BILITOLERANCE aimed at examining a potential role of BVRA in the establishment of disease tolerance to infection. BVRA is a central enzyme in heme catabolism, responsible for converting biliverdin to the antioxidant bilirubin following heme degradation by HO-1. Heme catabolism has been shown to be central for the establishment of disease tolerance to infection and is generally regarded as a potent cytoprotective mechanism. However, although BVRA is an essential component of the heme catabolic pathway, it was not known whether its expression was protective in severe infections leading to sepsis. BILITOLERANCE tested this hypothesis and concluded that Bvra expression is negligible in polymicrobial sepsis. Nevertheless, contingent on these results, we proposed alternative hypotheses regarding a potential role for BVRA in other infection models, namely influenza infection, toxoplasmosis and malaria. We tested these alternative hypotheses and uncovered a hitherto unknown critical role for BVRA in surviving a mouse model of malaria, in that mice lacking Bvra expression fully succumb to an otherwise non-lethal Pcc infection (see attached Fig. 3A). These results are still in line with the main postulate that BVRA plays a role in establishing disease tolerance to infection, in particular within the scope of Pcc infection and malaria. We have additionally discovered that in the absence of Bvra expression, mice are unable to clear the invading parasite, indicating that BVRA likely plays a role in resistance to infection as well.
Malaria is responsible for ~200 million yearly infections and 400.000 deaths worldwide (WHO data), and is at risk of spreading to non-endemic areas due to climate alterations that favor insect vector growth. This, combined with increasing resistance to anti-malarial drugs makes it urgent that new therapeutic options are developed and put into action.
Our data provide a significant advance in our understanding of malaria and provides a basis for therapeutic exploitation targeting aspects of both disease tolerance and resistance mechanisms. For instance, the salutary effects of BVRA could be mimicked or enhanced via therapeutic bilirubin administration, or by other means that enhance its protective activity in Plasmodium spp. Infections. This work is still ongoing and is expected to generate molecular targets that can be further researched and harnessed for their potential therapeutic effects in infection. As such, the outcome of BILITOLERANCE has generated important knowledge for academia, which also bears the potential to directly decrease disease burden of infectious diseases globally, and better equip the EU to deal with possible future challenges of spreading tropical infectious diseases like malaria.
