Miguel Soares Lab

Inflammation

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:

1. Identified that renal iron-heme metabolism in the kidney is essential to counter the pathogenesis of severe malaria (Proc. Natl. Acad. Sci. USA. 2019).
2. Identified a cross-regulatory network between iron and glucose metabolism that is essential to establish disease tolerance to sepsis (Cell 2017).
3. Uncovered a symbiotic interaction whereby bacterial components of the gut microbiota elicit an antibody response that counters malaria transmission (Cell, 2014).
4. Discovered that regulation of iron metabolism and establishes disease tolerance to systemic infections (Cell Host & Microbe, 2012).
5. Discovered a central molecular mechanism via which sickle hemoglobin establishes disease tolerance to malaria (Cell, 2011).
6. 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).
7. 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).