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1.
mBio ; : e0254723, 2023 Nov 14.
Article in English | MEDLINE | ID: mdl-37962347

ABSTRACT

IMPORTANCE: Malaria is a devastating disease that has claimed many lives, especially children <5 years of age in Sub-Saharan Africa, as documented in World Malaria Reports by WHO. Even though vector control and chemoprevention tools have helped with elimination efforts in some, if not all, endemic areas, these efforts have been hampered by serious issues (including drug and insecticide resistance and disruption to social cohesion caused by the COVID-19 pandemic). Development of an effective malaria vaccine is the alternative preventative tool in the fight against malaria. Vaccines save millions of lives each year and have helped in elimination and/or eradication of global diseases. Development of a highly efficacious malaria vaccine that will ensure long-lasting protective immunity will be a "game-changing" prevention strategy to finally eradicate the disease. Such a vaccine will need to counteract the significant obstacles that have been hampering subunit vaccine development to date, including antigenic polymorphism, sub-optimal immunogenicity, and waning vaccine efficacy.

2.
Proc Natl Acad Sci U S A ; 118(11)2021 03 16.
Article in English | MEDLINE | ID: mdl-33836556

ABSTRACT

CD47 is an antiphagocytic "don't eat me" signal that inhibits programmed cell removal of self. As red blood cells (RBCs) age they lose CD47 expression and become susceptible to programmed cell removal by macrophages. CD47-/- mice infected with Plasmodium yoelii, which exhibits an age-based preference for young RBCs, were previously demonstrated to be highly resistant to malaria infection. Our study sought to test the therapeutic benefit of CD47 blockade on ameliorating the clinical syndromes of experimental cerebral malaria (ECM), using the Plasmodium berghei ANKA (Pb-A) murine model. In vitro we tested the effect of anti-CD47 mAb on Plasmodium-infected RBC phagocytosis and found that anti-CD47 treatment significantly increased clearance of Plasmodium-infected RBCs. Infection of C57BL/6 mice with Pb-A is lethal and mice succumb to the clinical syndromes of CM between days 6 and 10 postinfection. Strikingly, treatment with anti-CD47 resulted in increased survival during the cerebral phase of Pb-A infection. Anti-CD47-treated mice had increased lymphocyte counts in the peripheral blood and increased circulating levels of IFN-γ, TNF-α, and IL-22. Despite increased circulating levels of inflammatory cytokines, anti-CD47-treated mice had reduced pathological features in the brain. Survival of ECM in anti-CD47-treated mice was correlated with reduced cellular accumulation in the cerebral vasculature, improved blood-brain barrier integrity, and reduced cytotoxic activity of infiltrating CD8+ T cells. These results demonstrate the therapeutic benefit of anti-CD47 to reduce morbidity in a lethal model of ECM, which may have implications for preventing mortality in young African children who are the highest casualties of CM.


Subject(s)
CD47 Antigen/antagonists & inhibitors , Host-Parasite Interactions , Malaria, Cerebral/pathology , Animals , Antibodies, Monoclonal/immunology , CD47 Antigen/immunology , Erythrocytes/parasitology , Humans , Malaria, Cerebral/prevention & control , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Phagocytosis
3.
Article in English | MEDLINE | ID: mdl-29967019

ABSTRACT

Many previous in vitro and in vivo preclinical malaria drug studies have relied on low-parasite-number drug inhibition numerically compared to the untreated controls. In contrast, human malaria drug studies measure the high-parasite-density killing near 100 million/ml. Here we compared the in vivo single-dose pharmacodynamic properties of artesunate and the 4-aminoquinolines pyronaridine, chloroquine, and amodiaquine in a Plasmodium berghei ANKA-green fluorescent protein GFP-luciferase-based murine malaria blood-stage model. Pyronaridine exhibited dose-dependent killing, achieving parasite reductions near 5 to 6 logs at 48 h, with complete cure at 10 mg/kg of body weight compared to artesunate, which exhibited a 48-h dose-dependent killing with a 2-log drop at the noncurative 250-mg/kg dose. Chloroquine, which was noncurative, and amodiaquine, which was partially curative, had nearly the same initial dose-independent killing, with a lag phase of minimal parasite reduction at all doses between 6 and 24 h, followed by a 2.5-log reduction at 48 h. In experiments with drug-treated, washed infected blood transfer to naive mice, chloroquine and amodiaquine showed fewer viable parasites at the 24-h transfer than at the 8-h transfer, measured by a prolonged return to parasitemia, despite a similar parasite log reduction at these time points, in contrast to the correlation of the parasite log reduction to viable parasites with artesunate and pyronaridine. Artesunate in combination with pyronaridine exhibited an initial parasite reduction similar to that achieved with pyronaridine, while with chloroquine or amodiaquine, the reduction was similar to that achieved with artesunate. Single-oral-dose pyronaridine was much more potent in vivo than artesunate, chloroquine, and amodiaquine during the initial decline in parasites and cure.


