scholarly journals Elucidating Spatially-Resolved Changes in Host Signaling During Plasmodium Liver-Stage Infection

2022 ◽  
Vol 11 ◽  
Author(s):  
Elizabeth K. K. Glennon ◽  
Tinotenda Tongogara ◽  
Veronica I. Primavera ◽  
Sophia M. Reeder ◽  
Ling Wei ◽  
...  
Keyword(s):  
Blood Stream ◽  
Plasmodium Yoelii ◽  
Liver Stage ◽  
Infected Hepatocyte ◽  
Spatially Resolved ◽  
Spatial Profiling ◽  
Host Signaling ◽  
Infected Cells ◽  
Spatial Locations

Upon transmission to the human host, Plasmodium sporozoites exit the skin, are taken up by the blood stream, and then travel to the liver where they infect and significantly modify a single hepatocyte. Low infection rates within the liver have made proteomic studies of infected hepatocytes challenging, particularly in vivo, and existing studies have been largely unable to consider how protein and phosphoprotein differences are altered at different spatial locations within the heterogeneous liver. Using digital spatial profiling, we characterized changes in host signaling during Plasmodium yoelii infection in vivo without disrupting the liver tissue. Moreover, we measured alterations in protein expression around infected hepatocytes and identified a subset of CD163+ Kupffer cells that migrate towards infected cells during infection. These data offer the first insight into the heterogeneous microenvironment that surrounds the infected hepatocyte and provide insights into how the parasite may alter its milieu to influence its survival and modulate immunity.

scholarly journals Elucidating spatially-resolved changes in host signaling during Plasmodium liver-stage infection

2021 ◽  
Author(s):  
Elizabeth K.K. Glennon ◽  
Tinotenda Tongogara ◽  
Veronica I. Primavera ◽  
Sophia M. Reeder ◽  
Ling Wei ◽  
...  
Keyword(s):  
Blood Stream ◽  
Plasmodium Yoelii ◽  
Infected Hepatocyte ◽  
Spatially Resolved ◽  
Spatial Profiling ◽  
Host Signaling ◽  
Infected Cells ◽  
Spatial Locations

AbstractUpon transmission to the human host, Plasmodium sporozoites exit the skin, are taken up by the blood stream, and then travel to the liver where they infect and significantly modify a single hepatocyte. Low infection rates within the liver have made proteomic studies of infected hepatocytes challenging, particularly in vivo, and existing studies have been largely unable to consider how protein and phosphoprotein differences are altered at different spatial locations within the heterogeneous liver. Using digital spatial profiling, we characterized changes in host signaling during Plasmodium yoelii infection in vivo without disrupting the liver tissue, and measured variation between infected cells. Moreover, we measured alterations in protein expression around infected hepatocytes and identified a subset of CD163+ Kupffer cells that migrate towards infected cells during infection. These data offer the first insight into the heterogeneity of the infected hepatocyte in situ and provide insights into how the parasite may alter the local microenvironment to influence its survival and modulate immunity.

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 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 Human Antibodies against Plasmodium falciparumLiver-Stage Antigen 3 Cross-React with Plasmodium yoelii Preerythrocytic-Stage Epitopes and Inhibit Sporozoite Invasion In Vitro and In Vivo

2001 ◽  
Vol 69 (6) ◽  
pp. 3845-3852 ◽  
Author(s):  
Karima Brahimi ◽  
Edgar Badell ◽  
Jean-Pierre Sauzet ◽  
Lbachir BenMohamed ◽  
Pierre Daubersies ◽  
...  
Keyword(s):  
Peripheral Blood Lymphocytes ◽  
Plasmodium Yoelii ◽  
T Cell Epitopes ◽  
Liver Stage ◽  
Human Antibodies ◽  
In Vitro Invasion ◽  
Synthetic Polypeptides ◽  
Mouse Hepatocytes

ABSTRACT The Plasmodium falciparum liver-stage antigen 3 (LSA3), a recently identified preerythrocytic antigen, induces protection against malaria in chimpanzees. Using antibodies from individuals with hyperimmunity to malaria affinity purified on recombinant or synthetic polypeptides of LSA3, we identified four non-cross-reactive B-cell epitopes in Plasmodium yoelii preerythrocytic stages. On sporozoites the P. yoelii protein detected has a molecular mass similar to that of LSA3. T-cell epitopes cross-reacting withP. yoelii were also demonstrated using peripheral blood lymphocytes from LSA3-immunized chimpanzees. In contrast, no cross-reactive epitopes were found in Plasmodium berghei. LSA3-specific human antibodies exerted up to 100% inhibition of in vitro invasion of P. yoelii sporozoites into mouse hepatocytes. This strong in vitro activity was reproduced in vivo by passive transfer of LSA3 antibodies. These results indicate that the homologous epitopes may be biologically functional and suggest that P. yoelii could be used as a model to assess the antisporozoite activity of anti-LSA3 antibodies.

Transcriptional analysis of in vivo Plasmodium yoelii liver stage gene expression

2005 ◽  
Vol 142 (2) ◽  
pp. 177-183 ◽  
Author(s):  
John B. Sacci ◽  
Jose M.C. Ribeiro ◽  
Fengying Huang ◽  
Uzma Alam ◽  
Joshua A. Russell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasmodium Yoelii ◽  
Transcriptional Analysis ◽  
Liver Stage

scholarly journals Cytotoxic T cells recognize a peptide from the circumsporozoite protein on malaria-infected hepatocytes.

