CD68 acts as a major gateway for malaria sporozoite liver infection
Sung-Jae Cha1, Kiwon Park1, Prakash Srinivasan2
1W. Harry Feinstone Department of Molecular Microbiology and Immunology and Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health; and Department of Neurology, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD 21205 W. Harry Feinstone Department of Molecular Microbiology and Immunology and Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health; and Department of Neurology, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
Abstract:
After being delivered by the bite from an infected mosquito, Plasmodium sporozoites enter the blood circulation and infect the liver. Previous evidence suggests that Kupffer cells, a macrophage-like component of the liver blood vessel lining, are traversed by sporozoites to initiate liver invasion. However, the molecular determinants of sporozoite-Kupffer cell interactions are unknown. Understanding the molecular basis for this specific recognition may lead to novel therapeutic strategies to control malaria. Using a phage display library screen, we identified a peptide, P39, that strongly binds to the Kupffer cell surface and, importantly, inhibits sporozoite Kupffer cell entry. Furthermore, we determined that P39 binds to CD68, a putative receptor for sporozoite invasion of Kupffer cells that acts as a gateway for malaria infection of the liver.
Insights
Malaria parasites (Plasmodium sporozoites) invade the liver by entering Kupffer cells. A new peptide, P39, blocks this entry by binding to the CD68 receptor on Kupffer cells.
Area of Science:
- Immunology
- Infectious Diseases
- Malariology
Background:
- Malaria is transmitted by mosquito bites, with Plasmodium sporozoites infecting the liver.
- Kupffer cells, liver-resident macrophages, are implicated in initiating liver invasion by sporozoites.
- The molecular mechanisms governing sporozoite-Kupffer cell interactions remain poorly understood.
Purpose of the Study:
- To identify molecular factors mediating Plasmodium sporozoite interactions with Kupffer cells.
- To explore potential therapeutic targets for blocking malaria liver-stage infection.
Main Methods:
- Phage display library screening was employed to identify Kupffer cell-binding peptides.
- Functional assays were performed to assess the inhibitory effects of identified peptides on sporozoite entry.
- Immunological assays were used to determine the specific receptor targeted by the inhibitory peptide.
Main Results:
- A peptide, designated P39, was identified that strongly binds to the Kupffer cell surface.
- P39 effectively inhibits the entry of Plasmodium sporozoites into Kupffer cells.
- P39 binds to CD68, a molecule identified as a putative receptor for sporozoite invasion.
Conclusions:
- CD68 is a key receptor mediating malaria parasite invasion of Kupffer cells.
- The peptide P39, targeting CD68, represents a potential therapeutic strategy to block malaria liver infection.
- Understanding sporozoite-Kupffer cell molecular interactions offers novel avenues for malaria control.
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