Evolutionarily Selected Overexpression of the Cytokine BAFF Enhances Mucosal Immune Response Against P. falciparum.

Valeria Lodde,Rachel Munk,Maristella Steri,Kotb Abdelmohsen,Maria Laura Idda,Rajan Guha,Isabel Beerman,Myriam Gorospe,Valeria Orrù,Peter D Crompton,Francesco Cucca,Matteo Floris

doi:10.3389/fimmu.2020.575103

Abstract

We have previously shown that a variant of the TNFSF13B gene that we called BAFF-var increases the production of the cytokine BAFF, upregulating humoral immunity and increasing the risk for certain autoimmune diseases. In addition, genetic population signatures revealed that BAFF-var was evolutionarily advantageous, most likely by increasing resistance to malaria infection, which is a prime candidate for selective pressure. To evaluate whether the increased soluble BAFF (sBAFF) production confers protection, we experimentally assessed the role of BAFF-var in response to malaria antigens. Lysates of erythrocytes infected with Plasmodium falciparum (iRBCs) or left uninfected (uRBCs, control) were used to treat peripheral blood mononuclear cells (PBMCs) with distinct BAFF genotypes. The PBMCs purified from BAFF-var donors and treated with iRBCs showed different levels of specific cells, immunoglobulins, and cytokines as compared with BAFF-WT. In particular, a relevant differential effect on mucosal immunity B subpopulations have been observed. These findings point to specific immune cells and molecules through which the evolutionary selected BAFF-var may have improved fitness during P. falciparum infection.

Highlights

Malaria is one of the most prevalent infectious diseases and is a global public health challenge
To investigate the mechanism through which BAFF-var may have been selected for improved fitness against malaria infections, we used lysates of erythrocytes infected with P. falciparum or left uninfected to treat primary cells from Sardinian donors with different BAFF genotypes
peripheral blood mononuclear cells (PBMCs) from Sardinia donors were cultured with uRBCs for 48 h and soluble BAFF (sBAFF) levels were measured from the conditioned media by enzymelinked immunosorbent assay (ELISA)

Summary

Introduction

Malaria is one of the most prevalent infectious diseases and is a global public health challenge. Several therapeutic strategies against malaria have been employed with considerable success, but a highly definitive vaccine remains elusive, partially due to an incomplete understanding of the immune response to Plasmodium falciparum, the most deadly malaria parasite species that infects humans [1,2,3]. High sBAFF in Malaria Response cells, T cells, antibodies, cytokines, and their respective receptors all play crucial roles in the recruitment and activation of different cell types of the immune system, modulating the complex immunological response against malaria parasites [2, 3]. Upregulation of pro-inflammatory cytokines such as IFNγ (IFNG), IL12, and TNF-α (TNF) during the early stages of infection contributes to protection and resolution of parasite infection [9]. An appropriately balanced release of proand anti-inflammatory cytokines is critical for a positive outcome of malaria disease. Defects in the production of TGF-β (TGFB1) and IL10, two anti-inflammatory factors, are associated with acute, severe malaria, severe malaria anemia, and an overall negative outcome [10,11,12]

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Conclusion