The Bioenergetics of Infection

Infectious diseases emerge as pathogenic microorganisms, including bacteria, viruses, fungi, or protozoan parasites, bridge epithelial barriers and proliferate systemically to compromise host homeostasis. As infections progress, invading pathogens become confronted with a hostile metabolic environment, whereby the host restricts access to vital nutrients and metabolites. This defense strategy is coined as innate nutritional immunity. Pathogens co-evolve with their hosts to deploy virulence factors, enabling the acquisition of vital (micro)nutrients and metabolites, often to the detriment of their hosts. If not countered, this pathologic process dysregulates host metabolism, to become a major driving force in the pathogenesis of infectious diseases.

Anti-microbial defense strategies are triggered by inflammatory cytokines and prostaglandins that act systemically, including in the brain, where these trigger sickness behaviors. One hallmark sickness behavior is the transient loss of appetite (anorexia), which restrains the infected host from absorbing nutrients and metabolites from the diet, presumably as a component of innate nutritional immunity.

As an evolutionary trade-off, anorexia also reduces nutrient and metabolite supply to the host. When this falls below the energetic demands of the infected host, it compromises core biochemical processes that produce, store, and utilize energy to power the function of vital organs. This is prevented via metabolic reprogramming of the infected host towards a hypometabolic state, whereby catabolic metabolism and de novo macromolecule synthesis is favored over anabolic metabolism and energy production, respectively. Failure of this hypometabolic response to sustain energy metabolism leads to the development of life-threatening multiorgan failure, a condition known as sepsis, a major World Health Organization (WHO) health priority with an estimated incidence of 49 million and an associated mortality of 11 million per year.

The inflammation laboratory is developing several interdisciplinary research programs (at the crossroads of immunology, organismal metabolism and neuronal control of metabolism), to elucidate how the brain reprograms energy metabolism to prevent the onset of sepsis. These projects are enabled by cutting edge approaches, anchored on high-end mouse genetics and systems biology. Our objective is to gain a comprehensive understanding of how inflammation rewires organismal energy metabolism, as a defense strategy against viral, bacterial, fungal and protozoan infections.

Neurometabolic rewiring in hemolytic conditions

About 80% of all the (bio)available iron in mammals is contained in the prosthetic heme groups of hemoproteins that act as vital regulators of homeostasis. Perhaps the best example is illustrated by hemoglobin, a hemoprotein contained in red blood cells (RBC) that plays a vital role in O₂ delivery.

Hemolytic anemias refer to a number of pathologic conditions of distinct etiologies (e.g., genetic, infectious, traumatic or autoimmune), whereby hemolysis reduces the number of circulating RBC below a threshold that ensuresphysiologic O₂ delivery (hypoxia). The pathologic outcomes of hemolytic anemias are countered by an integrated response, whereby stress-erythropoiesis is called upon to restore RBC numbers, above the lower life-threatening threshold. This is coupled to the induction of stress-myelopoiesis, supporting iron-recycling by erythrophagocytic macrophages, to fuel heme-synthesis to support stress-erythropoiesis.

At the inflammation laboratory, we found that in severe hemolytic conditions, such as malaria (caused by Plasmodiuminfection), this integrated response involves an additional renal iron-recycling salvage pathway. Stress-erythropoiesis and myelopoiesis are highly energy-demanding anabolic processes, integrated at an organismal level by the brain to prevent the development of life-threatening anemia. We are developing interdisciplinary projects aimed at identifying and characterizing stress-responsive brain areas that coordinate stress-erythropoiesis and -myelopoiesis in response to hemolytic anemias.

The biology of bilirubin at host-microbe interfaces

Disease tolerance (see the Lab Description above) is enforced by evolutionarily conserved stress-responses. At the Inflammation laboratory we found that these stress-responses are organized as a transcriptional network, which regulates the expression of a restricted number of core effector genes, which provide tissue damage control as the means to limit the fitness costs of infection. One of such core effector genes is HMOX1, encoding the heme catabolizing enzyme heme oxygenase 1 (HO-1).

