Invasive aspergilliosis

Effect of biogenic calcium oxalate formation on the immune response associated to invasive aspergilliosis.

The antibiotics crisis is a major global public health issue. Recent estimates for 2017 suggest that the global burden of sepsis amounts to 11 million deaths worldwide. The risk of untreatable infections has been widely acknowledged and publicized in the case of bacterial infection, but recently, a potentially more worrisome problem has been highlighted regarding the rate of emergence of resistance among opportunistic fungal pathogens. Indeed, the very limited chemical arsenal available for treatment inhuman health and agriculture, has led to the rise of cross-resistance in both humanand plantfungal pathogens. Mycosis have emerged over the last three decades as life-threatening infectious diseases, particularly for immune-compromised hosts. Therefore, there is a pressing need for a more comprehensive integrated disease management approach that considersnot only the interconnectivity of human health, agriculture and the environment (one health approach), but also that reduces our reliance on chemical control agents alone.Very recently, we have proposed to explore a new paradigm of treatment in which the focus of the therapeutic intervention is not the pathogen, but rather theenvironment in which the pathogen attacks successfullythe host. Indeed, in order to establish a successful infection, most pathogens would manipulate the environmental conditions in order to optimize for instance the activity of extracellular enzymes or trigger morphological changes. Based onthis, we developed the principle of nutritional interference in which bacteria will consume some of the metabolites excreted by the pathogen during the infection process. More concretely,we demonstrated that oxalotrophic bacteria (bacteria consuming oxalic acid) are able to control the infection ofa fungal pathogen for which oxalic acid secretion is essential for pathogenesis(Aspergillus niger). This representsa significant step forward in the development ofan integrated disease management strategy.Three environmental factors were modified by the pathogenupon infection: pH, Ca2+concentration and soluble oxalic acidconcentrations.Those were returned to a physiological level by co-culturing with the biocontrol bacteria.The dramatic effect observed on the concentration of Ca2+in response tothe secretion of oxalic acid by the fungus is very significant. Calcium is known to be a secondary messenger in many cell types, including those responsible of the immune response. Therefore, the results obtained suggest a potential role of oxalic acid not onlytoallow the pathogen to thrive in the lung tissue, but also to inhibit the immune response.Therefore, the aim of this proposal is to demonstratethe effect of oxalic acid secretion by A. niger (includingbiogenic calcium oxalate crystal formation)on blocking the inflammationsignaling cascadein monocytesand their derivedmacrophages and dendritic cells.