TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection.
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 Kupffer-hepatocyte cross-talk in the control Plasmodium liver stage infection and demonstrate that TREM2 is involved in host responses against the malaria parasite.
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
Lígia Antunes
LA
Gonçalves
Lurdes
L
Rodrigues-Duarte
Joana
J
Rodo
Luciana
L
Vieira de Moraes
Isabel
I
Marques
Carlos
C
Penha-Gonçalves
D000818:Animals; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D056426:Genetic Loci / Q000235:genetics / Q000276:immunology; D005838:Genotype; D007113:Immunity, Innate / Q000276:immunology*; D007728:Kupffer Cells / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000469:parasitology*; D008288:Malaria / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018895:Microsatellite Repeats / Q000235:genetics; D010962:Plasmodium berghei / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism*; D018709:Statistics, Nonparametric
D017931:DNA Primers; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse