organisation - the Instituto Gulbenkian de Ciência

INFLAMMATION
Miguel P. Soares Principal Investigator
PhD in Science, University of Louvain, Belgium, 1995
Research Fellow, Harvard Medical School, Boston, MA, USA
Instructor in Surgery, Harvard Medical School, Boston, MA, USA
Lecturer, Harvard Medical School, Boston, MA, and USA
Invited Professor at Lisbon Medical School, Universidade de Lisboa, Portugal
Head of IGC Histopathology Unit
Principal Investigator at the IGC since 2004
Inflammation is an immediate response to foreign challenge and/or tissue injury
characterised by local and transient extravasation of soluble molecules and leukocytes
from blood into non-lymphoid tissues. While the physiologic purpose
of inflammation is to restore homeostasis there are many instances where inflammation
becomes pathological. Moreover, there is a general consensus that
some of the major causes of human morbidity and mortality are in fact due to
pathological conditions in which inflammation and/or immunity are the underlying
cause of disease. The research effort developed in our laboratory is aimed
at understanding the cellular and molecular mechanisms assuring that in the
overwhelming majority of cases inflammation exerts its physiologic purpose
without becoming pathological. Our body of work supports the notion that one
of such mechanisms relies on the expression of cytoprotective genes that allow
inflammation to progress without causing irreversible tissue damage.
MODULATION OF PROGRAMMED CELL DEATH BY FREE HEME
Under homeostasis, the reactivity of heme prosthetic groups is controlled by
their insertion into the “heme pockets” of hemoproteins. Under oxidative stress
however, some hemoproteins can release their heme prosthetic groups. The
non-protein-bound (free) heme becomes highly cytotoxic, most probably due
to the Fe atom contained within its protoporphyrin IX ring. When this occurs,
free heme can catalyse, in an unfettered manner, the production of free radicals
via Fenton chemistry and sensitise cells to undergo programmed cell death.
In our laboratory we have shown that the cytotoxic effect of free heme plays
an important role in the pathogenesis of a variety of inflammatory diseases in
which hemoproteins release their prosthetic heme groups.
MECHANISMS OF DISEASE TOLERANCE
Malaria, the disease caused by Plasmodium infection, remains one of the main
causes of morbidity/mortality worldwide. Epidemiologically however, less than
1-2% of Plasmodium-infected individuals succumb to severe forms of malaria.
This suggests that Plasmodium has co-evolved with its human host to
reach an evolutionary “trade off” in which infection “rarely” compromises host
viability. This trade off is thought to rely almost exclusively on the ability of the
host’s immune system to control parasite burden, a defence strategy referred
to as resistance to infection. However, there is an additional host defence strategy
that operates during Plasmodium infection and that limits disease severity
irrespectively of parasite burden, i.e. tolerance to infection. The mechanisms
underlying host tolerance to Plasmodium infection remain poorly understood.
We are exploring the hypothesis that several genes that regulate the deleterious
effects of free heme might control host tolerance to infection.
GROUP MEMBERS
Ana Ferreira (Post-doc, left in March)
Josina Filipe (Post-doc, left in January)
Virgínia Oliveira Marques (Post-doc, left in January)
Ana Cunha (Post-doc)
Rafaella Gozzelino (Post-doc)
Susana Ramos (Post-doc, started in February)
Rasmus Larsen (Post-doc)
Zélia Gouveia (External PhD Student)
Andreia Cunha (PhD student)
Nadja Pejanovic (PhD student)
Ivo Marguti (PhD student, left in July)
Bahtiyar Yilmaz (PhD Student)
Sofia Rebelo (Lab Manager)
Sílvia Cardoso (Laboratory Assistant)
COLLABORATORS
Josef Anrather (Cornell University, New York, USA)
Leo Otterbein (Harvard Medical School, Boston, USA)
Ann Smith (University of Missouri - Kansas City, USA)
Ingo Bechmann (Johann Wolfgang Goethe-University, Frankfurt/Main,
Germany)
Yves Beuzard (Hospital Saint Louis, Paris, France)
Lukas Kühn (Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland)
Carlos Penha Gonçalves (IGC, Portugal)
Jocelyne Demengeot (IGC, Portugal)
Henrique Silveira (Instituto de Higiene e Medicina Tropical (IHMT), Portugal)
Salome Gomes (IBMC- Universidaded do Porto, Portugal)
FUNDING
FP6 Framework Programme 6, European Commission
GEMI Fund Linde Healthcare
The Bill & Melinda Gates Foundation, USA
Fundação para a Ciência e a Tecnologia (FCT), Portugal
PROTECTION AGAINST MALARIA BY "NATURAL" ANTIBODIES
We are testing the hypothesis that antibodies directed against a specific carbohydrate
produced by gut pathogens might play a role in immunity against
severe forms of malaria. Newborns and young children, who are most susceptible
to these severe forms of the disease, have not yet built up antibodies to this
carbohydrate. We will assess whether stimulating production of this antibody
after birth can offer increased protection.
REGULATION OF ADAPTIVE IMMUNITY BY HEME OXYGENASE-1 (HO-1)
Over the past few years we extended our original studies to test the hypothesis
that HO-1 might regulate T cell mediated autoimmunity leading to the pathogenesis
of immune mediated inflammatory diseases such as diabetes, arthritis
or multiple sclerosis (MS). We found that this is indeed the case for MS, where
disease progression is caused by T cell driven neuroinflammation, leading to
central nervous system injury. The mechanism underlying the protective effect
of HO-1 against autoimmune neuroinflammation is not clear. We are testing the
IGC ANNUAL REPORT ‘11
RESEARCH GROUPS
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