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Control of disease tolerance to infection by Biliverdin Reductase A

Periodic Reporting for period 1 - BILITOLERANCE (Control of disease tolerance to infection by Biliverdin Reductase A)

Reporting period: 2018-12-01 to 2020-11-30

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. While long recognized as a global unmet medical need, recent estimates revealed a far greater global health impact, in that sepsis accounts for 1 in 5 deaths worldwide.
Protection from sepsis is classically attributed to the capacity of the host immune system to sense and clear pathogens. This is well illustrated by the overwhelming success of therapeutic approaches that mimic immune resistance mechanisms, such as vaccination or anti-microbial drugs and would suggest that resistance mechanisms are the only relevant defense strategy against infectious diseases. However, resistance mechanisms are not sufficient per se to prevent the pathogenesis of sepsis, as most sepsis patients succumb after pathogen elimination. An alternative view is that the pathogenesis of sepsis is driven by a dysregulated immune response, impairing organismal metabolism and leading to life-threatening organ dysfunction. In line with this, disease tolerance has recently emerged as an equally important defense strategy against infection, which aims at limiting damage to functions and structures imposed upon the host during infection, without exerting negative pressure on the pathogen.
Recent studies have highlighted the real burden of severe infection and sepsis, showing that its impact is roughly double of what was previously thought, with 20% worldwide mortality being attributed to sepsis. The lack of specific therapies makes sepsis one of the most pressing unmet medical needs, further compounded by the rise of pathogen resistance to anti-microbial drugs. In fact, the need for alternative therapies to overcome rising antibiotic resistance has been highlighted by the World Health Organization as one of the main global health challenges currently faced by mankind. BILITOLERANCE aimed at the generation of basic and translational knowledge directly related to the role of BVRA in the establishment of disease tolerance in severe infection and sepsis. This should reveal new therapeutic targets against a broad range of infectious diseases, where the fast-paced rising threat of antibiotic resistance makes the modulation of disease tolerance an extremely attractive novel therapeutic strategy. The translational aspect of BILITOLERANCE bore the potential to directly decrease the rising disease burden of infectious diseases within the EU, and to generate important knowledge for academia as well as for clinical research and practice, with concrete benefits for the European economy and society in general.
We utilized Bvra-/- (KO) mice to test the hypothesis that Bvra is a central gene that promotes disease tolerance to infection. Specifically, we performed cecal ligation and puncture procedures to mimic polymicrobial sepsis on Bvra-/- and wild type (WT; control) mice. Contrary to our hypothesis, we found no significant differences in vital parameters (body weight, temperature and blood glucose levels), as well as in survival between WT and Bvra-/- mice following CLP. These data prompted us to reassess our first hypothesis, and we focused on other infection models where BVRA could potentially play a role in establishing disease tolerance to infection.

Our laboratory has shown that heme catabolism is at the center stage of disease tolerance to Plasmodium spp. infection, the causative agent of malaria. This is in line with the fact that a major hallmark of malaria is the occurrence of severe intravascular hemolysis that leads to very high levels of labile heme in the circulation. Considering this, we alternatively hypothesized that BVRA is required to establish disease tolerance to Plasmodium spp. Infection. To test the hypothesis that Bvra expression is crucial for the establishment of disease tolerance to malaria, we infected WT and Bvra-/- mice with a mouse Plasmodium species (Plasmodium chabaudi chabaudi; Pcc) which is non-lethal to WT mice. We found that BVRA is strictly required for survival to Pcc infection, as all Bvra-/- animals succumbed to the infection, whereas all WT mice survived. Bvra-/- mice displayed increased disease severity when compared to WT mice. Bvra-/- mice also displayed dysregulated glucose metabolism following Pcc infection, with a sharp peak in blood glucose levels around day 7 post infection, whereas WT mice show a minor and transient drop in blood glucose levels. Taken together, our data provide a significant advance towards the understanding of malaria pathophysiology and provides a novel avenue for therapeutic exploitation targeting aspects of both disease tolerance and resistance mechanisms.
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.
BVRA and infection - summary