Iron and Innate Immunity

 

Previous Research Results

Due to its unique redox capability, iron is an essential element required for a wide array of cellular process, but also potentially highly toxic. Iron availability and distribution is thus subject to a tight regulation. As an essential nutrient for both host and pathogen, iron is at the center of a crucial dispute during infectious processes. In our group, we investigate: a) the molecular and cellular circuits involved in the re-modeling of host iron metabolism during chronic infection; b) the evolution of iron genes; c) iron-mediated oxidative stress and toxicity

Working mainly with mouse as a model, we have previously characterized two experimental models of hereditary haemochromatosis, the B2m-knock-out and the Hfe-ko, both of which show parenchymal iron accumulation with sparing of tissue macrophages. However, iron distribution is altered during infection with Mycobacterium avium, accumulating inside infected macrophages. Mice infected with M. avium develop mild anaemia and alter the expression levels of several iron-related genes such as ferritin, heme-oxigenase-1 and lipocalin-2, but show no significant induction of hepcidin, the main iron-regulating hormone.

We showed that iron overload favours bacterial growth in mice and also in fish and we developed new iron chelators with significant inhibitory effect on M. avium growth.

We demonstrated that the dual activation of hepcidin by iron and infection also occurs in fish, showing that these pathways are well conserved throughout evolution. We also described a case of synfunctionalization where the slc11a1 gene, which is absent in teleost fish, is functionally replaced by one of the duplicated paralogs of slc11a2 , a gene that is involved in both iron metabolism and response to bacterial infection.

Interestingly and in sharp contrast with mycobacteria, infection by the protozoan parasite Leishmania infantum is more easily circumvented in iron overloaded mice and we have evidence that iron-induced parasite killing is mediated by host-derived oxygen and nitrogen species.

 

IMAGE: Iron staining (DAB-enhanced Perls reaction) of a C57BL6 mouse liver section after Fe-dextran injection showing iron deposition in periportal hepatocytes and Kupfer cells

 

Future Research

Our future research goals include the further elucidation of the links between iron metabolism, oxidative stress and inflammation in the context of the innate immune response to infection.

We have recently accumulated evidence that iron may exacerbate infection through oxidative stress and inflammatory mechanisms. Iron induces Nrf2 signalling, which in turn protects cells against iron-mediated oxidative stress. Likewise, mice genetically deficient in heme-oxygenase-1, a transcriptional target of Nrf2, are more susceptible to M. avium. We will now aim at understanding the relevance of Nrf2 activation by iron in vivo and at identifying the mechanisms by which heme-oxygenase-1 protects against M. avium infection.

Following our findings indicating the evolutionary conservation of hepcidin dual functions in response to iron overload and bacterial infection, we will investigate the molecular mechanisms of hepcidin regulation in teleost fish.

We are also determined to investigate the molecular and cellular mechanisms of the anemia induced by M. avium in mice. Lipocalin-2 is one of the most highly induced iron-related genes in the liver of M. avium-infected mice. Since it has been suggested in the literature that lipocalin-2 inhibits erythropoiesis, we will analyse the impact of M. avium infection on the iron metabolism of lipocalin-2-deficient mice, particularly in what concerns the red blood cell compartment.

Finally, we will continue our collaborations with the Chemistry Department (FCUP) for the development of new therapies against Mycobacteria and Leishmania infection, based on iron chelators and iron-containing compounds, respectively.

 

Selected references

Gomes-Pereira, S., Rodrigues, P., Appelberg, R. and Gomes, M.S. Increased susceptibility to Mycobacterium avium in hemochromatosis protein HFE-deficient mice. Infection and Immunity (2008) 76:4713-4719

Rodrigues, P., Vasquez-Dorado, S., Neves, J. and Wilson J. Fish hepcidin dual function: its response to experimental iron overload and bacterial infection in Sea bass (Dicentrarchus labrax). Developmental and Comparative Immunology (2006), 30:1156-1167

Neves, J., Wilson J. and Rodrigues, P. Transferrin and ferritin response to bacterial infection: the role of the liver and brain in fish. Developmental and Comparative Immunology (2009), 33(7):848-857

Fernandes, S.S., Nunes, A., Gomes, A.R., de Castro, B., Hider, R.C., Rangel, M., Appelberg, R. and Gomes, M.S. Identification of a new hexadentate iron chelator capable of restricting the intramacrophagic growth of Mycobacterium avium. Microbes and Infection (2010) 12:287-294

Rodrigues, P., Lopes, C., Mascarenhas, C., Arosio, P., Porto, G., and De Sousa M. Comparative study between Hfe-/- and β2m-/- mice: Progression with age of iron status and liver pathology. International Journal of Experimental Pathology (2006), 87(4):317-324

Rodrigues, P., Silva Gomes, S., Neves, J.; Gomes-Pereira, S., Correia-Neves, M., Nunes-Alves, C., Stolte, J., Sanchez, M., Appelberg, R., Muckenthaler, M., and Gomes S. Mycobacteria-induced anaemia revisited: A molecular approach reveals the involvement of Nramp-1 and Lipocalin-2, but not of Hepcidin. Immunobiology (2011)

 

 

 

 

Group Leader
228.jpeg
prodrigu@ibmc.up.pt
People
Researchers

Carolina Moreira, Ana
ana.s.moreira@ibmc.up.pt

Gomes, Salomé
sgomes@ibmc.up.pt

Neves, João
jneves@ibmc.up.pt

Renata Freitas, Carla
renata.freitas@ibmc.up.pt

PosDocs

Cordeiro Gomes, Ana
ana.c.gomes@i3s.up.pt

Martins da Silva, Tânia
tania.silva@ibmc.up.pt

Phd Students

Barroso, Carolina
carolina.barroso@i3s.up.pt

MSc Students

Bento, Clara
clara.bento@i3s.up.pt

Trainees

Laranja Mesquita, Gonçalo
goncalo.mesquita@i3s.up.pt

Collaborators

Balaseviciute, Ugne
ugneba@gmail.com

Oliveira, Tiago
tcoliveira@ibmc.up.pt

Soares, Luís Miguel
lmiguel1996@hotmail.com


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