1990 ◽  
Vol 171 (3) ◽  
pp. 763-773 ◽  
Author(s):  
W R Weiss ◽  
S Mellouk ◽  
R A Houghten ◽  
M Sedegah ◽  
S Kumar ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Plasmodium Yoelii ◽  
Liver Stage ◽  
Infected Hepatocyte ◽  
Specific Manner ◽  
Protection Against Infection ◽  
Amino Acid Epitope

Irradiated malaria sporozoites can induce CD8+ T cells that are required for protection against infection. However, the parasite antigens targeted by this immune response are unknown. We have discovered a 16-amino acid epitope from the Plasmodium yoelii circumsporozoite (CS) protein that is recognized by cytotoxic T cells from immune mice. Lymphocytes stimulated with this peptide can kill P. yoelii liver stage parasites in vitro in an MHC-restricted, antigen-specific manner. Thus, epitopes from the CS protein are presented on the surface of infected hepatocytes and can be targets for T cells, even though intact CS protein has not been detected on the surface of the infected hepatocyte. A vaccine that induced CTL to parasite antigens might protect humans against malaria by eliminating liver stage parasites.

scholarly journals Kinetic aspects of virus targeting by nanoparticles in vivo

2021 ◽  
Author(s):  
Vladimir P. Zhdanov
Keyword(s):  
Immune System ◽  
Kinetic Model ◽  
Order Of Magnitude ◽  
Eradication Of Infection ◽  
Infected Cells

AbstractOne of the suggested ways of the use of nanoparticles in virology implies their association with and subsequent deactivation of virions. The conditions determining the efficiency of this approach in vivo are now not clear. Herein, I propose the first kinetic model describing the corresponding processes and clarifying these conditions. My analysis indicates that nanoparticles can decrease concentration of infected cells by a factor of one order of magnitude, but this decrease itself (without feedback of the immune system) is insufficient for full eradication of infection. It can, however, induce delay in the progress of infection, and this delay can help to form sufficient feedback of the immune system.

scholarly journals Effect of cannulation site on emboli travel during cardiac surgery

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Mira Puthettu ◽  
Stijn Vandenberghe ◽  
Stefanos Demertzis
Keyword(s):  
Cardiac Surgery ◽  
In Vitro Study ◽  
Blood Stream ◽  
Air Bubbles ◽  
Arterial Tree ◽  
Air Bubble ◽  
Cannulation Site ◽  
The Brain

Abstract Background During cardiac surgery, micro-air emboli regularly enter the blood stream and can cause cognitive impairment or stroke. It is not clearly understood whether the most threatening air emboli are generated by the heart-lung machine (HLM) or by the blood-air contact when opening the heart. We performed an in vitro study to assess, for the two sources, air emboli distribution in the arterial tree, especially in the brain region, during cardiac surgery with different cannulation sites. Methods A model of the arterial tree was 3D printed and included in a hydraulic circuit, divided such that flow going to the brain was separated from the rest of the circuit. Air micro-emboli were injected either in the HLM (“ECC Bubbles”) or in the mock left ventricle (“Heart Bubbles”) to simulate the two sources. Emboli distribution was measured with an ultrasonic bubble counter. Five repetitions were performed for each combination of injection site and cannulation site, where air bubble counts and volumes were recorded. Air bubbles were separated in three categories based on size. Results For both injection sites, it was possible to identify statistically significant differences between cannulation sites. For ECC Bubbles, axillary cannulation led to a higher amount of air bubbles in the brain with medium-sized bubbles. For Heart Bubbles, aortic cannulation showed a significantly bigger embolic load in the brain with large bubbles. Conclusions These preliminary in vitro findings showed that air embolic load in the brain may be dependent on the cannulation site, which deserves further in vivo exploration.

Studies of two temperature-sensitive mutants of Mengo virus

1979 ◽  
Vol 57 (6) ◽  
pp. 902-913 ◽  
Author(s):  
Patrick W. K. Lee ◽  
John S. Colter
Keyword(s):  
Rna Synthesis ◽  
Viral Rna ◽  
Temperature Sensitive ◽  
Supporting Evidence ◽  
Structural Polypeptide ◽  
Infected Cells ◽  
Mengo Virus ◽  
In Vitro Stability

Studies of the synthesis of viral ribonucleates and polypeptides in cells infected with two RNA−ts mutants of Mengo virus (ts 135 and ts 520) have shown that when ts 135 infected cells are shifted from the permissive (33 °C) to the nonpermissive (39 °C) temperature: (i) the synthesis of all three species of viral RNA (single stranded, replicative form, and replicative intermediate) is inhibited to about the same extent, and (ii) the posttranslational cleavage of structural polypeptide precursors A and B is partially blocked. Investigations of the in vivo and in vitro stability of the viral RNA replicase suggest that the RNA− phentotype reflects a temperature-sensitive defect in the enzyme. The second defect does not appear to result from the inhibition of viral RNA synthesis at 39 °C, since normal cleavage of polypeptides A and B occurs in wt Mengo-infected cells in which viral RNA synthesis is blocked by cordycepin, and at the nonpermissive temperature in ts 520 infected cells. Considered in toto, the evidence suggests that ts 135 is a double mutant.Subviral (53 S) particles have been shown to accumulate in ts 520 (but not ts 135) infected cells when cultures are shifted from 33 to 39 °C. This observation provides supporting evidence for the proposal that this recently discovered particle is an intermediate in the assembly pathway of Mengo virions.

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