Heme catabolism by HO-1 produces equimolar amounts of carbon monoxide, iron and biliverdin IXa. This catabolic process is coupled to the reduction of biliverdin IXa into bilirubin IXa, catalyzed by biliverdin reductase (BVRA). Unconjugated bilirubin IXa is lipophilic and circulates in plasma bound to albumin. Bilirubin conjugation to glucuronic acid, catalyzed by the UDP-glucuronosyltransferase 1A1 (UGT1A1), produces water soluble conjugated bilirubin that is excreted into the bile duct.

At the inflammation laboratory we are developing several interdisciplinary research projects aimed at identifying and characterizing how the BVRA/UGT1A1 pathway impacts on a number of symbiotic host microbe interactions. We posit that the BVRA/UGT1A1 pathway acts in a conserved way to control the accumulation of unconjugated bilirubin IXa in plasma and provide a fitness advantage against a number of host-microbe interactions. These include host-microbiota interactions as well host interactions with different classes of pathogens. Of note, the protective effects of the BVRA/UGT1A1 carry as a fitness cost the development of neonatal hyperbilirubinemia.

The biology of erythrophagocytic macrophages

Erythrophagocytosis is critical to maintain organismal homeostasis, providing the means to recycle the iron contained in the prosthetic heme groups of hemoglobin in senescent red blood cells (RBC). Under steady state conditions this is achieved by erythrophagocytic macrophages in the red pulp of the spleen. These arise from a developmental program that allows for a high rate of heme catabolism via heme oxygenase 1 (HO-1). If not tightly controlled, the catalytic iron extracted from heme by HO-1 becomes hazardous and catalyzes the production of reactive oxygen species (ROS), unleashing a chain reaction whereby lipid peroxidation induces programmed cell death via ferroptosis. The mechanism via which erythrophagocytic macrophages prevent the accumulation of catalytic iron from triggering programmed cell death via ferroptosis is not clear. This is thought to occur via a transcriptional program enforced by the oxidative-stress responsive nuclear factor-erythroid 2 related factor 2 (NRF2), regulating the transcription of genes controlling cellular redox and preventing ferroptosis. At the inflammation laboratory we are characterizing the different elements that partake in this transcriptional program to protect erythrophagocytic macrophages from undergoing ferroptosis.

September 2022-2025: Fundação para a Ciência e Tecnologia, Portugal. PTDC/MED-FSL/02426/2022. Principal Investigator: Miguel P. Soares. Title: A non-canonical protective response against malaria. Acronym: MALLBILL. Institution: Instituto Gulbenkian de Ciência.

June 2021-2026:  COST (European Cooperation in Science and Technology), European Community. Principal Investigator: Antonio Quadrado, Spain. Title: Bench to bedside transition for pharmacological regulation of NRF2 in non-communicable diseases. Acronym: BenBedPhar Code: CA20121. Institution: Instituto Gulbenkian de Ciência.

March 2021-2024: Fundação para a Ciência e Tecnologia, Portugal. PTDC/MED-FSL/4681/2020. Principal Investigator: Miguel P. Soares. Title: Metabolic reprograming as a defense strategy against infection. Acronym: INFECTENERGY. Institution: Instituto Gulbenkian de Ciência.

Wu Q, Carlos AR, Braza F, […] Ramos S, Soares MP (2024) Ferritin heavy chain supports stability and function of the regulatory T cell lineage. EMBO J. 43(8):1445–1483. DOI: 10.1038/s44318-024-00064-x

Ramos S, Ademolue TW, […] Soares MP (2022) A hypometabolic defense strategy against malaria. Cell Metab. 34(8):1183–1200.e12. DOI: 10.1016/j.cmet.2022.06.011

Weis S, […] Soares MP (2017) Metabolic adaptation establishes disease tolerance to sepsis. Cell. 169(7):1263–1275.e14. doi: 10.1016/j.cell.2017.05.031

