scholarly journals Chemically Attenuated Blood-Stage Plasmodium yoelii Parasites Induce Long-Lived and Strain-Transcending Protection

2016 ◽  
Vol 84 (8) ◽  
pp. 2274-2288 ◽  
Author(s):  
Amber I. Raja ◽  
Yeping Cai ◽  
Jennifer M. Reiman ◽  
Penny Groves ◽  
Sumana Chakravarty ◽  
...  
Keyword(s):  
T Cells ◽  
Strong Support ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Liver Stage ◽  
Content Type ◽  
Successful Vaccine ◽  
Blood Stage Infection ◽  
Induced Immunity

The development of a vaccine is essential for the elimination of malaria. However, despite many years of effort, a successful vaccine has not been achieved. Most subunit vaccine candidates tested in clinical trials have provided limited efficacy, and thus attenuated whole-parasite vaccines are now receiving close scrutiny. Here, we test chemically attenuatedPlasmodium yoelii17X and demonstrate significant protection following homologous and heterologous blood-stage challenge. Protection against blood-stage infection persisted for at least 9 months. Activation of both CD4+and CD8+T cells was shown after vaccination; however,in vivostudies demonstrated a pivotal role for both CD4+T cells and B cells since the absence of either cell type led to loss of vaccine-induced protection. In spite of significant activation of circulating CD8+T cells, liver-stage immunity was not evident. Neither did vaccine-induced CD8+T cells contribute to blood-stage protection; rather, these cells contributed to pathogenesis, since all vaccinated mice depleted of both CD4+and CD8+T cells survived a challenge infection. This study provides critical insight into whole-parasite vaccine-induced immunity and strong support for testing whole-parasite vaccines in humans.

scholarly journals Phenotypic and functional profiling of malaria-induced CD8 and CD4 T cells during blood-stage infection with Plasmodium yoelii

Immunology ◽  
2010 ◽  
Vol 132 (2) ◽  
pp. 273-286 ◽  
Author(s):  
Anmol Chandele ◽  
Paushali Mukerjee ◽  
Gobardhan Das ◽  
Rafi Ahmed ◽  
Virander S. Chauhan
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Functional Profiling ◽  
Blood Stage Infection ◽  
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.

scholarly journals Model forIn VivoAssessment of Humoral Protection against Malaria Sporozoite Challenge by Passive Transfer of Monoclonal Antibodies and Immune Serum

2013 ◽  
Vol 82 (2) ◽  
pp. 808-817 ◽  
Author(s):  
Brandon K. Sack ◽  
Jessica L. Miller ◽  
Ashley M. Vaughan ◽  
Alyse Douglass ◽  
Alexis Kaushansky ◽  
...  
Keyword(s):  
Natural Infection ◽  
Passive Transfer ◽  
Plasmodium Yoelii ◽  
Immune Serum ◽  
Liver Stage ◽  
Content Type ◽  
Mosquito Bite ◽  
Infection Inhibition ◽  
Liver Infection

ABSTRACTEvidence from clinical trials of malaria vaccine candidates suggests that both cell-mediated and humoral immunity to pre-erythrocytic parasite stages can provide protection against infection. Novel pre-erythrocytic antibody (Ab) targets could be key to improving vaccine formulations, which are currently based on targeting antigens such as the circumsporozoite protein (CSP). However, methods to assess the effects of sporozoite-specific Abs on pre-erythrocytic infectionin vivoremain underdeveloped. Here, we combined passive transfer of monoclonal Abs (MAbs) or immune serum with a luciferase-expressingPlasmodium yoeliisporozoite challenge to assess Ab-mediated inhibition of liver infection in mice. Passive transfer of aP. yoeliiCSP MAb showed inhibition of liver infection when mice were challenged with sporozoites either intravenously or by infectious mosquito bite. However, inhibition was most potent for the mosquito bite challenge, leading to a more significant reduction of liver-stage burden and even a lack of progression to blood-stage parasitemia. This suggests that Abs provide effective protection against a natural infection. Inhibition of liver infection was also achieved by passive transfer of immune serum from whole-parasite-immunized mice. Furthermore, we demonstrated that passive transfer of a MAb againstP. falciparumCSP inhibited liver-stage infection in a humanized mouse/P. falciparumchallenge model. Together, these models constitute unique and sensitivein vivomethods to assess serum-transferable protection againstPlasmodiumsporozoite challenge.

scholarly journals Immunization of Mice with Live-Attenuated Late Liver Stage-Arresting Plasmodium yoelii Parasites Generates Protective Antibody Responses to Preerythrocytic Stages of Malaria

2014 ◽  
Vol 82 (12) ◽  
pp. 5143-5153 ◽  
Author(s):  
Gladys J. Keitany ◽  
Brandon Sack ◽  
Hannah Smithers ◽  
Lin Chen ◽  
Ihn K. Jang ◽  
...  
Keyword(s):  
T Cells ◽  
Malaria Infection ◽  
Plasmodium Yoelii ◽  
Effective Vaccine ◽  
Mouse Strains ◽  
Liver Stage ◽  
Content Type ◽  
Mosquito Bite ◽  
Experimental Immunization

