Merozoite vaccination of rhesus monkeys against plasmodium knowlesi malaria; immunity to sporozoite (mosquito-transmitted) challenge

Five normal rhesus monkeys were infected with Plasmodium knowlesi sporozoites (A-strain); two developed rapidly fatal malaria and three chrinic relapsing infections. Vaccination with P. knowlesi (W-strain) merozoites (unmodified or formol-treated and freeze-dried) in Freund's complete adjuvant (FCA) did not inhibit pre-erythrocytic parasite development after challenge with A-strain sporozoites. However, the subsequent blood-stage infection was terminated in nine out of ten vaccinated monkeys even though the challenge strain was different form that used for vaccination. The degree of parasitaemia (0·01–0·70 %) and brevity of infection (1–12 days) in six animals vaccinated with untreated merzoites was similar to that observed after direct challenge with blood-stage parasites. Monkeys were equally resistant to sporozoite challenge given as the post-vaccination infection or administered 6 months after blood challenge. These results are discussed in relation to the development of a human malaria vaccine.

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Controlled Human Malaria Infection: Applications, Advances, and Challenges

Infection and Immunity ◽

10.1128/iai.00479-17 ◽

2017 ◽

Vol 86 (1) ◽

Cited By ~ 29

Author(s):

Danielle I. Stanisic ◽

James S. McCarthy ◽

Michael F. Good

Keyword(s):

Drug Development ◽

Malaria Infection ◽

Malaria Vaccine ◽

Blood Stage ◽

Content Type ◽

Human Malaria ◽

Recent Advances ◽

Blood Stage Infection ◽

Controlled Human Malaria Infection ◽

Stage Infection

ABSTRACT Controlled human malaria infection (CHMI) entails deliberate infection with malaria parasites either by mosquito bite or by direct injection of sporozoites or parasitized erythrocytes. When required, the resulting blood-stage infection is curtailed by the administration of antimalarial drugs. Inducing a malaria infection via inoculation with infected blood was first used as a treatment (malariotherapy) for neurosyphilis in Europe and the United States in the early 1900s. More recently, CHMI has been applied to the fields of malaria vaccine and drug development, where it is used to evaluate products in well-controlled early-phase proof-of-concept clinical studies, thus facilitating progression of only the most promising candidates for further evaluation in areas where malaria is endemic. Controlled infections have also been used to immunize against malaria infection. Historically, CHMI studies have been restricted by the need for access to insectaries housing infected mosquitoes or suitable malaria-infected individuals. Evaluation of vaccine and drug candidates has been constrained in these studies by the availability of a limited number of Plasmodium falciparum isolates. Recent advances have included cryopreservation of sporozoites, the manufacture of well-characterized and genetically distinct cultured malaria cell banks for blood-stage infection, and the availability of Plasmodium vivax-specific reagents. These advances will help to accelerate malaria vaccine and drug development by making the reagents for CHMI more widely accessible and also enabling a more rigorous evaluation with multiple parasite strains and species. Here we discuss the different applications of CHMI, recent advances in the use of CHMI, and ongoing challenges for consideration.

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

Infection and Immunity ◽

10.1128/iai.00225-07 ◽

2007 ◽

Vol 75 (8) ◽

pp. 3758-3768 ◽

Cited By ~ 114

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.

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Cytokine responses of CD4+ T cells during a Plasmodium chabaudi chabaudi (ER) blood-stage infection in mice initiated by the natural route of infection

Malaria Journal ◽

10.1186/1475-2875-6-77 ◽

2007 ◽

Vol 6 (1) ◽

pp. 77 ◽

Cited By ~ 16

Author(s):

Luis Fonseca ◽

Elsa Seixas ◽

Geoffrey Butcher ◽

Jean Langhorne

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Blood Stage ◽

Plasmodium Chabaudi ◽

Cytokine Responses ◽

Route Of Infection ◽

Blood Stage Infection ◽

Stage Infection

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

iScience ◽

10.1016/j.isci.2020.101381 ◽

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

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The Plasmodium falciparum var gene transcription strategy at the onset of blood stage infection in a human volunteer

Parasitology International ◽

10.1016/j.parint.2009.07.004 ◽

2009 ◽

Vol 58 (4) ◽

pp. 478-480 ◽

Cited By ~ 45

Author(s):

Christian W. Wang ◽

Cornelus C. Hermsen ◽

Robert W. Sauerwein ◽

David E. Arnot ◽

Thor G. Theander ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Gene Transcription ◽

Blood Stage ◽

Human Volunteer ◽

Blood Stage Infection ◽

Stage Infection ◽

Var Gene

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Transient Deficiency of Dendritic Cells Results in Lack of a Merozoite Surface Protein 1-Specific CD4 T Cell Response during Peak Plasmodium chabaudi Blood-Stage Infection

Infection and Immunity ◽

10.1128/iai.00820-12 ◽

2012 ◽

Vol 80 (12) ◽

pp. 4248-4256 ◽

Cited By ~ 6

Author(s):

Anne-Marit Sponaas ◽

Nikolai Belyaev ◽

Mika Falck-Hansen ◽

Alexandre Potocnik ◽

Jean Langhorne

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Surface Protein ◽

Merozoite Surface Protein ◽

T Cell Response ◽

Blood Stage ◽

Cd4 T Cell ◽

Blood Stage Infection ◽

Stage Infection

ABSTRACTSplenic dendritic cells are crucial for controlling the immune response to malaria by initiating a CD4 gamma interferon (IFN-γ) response early in a blood-stage infection, which contributes to parasite clearance as well as to acute-stage immunopathology. CD8−CD11chighdendritic cells have been described previously to be important antigen-presenting cells for induction of these CD4 T cell responses in the spleens ofPlasmodium chabaudi-infected mice. However, when isolated during the period of maximum parasitemia and shortly thereafter, the dendritic cells transiently lose their ability to stimulate T cells, recovering only as the parasitemia is controlled. This loss of a CD4 T cell response is also observedin vivoduring this part of the infection. CD4 T cells from a T cell receptor-transgenic mouse recognizing a peptide of merozoite surface protein 1 (MSP1) injected into BALB/c mice during peak parasitemia proliferate poorly, and very few cells produce IFN-γ and interleukin-2 (IL-2), compared with transgenic T cells injected earlier in the blood-stage infection. CD8−dendritic cells at day 10 can process and present peptides on major histocompatibility complex (MHC) class II with an efficiency similar to that of dendritic cells from earlier in infection. The failure of the day 10 dendritic cells to activate MSP1-specific CD4 T cells fullyin vitrois associated with reduced expression of CD86 and lower production of IL-12 rather than with induction of inhibitory DC receptors or production of IL-10.

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Malaria Blood Stage Suppression of Liver Stage Immunity by Dendritic Cells

Journal of Experimental Medicine ◽

10.1084/jem.20021072 ◽

2003 ◽

Vol 197 (2) ◽

pp. 143-151 ◽

Cited By ~ 168

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.

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