Human iPSC-Derived Hepatocyte-like Cells Support Plasmodium Liver-Stage Infection In Vitro

Malaria starts with Plasmodium sporozoites infection of the host's liver, where development into blood stage parasites occurs. It is not clear why natural infections do not induce protection against the initial liver stage and generate low CD8+ T cell responses. Using a rodent malaria model, we show that Plasmodium blood stage infection suppresses CD8+ T cell immune responses that were induced against the initial liver stage. Blood stage Plasmodium affects dendritic cell (DC) functions, inhibiting maturation and the capacity to initiate immune responses and inverting the interleukin (IL)-12/IL-10 secretion pattern. The interaction of blood stage parasites with DCs induces the secretion of soluble factors that inhibit the activation of CD8+ T cells in vitro and the suppression of protective CD8+ T cell responses against the liver stage in vivo. We propose that blood stage infection induces DCs to suppress CD8+ T cell responses in natural malaria infections. This evasion mechanism leaves the host unprotected against reinfection by inhibiting the immune response against the initial liver stage of the disease.

Download Full-text

Functional immunoassays using an in-vitro malaria liver-stage infection model: where do we go from here?

Trends in Parasitology ◽

10.1016/j.pt.2009.08.004 ◽

2009 ◽

Vol 25 (11) ◽

pp. 525-533 ◽

Cited By ~ 8

Author(s):

Brent L. House ◽

Michael R. Hollingdale ◽

John B. Sacci ◽

Thomas L. Richie

Keyword(s):

Infection Model ◽

Liver Stage ◽

Stage Infection

Download Full-text

A dual fluorescent Plasmodium cynomolgi reporter line reveals in vitro malaria hypnozoite reactivation

Communications Biology ◽

10.1038/s42003-019-0737-3 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 4

Author(s):

Annemarie M. Voorberg-van der Wel ◽

Anne-Marie Zeeman ◽

Ivonne G. Nieuwenhuis ◽

Nicole M. van der Werff ◽

Els J. Klooster ◽

...

Keyword(s):

Cell Infection ◽

Liver Stage ◽

Plasmodium Cynomolgi ◽

Prolonged Culture ◽

Blood Stage Infection ◽

Transgenic Parasites ◽

Stage Development ◽

Green Fluorescent ◽

Stage Infection

AbstractPlasmodium vivax malaria is characterized by repeated episodes of blood stage infection (relapses) resulting from activation of dormant stages in the liver, so-called hypnozoites. Transition of hypnozoites into developing schizonts has never been observed. A barrier for studying this has been the lack of a system in which to monitor growth of liver stages. Here, exploiting the unique strengths of the simian hypnozoite model P. cynomolgi, we have developed green-fluorescent (GFP) hypnozoites that turn on red-fluorescent (mCherry) upon activation. The transgenic parasites show full liver stage development, including merozoite release and red blood cell infection. We demonstrate that individual hypnozoites actually can activate and resume development after prolonged culture, providing the last missing evidence of the hypnozoite theory of relapse. The few events identified indicate that hypnozoite activation in vitro is infrequent. This system will further our understanding of the mechanisms of hypnozoite activation and may facilitate drug discovery approaches.

Download Full-text

Plasmodium-encoded murine IL-6 impairs liver stage infection and elicits long-lasting sterilizing immunity

10.1101/2021.11.16.468835 ◽

2021 ◽

Author(s):

Selma Belhimeur ◽

Sylvie Briquet ◽

Roger Peronet ◽

Jennifer Pham ◽

Pierre-Henri Commere ◽

...

Keyword(s):

Mammalian Host ◽

Vaccine Strategy ◽

Liver Stage ◽

Anopheles Mosquitoes ◽

Novel Approach ◽

Blood Stage Infection ◽

Early Production ◽

Sterilizing Immunity ◽

Stage Infection

Plasmodium sporozoites inoculated by Anopheles mosquitoes into the skin of the mammalian host migrate to the liver before infecting hepatocytes. Previous work demonstrated that early production of IL-6 in the liver was found to be detrimental for the parasite growth, leading to the acquisition of a long-lasting immune protection. Considering IL-6 as a critical pro-inflammatory signal, we explored a novel approach whereby the parasite itself encodes for the murine IL-6 gene. We generated transgenic P.berghei parasites that express murine IL-6 during liver stage development. Though IL-6 transgenic sporozoites develop into exo-erythrocytic forms in cultured hepatocytes in vitro, these parasites were not capable of inducing a blood stage infection in mice. Furthermore, immunization of mice with transgenic IL-6 sporozoites elicited a long-lasting CD8+ T cell-mediated protective immunity against a subsequent infectious sporozoite challenge. Collectively, this study demonstrates that parasite-encoded IL-6 impairs Plasmodium infection at the liver stage, forming the basis of a novel suicide vaccine strategy to elicit protective antimalarial immunity.

Download Full-text

Faculty Opinions recommendation of Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718215365.793518981 ◽

2016 ◽

Author(s):

Frank Seeber

Keyword(s):

Innate Immunity ◽

Host Cell ◽

Liver Stage ◽

Stage Infection

Download Full-text

Small Molecules Effective Against Liver and Blood Stage Malarial Infection

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666181129143623 ◽

2019 ◽

Vol 18 (23) ◽

pp. 2008-2021 ◽

Cited By ~ 3

Author(s):

Snigdha Singh ◽

Neha Sharma ◽

Charu Upadhyay ◽

Sumit Kumar ◽

Brijesh Rathi ◽

...

Keyword(s):

Drug Targets ◽

Malaria Parasite ◽

Blood Stage ◽

Culture Methods ◽

Liver Stage ◽

Malarial Infection ◽

Dual Stage ◽

New Treatment ◽

Global Threat

Malaria is a lethal disease causing devastating global impact by killing more than 8,00,000 individuals yearly. A noticeable decline in malaria related deaths can be attributed to the most reliable treatment, ACTs against P. falciparum. However, the cumulative resistance of the malaria parasite against ACTs is a global threat to control the disease and, therefore the new effective therapeutics are urgently needed, including new treatment approaches. Majority of the antimalarial drugs target BS malarial infection. Currently, scientists are eager to explore the drugs with potency against not only BS but other life stages such as sexual and asexual stages of the malaria parasite. Liver Stage is considered as one of the important drug targets as it always leads to BS and the infection can be cured at this stage before it enters into the Blood Stage. However, a limited number of compounds are reported effective against LS malaria infection probably due to scarcity of in vitro LS culture methods and clinical possibilities. This mini review covers a range of chemical compounds showing efficacy against BS and LS of the malaria parasite’s life cycle collectively (i.e. dual stage activity). These scaffolds targeting dual stages are essential for the eradication of malaria and to evade resistance.

Download Full-text