Immunity evolved in multicellular organisms to limit the potential negative impact resulting from continuous exposure to microbes. Innate and adaptive components of the immune system are endowed with the capacity to sense and target pathogenic microorganisms for containment, destruction or expulsion as the means to preserve organismal homeostasis and fitness. Resistance to infection refers to the output of these immune functions.
Multicellular organisms also evolved another defense strategy that preserves organismal homeostasis and fitness without exerting a direct negative impact on microorganisms. This defense strategy, referred to as disease tolerance, relies on evolutionarily conserved stress and damage responses that limit the extent of metabolic dysfunction and damage imposed on parenchyma tissues, either directly by pathogenic microorganisms or indirectly by immune-driven resistance mechanisms.
The overall aim of the Inflammation Laboratory is to identify and characterize these stress and damage responses which confer tissue damage control and establish disease tolerance to infection.
The central hypothesis tested is that a functional interplay between immune-driven resistance mechanisms, and stress and damage responses acting in parenchyma tissues, exists to limit, counter and repair the pathogenic effects of infection.
Understanding the cellular and molecular mechanisms governing this network of interactions and responses should be transformative in our understanding of host-microbe interactions, with direct impact on the treatment of infectious diseases.
Original Scientific contributions:
- Identified that renal iron-heme metabolism in the kidney is essential to counter the pathogenesis of severe malaria (Proc. Natl. Acad. Sci. USA. 2019).
- Identified a cross-regulatory network between iron and glucose metabolism that is essential to establish disease tolerance to sepsis (Cell 2017).
- Uncovered a symbiotic interaction whereby bacterial components of the gut microbiota elicit an antibody response that counters malaria transmission (Cell, 2014).
- Discovered that regulation of iron metabolism and establishes disease tolerance to systemic infections (Cell Host & Microbe, 2012).
- Discovered a central molecular mechanism via which sickle hemoglobin establishes disease tolerance to malaria (Cell, 2011).
- Revealed that the stress responsive enzyme heme oxygenase-1 supports the survival of an infected host independently of its pathogen load, providing the first mechanistic basis for the establishment of disease tolerance to malaria (Nature Medicine, 2007 and Proc. Natl. Acad. Sci. USA. 2009) and to sepsis (Science TM, 2010; Science, 2012).
- Discovered that the gasotransmitter carbon monoxide (CO), generated via heme catabolism by heme oxygnease-1, acts therapeutically in a range of immune-mediated inflammatory conditions, including the rejection of transplanted organs (J. Immunology, 2001, Nature Medicine, 2003), arteriosclerosis (Nature Medicine, 2003), ischemia & reperfusion injury (FASEB Journal. 2004), autoimmune neuroinflammation (J. Clinical Investigation 2007) and severe malaria (Nature Medicine, 2007).
Our current body of work was sparked to a large extent by the original demonstration, with the late Fritz H. Bach at Harvard Medical School, that the gasotransmitter carbon monoxide(CO) acts in a cytoprotective (J. Exp. Med., 2001) and immunoregulatory (Nature Medicine, 2000) manner, providing a mechanistic basis for how transplanted organs prevent their own rejection (Nature Medicine, 1998).
Anorexia of infection is a component of sickness behavior that impacts on the outcome of infectious diseases.
Research on neurometabolic response regulated at the level of the hypothalamus and acting via the sympathetic nervous system, essential to establish disease tolerance.
Stress and damage responses evolved from ancestral forms of life, where these provided organismal adaptation to environmental variation.
Biliverdin reductase A (BVRA) is a multifunctional protein highly expressed by macrophages. Its enzymatic activity acts downstream of heme catabolism, converting biliverdin into bilirubin.
- Weis S., Carlos A.R:, Moita M.R., Singh S., Blankenhaus B., Cardoso S., Larsen R., Rebelo S., Schäuble S., Del Barrio L., Mithieux G., Rajas F., Lindig S., Bauer M., Soares M.P. (2017) Metabolic adaptation establishes disease tolerance to sepsis.Cell 169 (7) : 1263–1275.e14
- Yilmaz B., Portugal S, Tran T.T., Gozzelino R., Ramos S., Gomes J., Regalado A., Cowan P.J., d’Apice A.J.F., Chong A.S., Doumbo O.K., Traore B., Crompton P.D., Silveira H., Soares M.P. (2014) Gut microbiota elicits a protective immune response against malaria transmission. Cell 159 (6) : 1277-1289. Reviewed in: Nature Reviews Immunology; Trends in Parasitology; Highlighted in: The Scientist; Science daily, BBC more recently in the New York Times
- Medzhitov, R., Schneider, D., Soares M.P. (2012) Disease tolerance as a host defense strategy. Science 335 (6071) : 936-941
- Ferreira A., Marguti I. Bechmann I., Chora A., Palha N.R., Rebelo S., Henri A., Beuzard Y., Soares M.P. (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145(3) : 398-409. Referred in: Cell Research Highlights; Science Editor's choice; The New England Journal of Medicine; Faculty of 1000Prime
- Larsen R., Gozzelino R., Jeney V., Tokaji L., Bozza F.A., Japiassú A.M., Bonaparte D., Cavalcante M.M., Chora A., Ferreira A., marguti I., Cardoso S., Sepúlveda N., Smith A., Soares M.P. (2010) A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med. 2 (51) : 51ra71
- Pamplona, A., Ferreira, A., Balla, J., Jeney, V., Balla, G., Epiphanio, S., Chora, A., Rodrigues, C.D., Cunha-Rodrigues, M., Portugal, S., Soares, M.P.* Mota, M.M*. *Equal contribution. (2007) Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med. 13 (6) : 703-710. Reviewed in Faculty of 1000 Biology and in Faculty of 1000 Medicine (currently merged in F10000Prime )
- Otterbein, L.E., Haga, M., Zuckerbraun, B.Z., Liu, F., Ruiping Song, R., Usheva, A., Stachulak, C.H., Bodyak, N., Smith, N.R., Cismadia, E., Akamatsu, Y., Flavell R., Billiar, T.R., Tzeng, E., Bach, F.H., Choi, A.M.K., Soares, M.P. (2003) Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med. 9 (2) : 183-190
- Otterbein L., Bach F.H., Alam J., Soares, M.P., Lu H.T., Wysk M., Davis R.J., Flavell R., Choi A. M. (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 6 (4) : 422-428
- Brouard S., Otterbein L., Anrather J., Tobiasch E., Bach F.H., Choi A.M.K., Soares, M.P. (2000) Carbon monoxide generated by heme oxygenase-1 suppresses endothelial cell apoptosis. J Exp Med. 192(7) : 1015-1026
- Soares, M.P., Lin Y., Anrather, J., Csizmadia, E., Takigami, K, Sato, K., Grey S.T., Colvin, R.B., Choi, A.M., Poss, K.D and Bach, F.H. (1998) Expression of heme-oxygenase-1 (HO-1) can determine cardiac xenograft survival. Nat Med. 4(9) : 1073-1077
Miguel Soares, Principal Investigator
PhD in Cell Biology, University of Louvain, Belgium
Phone: +351 214464520
E-mail: [email protected]