Plasmodium sporozoite phospholipid scramblase interacts with mammalian carbamoyl-phosphate synthetase 1 to infect hepatocytes

Sung-Jae Cha,Chan Hyun Na,Marcelo Jacobs-Lorena,Min-Sik Kim

doi:10.1038/s41467-021-27109-7

Abstract

After inoculation by the bite of an infected mosquito, Plasmodium sporozoites enter the blood stream and infect the liver, where each infected cell produces thousands of merozoites. These in turn, infect red blood cells and cause malaria symptoms. To initiate a productive infection, sporozoites must exit the circulation by traversing the blood lining of the liver vessels after which they infect hepatocytes with unique specificity. We screened a phage display library for peptides that structurally mimic (mimotope) a sporozoite ligand for hepatocyte recognition. We identified HP1 (hepatocyte-binding peptide 1) that mimics a ~50 kDa sporozoite ligand (identified as phospholipid scramblase). Further, we show that HP1 interacts with a ~160 kDa hepatocyte membrane putative receptor (identified as carbamoyl-phosphate synthetase 1). Importantly, immunization of mice with the HP1 peptide partially protects them from infection by the rodent parasite P. berghei. Moreover, an antibody to the HP1 mimotope inhibits human parasite P. falciparum infection of human hepatocytes in culture. The sporozoite ligand for hepatocyte invasion is a potential novel pre-erythrocytic vaccine candidate.

Highlights

After inoculation by the bite of an infected mosquito, Plasmodium sporozoites enter the blood stream and infect the liver, where each infected cell produces thousands of merozoites
Malaria infection is initiated by the release from an infected Anopheles mosquito of 50–100 Plasmodium sporozoites into the skin of a vertebrate host[1]
HP1 is a structural mimic of the sporozoite ligand phospholipid scramblase (PLS) that for infection, interacts with the hepatocyte receptor carbamoyl-phosphate synthetase 1 (CPS1)

Summary

Introduction

After inoculation by the bite of an infected mosquito, Plasmodium sporozoites enter the blood stream and infect the liver, where each infected cell produces thousands of merozoites. Circulating sporozoites must exit in the liver, where they infect hepatocytes, each of which produces thousands of merozoites that are released into the blood circulation and cause disease symptoms[2]. This complex cycle requires specific parasite–host recognition at each stage. We hypothesize that infection requires recognition via interaction of a sporozoite ligand with a hepatocyte receptor. We show that a peptide—HP1—identified by the use of a phage display library, binds to hepatocytes and by doing so, inhibits Plasmodium sporozoite infection. HP1 is a structural mimic of the sporozoite ligand phospholipid scramblase (PLS) that for infection, interacts with the hepatocyte receptor carbamoyl-phosphate synthetase 1 (CPS1)

Methods

Results

Conclusion