IDO1-AhR axis increases T regulatory cells in Plasmodium vivax malaria infection

Rafaella Oliveira dos Santos¹Nani Oliveira Carvalho¹Thiago Barros do Nascimento de Morais¹Wlademir Braga Salgado Sobrinho¹Maria Geuziane Soares da Cruz¹Elaine Speziali de Faria²Fernanda Fortes De Araújo²Vanessa Peruhype Pascoal²Stefanie Costa Pinto Lopes¹Adriana Malheiros³Adolfo José da Mota³Helton da Costa Santiago⁴Paulo Afonso Nogueira¹Andréa Teixeira-Carvalho²Marcus Vinícius Guimarães de Lacerda¹Pritesh Lalwani^1*

• ¹Instituto Leônidas & Maria Deane (ILMD/Fiocruz Amazônia), Manaus, Brazil
• ²René Rachou Institute, Oswaldo Cruz Foundation (Fiocruz), Belo Horizonte, Minas Gerais, Brazil
• ³Federal University of Amazonas, Manaus, Amazonas, Brazil
• ⁴Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

Malaria remains a major public health problem in Brazil where Plasmodium vivax (P. vivax) is the predominant species. An inappropriate immune response to parasite infection is one of the primary drivers of malaria pathogenesis. Indoleamine 2,3-Dioxygenase (IDO) catabolizes tryptophan (TRP) an essential amino acid into an immunosuppressive metabolite kynurenine (KYN). In this study, we investigated the relationship between tryptophan catabolism and regulatory T cells in P. vivax malaria infection. In vitro stimulation of PBMCs with P. vivax -infected erythrocyte (Pv-iE) lysate increased IDO-1 expression in CD14+ cells, KYN/TRP ratio and pro-inflammatory cytokines. Furthermore, in presence of IDO inhibitor a decrease in KYN/TRP ratio and Treg cell frequencies was observed upon iPV-RBC lysate stimulation. In addition, inhibition of MyD88 decreased KYN/TRP ratio, IDO-1 enzyme expression. Inhibition of AhR also decreased Treg frequencies and CD4+ T cell proliferation. KYN/TRP ratio and Tregs were elevated in patients acutely infected vivax malaria. Also, a positive correlation between KYN/TRP and Tregs was observed. Individuals with previous vivax malaria infection has lower Tregs and plasma IFN-g and KYN/TRP compared to patients with first malaria episode. These data provide new insight into the mechanisms of the innate activation-induced tolerogenic phenotype in P. vivax infection, which can help the better understanding of processes involved in induction and resolution of chronic inflammation and tolerance.