Tuesday June 28, from 14.00 to 15.00
Point Centre, auditorium Albert Claude
Common seminar IBMM-IMI with Miguel Soares, Instituto Gulbenkian de Ciência, Oeiras, Portugal
"Tissue damage control: a central component in the establishment of host tolerance to infection"
There are two evolutionarily conserved defense strategies against infection that act in a concerted manner to control host disease severity. One relies on the capacity of the infected host to mount an appropriate immune response reducing its pathogen load. This is referred to as resistance to infection. The other defense strategy however, acts irrespectively of pathogen load to prevent tissue damage associated with infection. This is referred to as tolerance to infection (1), which is not to be mistaken with “immunological tolerance” that refers to a distinct and unrelated biological phenomenon. While recognized as a major component of host protection against infection in plants and flies (1, 2), tolerance to infection was only recently demonstrated to operate in mammals (3-8). In this presentation I will argue that tolerance to infection relies on the expression of stress-responsive genes that restrain the extent of tissue damage imposed directly by pathogens or indirectly by the host immune response elicited by those pathogens. I will refer to this protective mechanism as “tissue damage control” and will present experimental evidence illustrating how stress-responsive genes provide tissue damage control and hence confer host tolerance to infection in mice. Supporting the notion that tolerance to infection is a host defense strategy with major relevance to human disease is the demonstration that sickle cell hemoglobin (Hb) confers tolerance to Plasmodium infection (4), the causative agent of malaria. In a similar manner to the human sickle cell trait that confers a survival advantage against malaria in human populations, mice expressing sickle Hb have a survival advantage against malaria. This defense mechanism is exerted irrespectively of parasite load, demonstrating that sickle Hb can confer tolerance to Plasmodium infection. The mechanism underlying the protective effect of sickle Hb relies on induction of the heme-catabolizing enzyme heme oxygenase-1 (HO?1) via the transcription factor NF?E2?related factor 2 (Nrf2). Carbon monoxide, a byproduct of heme catabolism by HO-1, accounts for the survival advantage afforded by sickle Hb against malaria. Presumably induction of the Nrf2/HO-1 system associated with sickle Hb and probably with other often clinically silent genetic red blood cell defects is a general mechanism that confers tolerance to Plasmodium infection in human populations.
1. D. S. Schneider, J. S. Ayres, Nat Rev Immunol 8, 889 (Oct 17, 2008).
2. L. Raberg, A. L. Graham, A. F. Read, Philos Trans R Soc Lond B Biol Sci 364, 37 (Jan 12, 2009).
3. L. Raberg, D. Sim, A. F. Read, Science 318, 812 (Nov 2, 2007).
4. A. Ferreira et al., Cell 145, 398 (2011).
5. E. Seixas et al., Proc Natl Acad Sci U S A 106, 15837 (Sep 15, 2009).
6. R. Medzhitov, Proc Natl Acad Sci U S A 106 15525 (2009).
7. R. Larsen et al., Sci Transl Med 2, 51ra71 (Sep 29, 2010).
8. A. Pamplona et al., Nat Med 13, 703 (Jun, 2007).