Biliverdin reductase A (BVRA) is a multifunctional protein highly expressed by macrophages.

Its enzymatic activity acts downstream of heme catabolism, converting biliverdin into bilirubin. Both end-products are physiologic ligands of the nuclear Aryl hydrocarbon receptor, an immunoregulatory component of the transcriptional stress and damage control network that promotes disease tolerance to infection.

Bilitolerance is aimed to address whether BVRA promotes disease tolerance.

This translational study is designed to expand our pre-clinical data in assessing the relative efficiency of targeting α-gal glycans to prevent Plasmodium infection and malaria transmission, for possible inclusion in future malaria vaccines.

The study consists of calibrating the protective effect of α-gal-specific antibodies against well-established protective antibodies recognizing Plasmodium falciparum circumsporozoite protein (PfCSP).

The primary outcomes of this study are to determine:

• anti-infection benefit of targeting α-gal over PfCSP antigens alone or in combination; and
• transmission-blocking activity of targeting α-gal.

Intermediate outputs include:

• define functionally the α-gal glycans targeted by α-gal-specific Ab,
• compare the anti-infection effect of antibodies targeting distinct α-gal glycans and
• compare Plasmodium gametocyte killing and transmission-blocking effects of antibodies targeting α-gal glycans.

Anorexia of infection is a component of sickness behavior that impacts on the outcome of infectious diseases.

The mechanisms regulating this metabolic response remain elusive. We found that anorexia of infection is associated with induction of ferritin expression in the liver.

This master regulator of iron metabolism induces the expression of G6Pase, sustaining hepatic glucose production and maintaining blood glucose within upper and lower threshold levels compatible with host survival.

Glucoinfect addresses how this metabolic response operates to establish disease tolerance to viral, bacterial and protozoan infections.

We are investigating a neurometabolic response regulated at the level of the hypothalamus and acting downstream via the sympathetic nervous system that appears to be essential to establish disease tolerance.

This neurometabolic response regulates:

i) lipolysis in white adipose tissue,

ii) thermogenesis in brown adipose tissue,

iii) glycogenolysis and gluconeogenesis in the liver and

iv) glucagon and insulin release from α and β cells of the pancreas, respectively.

Neurotolerance is aimed at characterizing how this neurometabolic response contributes to the establishment of disease tolerance to viral bacterial or protozoan infections.

Stress and damage responses evolved from ancestral forms of life, where these provided organismal adaptation to environmental variation. These variations, often associated with infection, are sensed and reacted upon by a transcriptional stress and damage response network, encompassing the nuclear factor (erythroid-derived 2)-like 2 (NRF2).

This master transcriptional regulator of oxidative stress responses induces the expression of target genes that are essential to establish disease tolerance to malaria and sepsis.

Tolerancenetwork is aimed at identifying and characterizing NRF2-effector genes regulating glucose/energy metabolism and establishing disease tolerance to infection.

Immune-driven resistance mechanisms can lead to immunopathology and compromise disease tolerance. Regulatory T cells (TREG) restrain immune-driven resistance mechanisms from operating beyond the protective capacity afforded by the transcriptional stress and damage response network.

We found that regulation of iron metabolism impacts on TREG lineage maintenance and function.

Tregtolerance is aimed at elucidating the mechanisms via which this occurs, towards the establishment of disease tolerance.