Inborn errors underlying herpes simplex encephalitis: From TLR3 to IRF3

1340 INSIGHTS | The Journal of Experimental Medicine After their inoculation by mosquitos and entry into the bloodstream, malaria sporozoites must cross the liver sinusoidal barrier to gain access to hepatocytes, where they can multiply as erythrocyte-infecting forms. In this issue, Cha et al. provide further evidence that Kupffer cells (KCs) offer a gateway for entry of sporozoites into the liver parenchyma and identify the receptor on the KCs that directs the passage of the parasite through this portal. A remarkably fruitful phage display strategy led to the identification of a peptide, P39, that bound to KCs. P39 strongly inhibited sporozoite entry into KCs in vitro and reduced liver infection in vivo. It was also shown to bind specifically to CD68, a heavily glycosylated transmembrane protein similar to LAMPs in its cellular distribution, sequence, and structure. Furthermore, the expression of CD68, at least in the liver, is confined to KCs. The function of CD68 as a receptor for sporozoite entry into KCs in vitro was supported by silencing, overexpression, and ectopic expression of the CD68 gene and by antibody inhibition. More critically, parasite liver burden in CD68 knockout mice was reduced by 71%, substantiating CD68 as a key receptor for sporozoite interaction with KCs in vivo, and KCs as the paramount gateway cells. Finally, CD68 knockout mice treated with clodronate to deplete KCs showed liver parasite burdens that were comparable to clodronate-treated, wild-type mice, which in turn had comparable infections to untreated wildtype mice. The authors conclude that CD68 serves as such an efficient gateway that sporozoite transit to the liver parenchyma proceeds as if the sinusoidal barrier did not exist. These findings still need to be reconciled with prior quantitative imaging studies that attribute a greater role for endothelial cells in sinusoid traversal and that reveal a negative impact of KCs on sporozoite survival. Beyond its function as a receptor for sporozoite entry, the nature and consequences of CD68 engagement need to be further explored. Does CD68-mediated sporozoite entry into KCs involve active penetration or phagocytosis? Is there damage to the host cell? Does CD68 engagement inhibit antigen presentation function and/or trigger release of antiinflammatory cytokines that contribute to the state of relative immune tolerance in the liver? And, crucially, what is the parasite ligand for CD68? Assuming its accessibility for antibody targeting in its native state, it would seem an ideal component of a pre-erythrocytic vaccine.