Yilmaz B, […] Soares MP (2014) Gut microbiota elicits a protective immune response against malaria transmission. Cell. 159(6):1277–1289. DOI: 10.1016/j.cell.2014.10.053

Ferreira A, […] Soares MP (2011) Sickle hemoglobin confers tolerance to Plasmodium infection. Cell. 145(3):398–409. DOI: 10.1016/j.cell.2011.03.049

Larsen R, […] Soares MP (2010) A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med. 2:51ra71–51ra71. DOI: 10.1126/scitranslmed.3001118

Pamplona A, Ferreira A, […] Soares MP*, Mota MM* (2007) Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med. 13:703–710. DOI: 10.1038/nm1586 (*Equal contribution)

Otterbein LE, […] Soares MP (2003) Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med. 9:183–190. DOI: 10.1038/nm817

Brouard S, […] Soares MP (2000) Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med. 192(7):1015–1026. DOI: 10.1084/jem.192.7.1015

Soares MP*, Lin Y*, Anrather J, Csizmadia E, Takigami K, Sato K, Grey ST, Colvin RB, Choi AM, Poss KD, Bach FH (1998) Expression of heme-oxygenase-1 (HO-1) can determine the cardiac xenograft survival. Nat Med. 4:91–98. DOI: 10.1038/2063 (*Equal contribution)

• 2023: Ranked among the top 2% of scientists worldwide (across all areas).
  Source: Ioannidis, John P.A. (2023), “October 2023 data-update for “Updated science-wide author databases of standardized citation indicators”,” Elsevier Data Repository, V6, doi: 10.17632/btchxktzyw.6
• 2015: Pulido Valente Science Award (Portugal) awarded to Bahtiyar Yilmaz, Ph.D. student under Miguel Soares’ supervision at the Instituto Gulbenkian de Ciência, for research on microbiota-mediated protection against malaria.
• 2015: Basic Science Prize from the “Sociedade de Ciências Médicas de Lisboa” and Pfizer, Portugal, for work on microbiota protection against malaria.
  Source: Sociedade de Ciências Médicas de Lisboa
• 2014: Marian Elliott Koshland Award for Distinguished, Lifelong Contributions to Immunologic Research and Education, awarded by the Committee on Immunology, University of Chicago, USA.
• 2012: Annual Prize of the Portuguese Society of Human Genetics awarded to Ana Ferreira, a postdoctoral researcher in Miguel Soares Lab at the Instituto Gulbenkian de Ciência, for work on the protective mechanism of sickle hemoglobin against malaria.
• 2011: Recognition Prize from the Roche Organ Transplantation Research Foundation (ROTRF) for Excellence in Organ Transplantation Research.
  Source: ROTRF
• 2010: Listed among the “10 Personalities of 2010” by the national Portuguese newspaper Público. Source: Público
• 2010: National “Seeds of Science” Prize awarded by Ciência Hoje, Portugal. Source: Ciência Hoje
• 2009: National Basic Science Prize from the “Sociedade de Ciências Médicas de Lisboa” and Pfizer, Portugal, for research on disease tolerance to infection.
• 2008: National NEDAI Research Prize in Auto-immunity awarded by the Portuguese Society of Internal Medicine (SPMI), sponsored by Schering-Plough Laboratories.
• 2004: International CESPU Research Prize from the “Cooperativa de Ensino Superior Politécnico e Universitário,” Portugal.
• 2004: National Basic Science Prize from the “Sociedade de Ciências Médicas de Lisboa” and Pfizer, Portugal, awarded to Lazlo Tokaji, a Ph.D. student under my supervision at the Instituto Gulbenkian de Ciência.
• 2000: Phyllis and Paul Fireman Junior Faculty Fellowship, part of the Eleanor and Miles Shore 50th Anniversary Fellowship Program for Scholars in Medicine, Harvard Medical School, Boston, USA.
• 1990-1994: Ph.D. Fellowship from the Belgian Institute for Industrial and Agricultural Research (IRSIA).

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