ABSTRACTUnderstanding protective immunity to malaria is essential for the design of an effective vaccine to prevent the large number of infections and deaths caused by this parasitic disease. To date, whole-parasite immunization with attenuated parasites is the most effective method to confer sterile protection against malaria infection in clinical trials. Mouse model studies have highlighted the essential role that CD8+T cells play in protection against preerythrocytic stages of malaria; however, there is mounting evidence that antibodies are also important in these stages. Here, we show that experimental immunization of mice withPlasmodium yoeliifabb/f−(Pyfabb/f−), a genetically attenuated rodent malaria parasite that arrests late in the liver stage, induced functional antibodies that inhibited hepatocyte invasionin vitroand reduced liver-stage burdenin vivo. These antibodies were sufficient to induce sterile protection from challenge byP. yoeliisporozoites in the absence of T cells in 50% of mice when sporozoites were administered by mosquito bite but not when they were administered by intravenous injection. Moreover, among mice challenged by mosquito bite, a higher proportion of BALB/c mice than C57BL/6 mice developed sterile protection (62.5% and 37.5%, respectively). Analysis of the antibody isotypes induced by immunization withPyfabb/f−showed that, overall, BALB/c mice developed an IgG1-biased response, whereas C57BL/6 mice developed an IgG2b/c-biased response. Our data demonstrate for the first time that antibodies induced by experimental immunization of mice with a genetically attenuated rodent parasite play a protective role during the preerythrocytic stages of malaria. Furthermore, they highlight the importance of considering both the route of challenge and the genetic background of the mouse strains used when interpreting vaccine efficacy studies in animal models of malaria infection.

scholarly journals Nonspecific CD8+ T Cells and Dendritic Cells/Macrophages Participate in Formation of CD8+ T Cell-Mediated Clusters against Malaria Liver-Stage Infection

2018 ◽  
Vol 86 (4) ◽  
pp. e00717-17 ◽  
Author(s):  
Masoud Akbari ◽  
Kazumi Kimura ◽  
Ganchimeg Bayarsaikhan ◽  
Daisuke Kimura ◽  
Mana Miyakoda ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Cluster Formation ◽  
Dependent Manner ◽  
Liver Stage ◽  
Content Type ◽  
Stage Infection

ABSTRACT CD8+ T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around Plasmodium-infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8+ T cells in cluster formation and protective immunity. To this end, we used Plasmodium berghei ANKA expressing ovalbumin as well as CD8+ T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8+ T cells specific for an unrelated antigen, respectively. While antigen-specific CD8+ T cells were essential for cluster formation, both antigen-specific and nonspecific CD8+ T cells joined the clusters. However, nonspecific CD8+ T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8+ T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. In vivo imaging of the liver revealed that specific CD8+ T cells interact with CD11c+ cells around infected hepatocytes. The depletion of CD11c+ cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c+ dendritic cells and presumably macrophages in the formation of CD8+ T cell clusters around Plasmodium-infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8+ T cells, specific and unrelated activated CD8+ T cells join the clusters in a chemokine- and dendritic cell-dependent manner. Nonspecific CD8+ T cells seem to play a limited role in protective immunity against Plasmodium parasites.

scholarly journals Parasite-Specific CD4+IFN-γ+IL-10+T Cells Distribute within Both Lymphoid and Nonlymphoid Compartments and Are Controlled Systemically by Interleukin-27 and ICOS during Blood-Stage Malaria Infection

2015 ◽  
Vol 84 (1) ◽  
pp. 34-46 ◽  
Author(s):  
Ana Villegas-Mendez ◽  
Tovah N. Shaw ◽  
Colette A. Inkson ◽  
Patrick Strangward ◽  
J. Brian de Souza ◽  
...  
Keyword(s):  
T Cells ◽  
Malaria Infection ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Interleukin 10 ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Content Type ◽  
Ifn Γ ◽  
Blood Stage Malaria

Immune-mediated pathology in interleukin-10 (IL-10)-deficient mice during blood-stage malaria infection typically manifests in nonlymphoid organs, such as the liver and lung. Thus, it is critical to define the cellular sources of IL-10 in these sensitive nonlymphoid compartments during infection. Moreover, it is important to determine if IL-10 production is controlled through conserved or disparate molecular programs in distinct anatomical locations during malaria infection, as this may enable spatiotemporal tuning of the regulatory immune response. In this study, using dual gamma interferon (IFN-γ)–yellow fluorescent protein (YFP) and IL-10–green fluorescent protein (GFP) reporter mice, we show that CD4+YFP+T cells are the major source of IL-10 in both lymphoid and nonlymphoid compartments throughout the course of blood-stagePlasmodium yoeliiinfection. Mature splenic CD4+YFP+GFP+T cells, which preferentially expressed high levels of CCR5, were capable of migrating to and seeding the nonlymphoid tissues, indicating that the systemically distributed host-protective cells have a common developmental history. Despite exhibiting comparable phenotypes, CD4+YFP+GFP+T cells from the liver and lung produced significantly larger quantities of IL-10 than their splenic counterparts, showing that the CD4+YFP+GFP+T cells exert graded functions in distinct tissue locations during infection. Unexpectedly, given the unique environmental conditions within discrete nonlymphoid and lymphoid organs, we show that IL-10 production by CD4+YFP+T cells is controlled systemically during malaria infection through IL-27 receptor signaling that is supported after CD4+T cell priming by ICOS signaling. The results in this study substantially improve our understanding of the systemic IL-10 response to malaria infection, particularly within sensitive nonlymphoid organs.

