A protein that stops an opportunistic pathogen
It has two faces. In healthy people it produces mild infectionsHowever, in patients with weakened immunity, it becomes an opportunistic pathogen, reaching such virulence that it represents third cause of death due to hospital-acquired infection. What kind of fungus are we talking about? From Candida albicans. This mycosis significantly affects cancer, postoperative or intensive care patients with a weakened immune system, which leads to significant medical costs.
When invasive candidiasisis the most frequent fungal infection in hospitalized patients, with an incidence of 8 cases per 100,000 inhabitants in Spain and a mortality rate of up to 30%. Treatment is complicated by the limited availability of antifungal drugs and the development of resistance mechanisms to these drugs. All this has led to an urgent need to discover new therapeutic targets for the development of new antifungal agents.
His early detection is critical improve the prognosis of patients, although early diagnosis is difficult due to the limited presence of specific clinical symptoms of the disease compared to other infections. Sowing samples in a specific nutrient medium for fungi is the main system for diagnosing invasive candidiasis, but this method requires 2 to 5 days to monitor the growth of the microorganism. For this reason, there are other methods based on the detection of DNA or proteins of the microorganism in the patient’s blood.
When C. albicans enters the body, the first cells that try to stop the infection are phagocytes, such as neutrophils in the blood or macrophages in the tissues. These phagocytes, which are part of the first line of defense of our immune system, phagocytize the pathogen and try to destroy it by producing various oxidative compounds. In turn, the pathogen responds to this attack by activating various mechanisms that help it survive the oxidative stress caused by these compounds released by the immune system cells. Victor Arribas’ research group is studying this interaction between phagocytes and Candida albicans.
In this regard, he explains that one of the most characteristic oxidative compounds produced by these phagocytes is hydrogen peroxide. “If we study the effect of this hydrogen peroxide on Candida albicans and the reaction it causes to counteract this stress, we can identify Candida proteins that are essential for survival and infection. They thus become targets for possible new antifungals.
Therefore, he specifies that this equipment, after treating the Candida albicans culture with oxygenated water, extracts its proteins, identifies and quantifies them using mass spectrometry. In these studies, they determined that the Prn1 protein was one of the proteins that increased the most in response to hydrogen peroxide, and was therefore suspected of playing an important role in the oxidative stress response. From here, they are conducting analyses to determine whether this protein is involved in the oxidative stress response and whether it can be used as a possible target for antifungal drugs.
To do this, they analyzed a strain expressing the Prn1 protein and another that could not produce this protein, and treated them with hydrogen peroxide. In this way, they found that the C. albicans strain that does not express this protein is much more sensitive to oxidative stress. To decipher the role of this protein in the response to oxidative compounds produced by the immune system, they again performed mass spectrometry on the strain that expresses Prn1 and on the strain that does not produce it. In this way, they noticed that the amount of proteins responsible for the elimination of oxidative compounds was lower in the strain that does not produce the Prn1 protein. “This result confirms the importance of Prn1 in the response to oxidative stress caused by phagocytes, and therefore it becomes an interesting protein that can be neutralized by new potential antifungals,” comments the postdoctoral researcher.
There are currently only three classes of antifungal drugs to which many Candida strains have developed resistance mechanisms and treatment is no longer effective. This has led to the vast majority of deaths caused by invasive candidiasis being caused by infections with strains resistant to antifungals. Their project, they say, is innovative because it is aimed at finding new targets that are different from those that already exist and against which Candida species do not have resistance mechanisms. The goal is to develop new antifungals to treat patients with infections caused by strains resistant to antifungals. Moreover, he considers this project to be “extremely important” because of the “growing threat” of infections, especially among vulnerable populations.
Looking to the future, he says a key step will be to identify a substance that can inhibit the Prn1 protein so that it cannot perform its function and reduce the immune system’s response to the oxidative stress of C. albicans. “Prn1 has a high similarity to a protein called pyrin from mammalian cells. This pyrin has been shown to be inhibited by curcumin, which is an excellent antioxidant, as well as other enzyme inhibitors. So one of the main plans for the future is to analyze the role of curcumin as a possible inhibitor of Prn1 function in C. albicans.
Additionally, Arribas points out that Prn1 has three other homologous proteins: Prn2, Prn3, and Prn4, which may also play a role in the oxidative stress response, so he believes their study would be important to consider in the future as new targets for antifungal treatment.