allows macrophage-mediated bacterial killing, and essential for ferroptosis. Their deficiency makes the macrophages less capable of killing bacteria.
The researchers also identified molecules that could reverse these harmful changes by binding to key reactants in three diverse metabolic pathways affected by the presence of the gene variant. This discovery could thus help develop new medicines to treat this condition.
The P475 gene is so common in sub-Saharan Africa where malaria is also widely prevalent, the scientists then set out to look for any possible advantage this gene conferred on people infected with malaria.
They injected mice carrying this gene with the malarial toxin hemozoin and assessed the type of inflammatory response. Compared to mice with the normal p53 gene, the P475 variant was associated with a lower level of inflammation in response to this toxin.
This could, in turn, result in a less severe form of malaria, since most of the symptoms in malaria are produced by a very severe widespread inflammation in response to the toxin, brought about mostly by macrophages.
Says senior co-author Donna George, “While warranting further studies in humans, we believe that mechanistic knowledge obtained from studying the P47S variant provides a stepping stone in the field of personalized medicine to help address disparities arising from such polymorphisms.” Moreover, this knowledge could also help to tease out the link between the P475 gene variant, conditions associated with iron overload, and the higher prevalence of some bacterial infections and cancers in African Americans.
Eurekalert.org. (2020). TP53 gene variant in people of African descent linked to iron overload may improve malaria response. https://www.eurekalert.org/emb_releases/2020-01/twi-tgv012320.php