scholarly journals Plasmodium yoelii Macrophage Migration Inhibitory Factor Is Necessary for Efficient Liver-Stage Development

2012 ◽  
Vol 80 (4) ◽  
pp. 1399-1407 ◽  
Author(s):  
Jessica L. Miller ◽  
Anke Harupa ◽  
Stefan H. I. Kappe ◽  
Sebastian A. Mikolajczak
Keyword(s):  
Life Cycle ◽  
Immune Responses ◽  
Macrophage Migration Inhibitory Factor ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Macrophage Migration ◽  
Liver Stage ◽  
Content Type ◽  
Host Immune Responses ◽  
Stage Development

ABSTRACTMammalian macrophage migration inhibitory factor (MIF) is a multifaceted cytokine involved in both extracellular and intracellular functions. Malaria parasites express a MIF homologue that might modulate host immune responses against blood-stage parasites, but the potential importance of MIF against other life cycle stages remains unstudied. In this study, we characterized the MIF homologue ofPlasmodium yoeliithroughout the life cycle, with emphasis on preerythrocytic stages.P. yoeliiMIF (Py-MIF) was expressed in blood-stage parasites and detected at low levels in mosquito salivary gland sporozoites. MIF expression was strong throughout liver-stage development and localized to the cytoplasm of the parasite, with no evidence of release into the host hepatocyte. To examine the importance of Py-MIF for liver-stage development, we generated a Py-mifknockout parasite (P. yoeliiΔmif).P. yoeliiΔmifparasites grew normally as asexual erythrocytic-stage parasites and showed normal infection of mosquitoes. In contrast, theP. yoeliiΔmifstrain was attenuated during the liver stage. Mice infected withP. yoeliiΔmifsporozoites either did not develop blood-stage parasitemia or exhibited a delay in the onset of blood-stage patency. Furthermore,P. yoeliiΔmifparasites exhibited growth retardationin vivo. Combined, the data indicate thatPlasmodiumMIF is important for liver-stage development ofP. yoelii, during which it is likely to play an intrinsic role in parasite development rather than modulating host immune responses to infection.

scholarly journals A Plasmodium Parasite with Complete Late Liver Stage Arrest Protects against Preerythrocytic and Erythrocytic Stage Infection in Mice

2018 ◽  
Vol 86 (5) ◽  
pp. e00088-18 ◽  
Author(s):  
Ashley M. Vaughan ◽  
Brandon K. Sack ◽  
Dorender Dankwa ◽  
Nana Minkah ◽  
Thao Nguyen ◽  
...  
Keyword(s):  
Inbred Mice ◽  
Specific Protein ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Susceptible Mouse ◽  
Liver Stage ◽  
Content Type ◽  
Synthetic Lethal ◽  
Stage Development ◽  
Stage Infection

ABSTRACT Genetically attenuated malaria parasites (GAP) that arrest during liver stage development are powerful immunogens and afford complete and durable protection against sporozoite infection. Late liver stage-arresting GAP provide superior protection against sporozoite challenge in mice compared to early live stage-arresting attenuated parasites. However, very few late liver stage-arresting GAP have been generated to date. Therefore, identification of additional loci that are critical for late liver stage development and can be used to generate novel late liver stage-arresting GAPs is of importance. We further explored genetic attenuation in Plasmodium yoelii by combining two gene deletions, PlasMei2 and liver-specific protein 2 (LISP2), that each cause late liver stage arrest with various degrees of infrequent breakthrough to blood stage infection. The dual gene deletion resulted in a synthetic lethal phenotype that caused complete attenuation in a highly susceptible mouse strain. P. yoelii plasmei2− lisp2− arrested late in liver stage development and did not persist in livers beyond 3 days after infection. Immunization with this GAP elicited robust protective antibody responses in outbred and inbred mice against sporozoites, liver stages, and blood stages as well as eliciting protective liver-resident T cells. The immunization afforded protection against both sporozoite challenge and blood stage challenge. These findings provide evidence that completely attenuated late liver stage-arresting GAP are achievable via the synthetic lethal approach and might enable a path forward for the creation of a completely attenuated late liver stage-arresting P. falciparum GAP.

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