Impact of immunosuppressants on biologyand genetic evolution of a major fungal pathogen infecting organ transplant recipients, Cryptococcus neoformans
Infectious diseases caused by microscopic fungi – fungal infections – now represent a global public health scourge. The latest estimates attribute more than 3 million deaths a year to these conditions. It is worth noting that these figures far exceed the mortality rates for tuberculosis, malaria and even certain cancers. Those most at risk from these microbial infections remain patients with weakened or dysfunctional immune systems. Consequently, patients who have undergone organ or blood stem cell transplants are particularly vulnerable, as the immunosuppressant drugs they are given daily to prevent their immune system from attacking and rejecting the transplant also weaken their natural defences needed to fight off infectious agents.
In reality, our understanding of these dangerous infections in the context of transplantation remains very limited even today. Whilst recent studies suggest that antimicrobials administered to prevent infectious diseases in transplant recipients may promote the emergence of resistant microbes within the body, the impact of immunosuppressive drugs on the fungal species threatening transplant patients remains to be explored.
On this basis, the NeoformIS project aims to investigate the impact of the most commonly used immunosuppressants – which are employed to prevent organ and stem cell rejection – on the biology and genetic evolution of a major fungal pathogen infecting transplant recipients, Cryptococcus neoformans. Firstly, we will seek to determine the toxicity of these molecules on this species; in other words, to demonstrate that, in addition to modulating our immune system, these drugs also act, either wholly or in part, as antimicrobials. Next, we will identify genetic changes (alterations in DNA sequence) in C. neoformans following long-term exposure to immunosuppressants (a laboratory simulation experiment known as ‘in vitro’). Indeed, as immunosuppressants are administered to transplant recipients over several months, it is to be expected that the behaviour of the fungal microbes colonising the bodies of these immunocompromised patients will be influenced – or indeed that they may become more aggressive – as a result of daily exposure to these drugs. Finally, we will attempt to correlate our ‘in vitro’ (laboratory) results with the reality in a hospital setting (known as ‘in vivo’). In other words, we will investigate whether the genetic changes identified in C. neoformans following long-term exposure to immunosuppressants in the laboratory are comparable to those detected in fungal microorganisms taken directly from transplant patients who have developed an infection.
The identification of these ‘molecular markers’ could, in the short term, lead to new diagnostic tools for tailoring drug treatments to individual patients, thereby reducing the incidence of infectious diseases in transplant patients.
The IRF Unit would like to extend its warmest thanks to the Pays de la Loire Region for its financial support, which has made this research possible.
