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Iron released by heme oxygenase-1 activity impairs IFNγ-dependent NOS2 expression and bacterial replication control during Mycobacterium tuberculosis infection

Costa DL 1,2; Amaral EP 2; Namasivayam S 2; Mittereder LR 2; Fisher L 2; Bonfim CC 2; Sardinha-Silva A 2; Thompson RW 2; Hieny SE 2; Andrade BB 2,3,4,5,6,7,8,9; Sher A 2.

1 Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil; 2 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; 3 Wellcome Centre for Infectious Disease Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa; 4 Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil; 5 Multinational Organization Network Sponsoring Translational and Epidemiological Research (MONSTER) Initiative, Salvador, Brazil; 6 Curso de Medicina, Faculdade de Tecnologia e Ciências (FTC), Salvador, Brazil; 7 Universidade Salvador (UNIFACS), Laureate Universities, Salvador, Brazil; 8 Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador, Brazil; 9 Vanderbilt University School of Medicine, Nashville, TN, USA

Heme oxygenase-1 (HO-1) expression is highly induced by Mycobacterium tuberculosis (Mtb) infection in vitro and in vivo. Here, we show that inhibition of the enzyme activity by tin protoporphyrin (SnPP) treatment promotes improved pulmonary bacterial control in Mtb-infected mice. This effect is dependent on IFNγ production by T cells and NOS2 expression, since SnPP treatment of Mtb-infected IFNγ-/-, NOS2-/- or TCRα-/- animals adoptively transferred with IFNγ-/- T cells prior to infection fails to reduce pulmonary bacterial loads, contrarily to what is observed in wild type (WT) mice or TCRα-/- animals adoptively transferred with IFNγ-competent T cells. HO-1 inhibition also potentiates the control of bacterial replication in IFNγ-activated Mtb-infected macrophages, an effect that is not observed in NOS2-/- cells. Importantly, SnPP-induced HO-1 inhibition resulted in a reduction of iron accumulation in Mtb-infected lungs in vivo and macrophages in vitro and we observed that iron supplementation to Mtb-infected macrophages treated with IFNγ and SnPP reverted the HO-1 inhibition-induced enhancement of bacterial control, which was associated with decreased NOS2 expression and NO production. These results indicate that iron released by HO-1 activity suppresses T cell-mediated IFNγ/NOS2-dependent bacterial control and highlight the importance of the crosstalk between iron metabolism and adaptive immunity in determining the outcome of infection.

This work was supported by NIAID intramural research program.