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

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.

scholarly journals Malaria Blood Stage Suppression of Liver Stage Immunity by Dendritic Cells

2003 ◽  
Vol 197 (2) ◽  
pp. 143-151 ◽  
Author(s):  
Carlos Ocaña-Morgner ◽  
Maria M. Mota ◽  
Ana Rodriguez
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Blood Stage ◽  
Liver Stage ◽  
Cell Responses ◽  
Blood Stage Infection ◽  
Stage Infection

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.

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

2020 ◽  
Vol 3 (1) ◽  
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.

scholarly journals Plasmodium yoelii Sporozoites with Simultaneous Deletion of P52 and P36 Are Completely Attenuated and Confer Sterile Immunity against Infection

2007 ◽  
Vol 75 (8) ◽  
pp. 3758-3768 ◽  
Author(s):  
Mehdi Labaied ◽  
Anke Harupa ◽  
Ronald F. Dumpit ◽  
Isabelle Coppens ◽  
Sebastian A. Mikolajczak ◽  
...  
Keyword(s):  
Host Cell ◽  
Genetic Manipulation ◽  
Parasitophorous Vacuole ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Mammalian Host ◽  
Electron Microscopic ◽  
Rodent Host ◽  
Blood Stage Infection ◽  
Stage Infection

ABSTRACT Malaria infection starts when sporozoites are transmitted to the mammalian host during a mosquito bite. Sporozoites enter the blood circulation, reach the liver, and infect hepatocytes. The formation of a parasitophorous vacuole (PV) establishes their intracellular niche. Recently, two members of the 6-Cys domain protein family, P52 and P36, were each shown to play an important albeit nonessential role in Plasmodium berghei sporozoite infectivity for the rodent host. Here, we generated p52/p36-deficient Plasmodium yoelii parasites by the simultaneous deletion of both genes using a single genetic manipulation. p52/p36-deficient parasites exhibited normal progression through the life cycle during blood-stage infection, transmission to mosquitoes, mosquito-stage development, and sporozoite infection of the salivary glands. p52/p36-deficient sporozoites also showed normal motility and cell traversal activity. However, immunofluorescence analysis and electron microscopic observations revealed that p52/p36-deficient parasites did not form a PV within hepatocytes in vitro and in vivo. The p52/p36-deficient parasites localized as free entities in the host cell cytoplasm or the host cell nucleoplasm and did not develop as liver stages. Consequently, they did not cause blood-stage infections even at high sporozoite inoculation doses. Mice immunized with p52/p36-deficient sporozoites were completely protected against infectious sporozoite challenge. Our results demonstrate for the first time the generation of two-locus gene deletion-attenuated parasites that infect the liver but do not progress to blood-stage infection. The study will critically guide the design of Plasmodium falciparum live attenuated malaria vaccines.

scholarly journals A Humanized Mouse Model for Plasmodium vivax to Test Interventions that Block Liver Stage to Blood Stage Transition and Blood Stage Infection

iScience ◽  
2020 ◽  
Vol 23 (8) ◽  
pp. 101381
Author(s):  
Carola Schäfer ◽  
Wanlapa Roobsoong ◽  
Niwat Kangwanrangsan ◽  
Martino Bardelli ◽  
Thomas A. Rawlinson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Plasmodium Vivax ◽  
Blood Stage ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Liver Stage ◽  
Blood Stage Infection ◽  
Stage Transition ◽  
Stage Infection

scholarly journals PKAc is not required for the preerythrocytic stages of Plasmodium berghei

2019 ◽  
Vol 2 (3) ◽  
pp. e201900352 ◽  
Author(s):  
Hadi Hasan Choudhary ◽  
Roshni Gupta ◽  
Satish Mishra
Keyword(s):  
Plasmodium Berghei ◽  
Malaria Parasite ◽  
Rapid Expansion ◽  
Host Cells ◽  
Signaling Cascade ◽  
Mammalian Host ◽  
Dependent Protein Kinase ◽  
Blood Stage Infection ◽  
Dependent Protein ◽  
Stage Infection

Plasmodium sporozoites invade hepatocytes to initiate infection in the mammalian host. In the infected hepatocytes, sporozoites undergo rapid expansion and differentiation, resulting in the formation and release of thousands of invasive merozoites into the bloodstream. Both sporozoites and merozoites invade their host cells by activation of a signaling cascade followed by discharge of micronemal content. cAMP-dependent protein kinase catalytic subunit (PKAc)–mediated signaling plays an important role in merozoite invasion of erythrocytes, but its role during other stages of the parasite remains unknown. Becaused of the essentiality of PKAc in blood stages, we generated conditional mutants of PKAc by disrupting the gene in Plasmodium berghei sporozoites. The mutant salivary gland sporozoites were able to glide, invaded hepatocytes, and matured into hepatic merozoites which were released successfully from merosome, however failed to initiate blood stage infection when inoculated into mice. Our results demonstrate that malaria parasite complete preerythrocytic stages development without PKAc, raising the possibility that the PKAc independent signaling operates in preerythrocytic stages of P. berghei.

