TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

Abstract

Plasmodium liver stage infection is a target of interest for the treatment of and vaccination against malaria. Here we used forward genetics to search for mechanisms underlying natural host resistance to infection and identified triggering receptor expressed on myeloid cells 2 (TREM2) and MHC class II molecules as determinants of Plasmodium berghei liver stage infection in mice. Locus belr1 confers resistance to malaria liver stage infection. The use of newly derived subcongenic mouse lines allowed to map belr1 to a 4-Mb interval on mouse chromosome 17 that contains the Trem2 gene. We show that Trem2 expression in the nonparenchymal liver cells closely correlates with resistance to liver stage infection, implicating TREM2 as a mediator of the belr1 genetic effect. Trem2-deficient mice are more susceptible to liver stage infection than their WT counterparts. We found that Kupffer cells are the principle cells expressing TREM2 in the liver, and that Trem2 −/− Kupffer cells display altered functional activation on exposure to P. berghei sporozoites. TREM2 expression in Kupffer cells contributes to the limitation of parasite expansion in isolated hepatocytes in vitro, potentially explaining the increased susceptibility of Trem2 −/− mice to liver stage infection. The MHC locus was also found to control liver parasite burden, possibly owing to the expression of MHC class II molecules in hepatocytes. Our findings implicate unexpected Kupfferhepatocyte cross-talk in the control Plasmodium liver stage infection and demonstrate that TREM2 is involved in host responses against the malaria parasite. M alaria liver stage infection is asymptomatic but is absolutely required in the progression of Plasmodium infection in the vertebrate host, preceding propagation of parasites in the blood and clinical manifestations of malaria (1, 2). Current efforts in therapy and vaccine development include strategies aimed at deterring infection at the liver stage, preventing subsequent clinical complications and malaria transmission (3, 4). During liver stage infection, one Plasmodium sporozoite develops into thousands of merozoites inside each infected hepatocyte (5). Identification of host genetic factors that control liver parasite expansion may help elucidate response mechanisms operating during liver stage infection.Gene deficiency models and gene expression studies focusing on hepatocyte infection have highlighted genes that control hepatocyte invasion and intrahepatocyte parasite expansion [e.g., CD81 (6), SR-B1 (7, 8)], but the mechanisms of host response to liver stage infection remain elusive. It has been proposed that sporozoites' ability to traverse liver macrophages (9) and/or hepatocytes (10) in the course of liver stage infection may favor the release of proinflammatory factors at liver sites of sporozoite expansion (11,12). Innate immune mechanisms might be involved in sensing Plasmodium sporozoites and in controlling liver stage infection (13).Mouse models of liver stage infection suggest that sporozoites induce a innate in...

Susceptibility to Plasmodium yoelii Preerythrocytic Infection in BALB/c Substrains Is Determined at the Point of Hepatocyte Invasion

“…Furthermore, differences in susceptibility to preerythrocytic infection between BALB/c and C57BL/6 mice have been mapped to the expression of TREM2 in macrophages (33,34). These data indicate that genetic differences that give rise to molecular changes in immune components can alter susceptibility to preerythrocytic infection.…”

TREM2, Microglia, and Neurodegenerative Diseases

“…As previously discussed, the TREM2 gene is highly expressed in a subset of myeloid cell typesnamely, microglia in the CNS, osteoclasts in the bone, and other tissue-specific macrophages, including Kupffer cells, as well as alveolar, intestinal, and peritoneal macrophages [58,73,[90][91][92][93][94][95]. Bone marrow cells and blood monocytes express low to undetectable levels of TREM2, although expression can be induced upon differentiation of the former into macrophages or dendritic cells in vitro [50,87,91].…”

Neuroprotective Effect of TREM-2 in Aging and Alzheimer’s Disease Model

“…Immunofluorescence was quantified using methods previously described [16]. Figure 1i) and in the stellate macrophages or Kuffer cells of the liver (Figure 1g; [43,44] and a β-actin probe was used on sections from hippocampus to assess hybridization stringency (Figure 1j). Given the limited localisation of TREM2 mRNA in brain parenchyma, these data suggest that TREM2 is being derived from elsewhere.…”