Regulation of macrophage function during acute infection with Plasmodium

Project Summary Plasmodium, the causative agent of malaria, remains one of the most prominent public health challenges today. The combined efforts of the innate and adaptive immune system lead to the control of parasite and disease burdens after infection. Macrophages and monocytes are key effector cells in the killing and removal of blood- stage parasites. The production of IFN-g promotes the recruitment and activation of monocytes in the spleen during the height of the T-cell mediated immune response against Plasmodium, leading to control of parasite burden. However, less is known about the contribution of tissue-resident macrophages to the control of parasite burden during the initial stages of the innate response before activation of the adaptive immune response. Nor do we fully understand the transcription factors that regulate their activity. Here we confirm that myeloid cell populations are essential for controlling early parasite growth in response to infection with the lethal murine P. yoelii 17XL strain. Furthermore, we provide preliminary data showing that the transcription factor Bhlhe40 is required to control early parasite burden after P. yoelii 17XL infection, as Bhlhe40-/- mice succumb to this infection at a similar time as macrophage-depleted mice. Moreover, we provide evidence that splenic macrophages and monocytes express Bhlhe40 after infection. Hence, we will test the hypothesis that Bhlhe40 regulates a transcriptional program in these myeloid cells that is required for controlling parasite burden in response to P. yoelii 17XL infection. We will test this hypothesis as part of two aims proposed here. Aim 1 will determine whether Bhlhe40 expression in macrophages and monocytes is required to promote parasite control after infection with P. yoelii 17XL. Aim 2 will determine how the loss of Bhlhe40 expression impacts the function of macrophages and monocytes in response to infection with P. yoelii 17XL. Together these studies will elucidate a role for Bhlhe40 expression in splenic macrophages and monocytes and determine how modulation of gene expression by this transcription factor impacts the host immune response to infection.