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

2015 ◽  
Vol 4 (3) ◽  
pp. 348-359 ◽  
Author(s):  
Shengyong Ng ◽  
Robert E. Schwartz ◽  
Sandra March ◽  
Ani Galstian ◽  
Nil Gural ◽  
...  
Keyword(s):  
Liver Stage ◽  
Human Ipsc ◽  
Stage Infection

scholarly journals Extrahepatic Exoerythrocytic Forms of Rodent Malaria Parasites at the Site of Inoculation: Clearance after Immunization, Susceptibility to Primaquine, and Contribution to Blood-Stage Infection

2012 ◽  
Vol 80 (6) ◽  
pp. 2158-2164 ◽  
Author(s):  
Tatiana Voza ◽  
Jessica L. Miller ◽  
Stefan H. I. Kappe ◽  
Photini Sinnis
Keyword(s):  
Common Property ◽  
Adaptive Immune Response ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Mammalian Host ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Content Type ◽  
Blood Stage Infection ◽  
Stage Infection

ABSTRACTPlasmodiumsporozoites are inoculated into the skin of the mammalian host as infected mosquitoes probe for blood. A proportion of the inoculum enters the bloodstream and goes to the liver, where the sporozoites invade hepatocytes and develop into the next life cycle stage, the exoerythrocytic, or liver, stage. Here, we show that a small fraction of the inoculum remains in the skin and begins to develop into exoerythrocytic forms that can persist for days. Skin exoerythrocytic forms were observed for bothPlasmodium bergheiandPlasmodium yoelii, two different rodent malaria parasites, suggesting that development in the skin of the mammalian host may be a common property of plasmodia. Our studies demonstrate that skin exoerythrocytic stages are susceptible to destruction in immunized mice, suggesting that their aberrant location does not protect them from the host's adaptive immune response. However, in contrast to their hepatic counterparts, they are not susceptible to primaquine. We took advantage of their resistance to primaquine to test whether they could initiate a blood-stage infection directly from the inoculation site, and our data indicate that these stages are not able to initiate malaria infection.

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

2009 ◽  
Vol 25 (11) ◽  
pp. 525-533 ◽  
Author(s):  
Brent L. House ◽  
Michael R. Hollingdale ◽  
John B. Sacci ◽  
Thomas L. Richie
Keyword(s):  
Infection Model ◽  
Liver Stage ◽  
Stage Infection

scholarly journals Chemical Attenuation of Plasmodium berghei Sporozoites Induces Sterile Immunity in Mice

2008 ◽  
Vol 76 (3) ◽  
pp. 1193-1199 ◽  
Author(s):  
Lisa A. Purcell ◽  
Stephanie K. Yanow ◽  
Moses Lee ◽  
Terry W. Spithill ◽  
Ana Rodriguez
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Berghei ◽  
Alkylating Agent ◽  
Blood Stage ◽  
Wild Type ◽  
Vaccine Strategy ◽  
Liver Stage ◽  
Stage Development

ABSTRACT Radiation and genetic attenuation of Plasmodium sporozoites are two approaches for whole-organism vaccines that protect against malaria. We evaluated chemical attenuation of sporozoites as an alternative vaccine strategy. Sporozoites were treated with the DNA sequence-specific alkylating agent centanamycin, a compound that significantly affects blood stage parasitemia and transmission of murine malaria and also inhibits Plasmodium falciparum growth in vitro. Here we show that treatment of Plasmodium berghei sporozoites with centanamycin impaired parasite function both in vitro and in vivo. The infection of hepatocytes by sporozoites in vitro was significantly reduced, and treated parasites showed arrested liver stage development. Inoculation of mice with sporozoites that were treated in vitro with centanamycin failed to produce blood stage infections. Furthermore, BALB/c and C57BL/6 mice vaccinated with treated sporozoites were protected against subsequent challenge with wild-type sporozoites. Our findings demonstrate that chemically attenuated sporozoites could be a viable alternative for the production of an effective liver stage vaccine for malaria.

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