Subject(s)
Amodiaquine/pharmacology , Artesunate/pharmacology , Chloroquine/pharmacology , Luciferases/metabolism , Naphthyridines/pharmacology , Plasmodium berghei/drug effects , Plasmodium berghei/metabolism , Animals , Antimalarials/pharmacology , Female , Malaria/drug therapy , Malaria/metabolism , Mice , Mice, Inbred BALB C , Parasitemia/drug therapy , Parasitemia/metabolism
4.
PLoS One ; 13(7): e0201043, 2018.
Article in English | MEDLINE | ID: mdl-30044851

ABSTRACT

Macrophages express a wide array of invariant receptors that facilitate host defense and mediate pathogenesis during pathogen invasion. We report on a novel population of CD11bhighCD14+F4/80+ macrophages that express TCRß. This population expands dramatically during a Plasmodium berghei ANKA infection and sequesters in the brain during experimental cerebral malaria. Importantly, measurement of TCRß transcript and protein levels in macrophages in wildtype versus nude and Rag1 knockout mice establishes that the observed expression is not a consequence of passive receptor expression due to phagocytosis or trogocytosis of peripheral T cells or nonspecific antibody staining to an Fc receptor or cross reactive epitope. We also demonstrate that TCRß on brain sequestered macrophages undergoes productive gene rearrangements and shows preferential Vß usage. Remarkably, there is a significant correlation in the proportion of macrophages that express TCRß and peripheral parasitemia. In addition, presence of TCRß on the macrophage also correlates with a significant increase (1.9 fold) in the phagocytosis of parasitized erythrocytes. By transcriptional profiling, we identify a novel set of genes and pathways that associate with TCRß expression by the macrophage. Expansion of TCRß-expressing macrophages points towards a convergence of the innate and adaptive immune responses where both arms of the immune system cooperate to modulate the host response to malaria and possibly other infections.


Subject(s)
Gene Expression Regulation , Macrophages/metabolism , Macrophages/parasitology , Malaria, Cerebral/genetics , Malaria, Cerebral/immunology , Phagocytosis , Receptors, Antigen, T-Cell, alpha-beta/genetics , Animals , Brain/immunology , Brain/parasitology , Erythrocytes/parasitology , Female , Gene Rearrangement , Leukocytes/metabolism , Macrophages/immunology , Malaria, Cerebral/parasitology , Mice , Mice, Inbred C57BL , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription, Genetic
5.
Infect Immun ; 86(7)2018 07.
Article in English | MEDLINE | ID: mdl-29685989

ABSTRACT

Recent studies have demonstrated that a subpopulation of neutrophils express the TCRαß combinatorial immunoreceptor in humans and mice. Here, we report that a Plasmodium berghei ANKA murine malaria infection induces expansion of TCRß expressing CD11b+ Ly6G+ neutrophils in the spleen during the early phase of infection. Measurement of TCRß transcript and protein levels of neutrophils in wild-type versus nude and Rag1 knockout mice establishes that the observed expression is not a consequence of nonspecific antibody staining or passive receptor expression due to phagocytosis or trogocytosis of peripheral T cells. Remarkably, on day 3 postinfection, we observed a highly significant correlation between the proportion of neutrophils that express TCRß and peripheral blood parasite burden. In addition, TCRß+ neutrophils phagocytose parasitized erythrocytes with 4-fold greater efficiency than TCRß- neutrophils. Together these results signify that TCR expression by the neutrophil plays an important role in the regulation of parasite burden by enhancing the phagocytic capacity of the neutrophil.


Subject(s)
Malaria/immunology , Neutrophils/immunology , Parasitemia/immunology , Phagocytosis , Plasmodium berghei , Receptors, Antigen, T-Cell, alpha-beta/analysis , Animals , Brain/immunology , Female , Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Receptors, Antigen, T-Cell, alpha-beta/genetics , Spleen/immunology
6.
J Liposome Res ; 24(1): 69-73, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24236475

ABSTRACT

CONTEXT: A newly-recognized pathogenic mechanism underlying light chain amyloidosis (AL) involves endothelial dysfunction and cell injury caused by misfolded light chain proteins (LC). Nanoliposomes (NL) are artificial phospholipid vesicles that could attach to misfolded proteins and reduce tissue injury. OBJECTIVE: To test whether co-treatment with NL reduces LC-induced endothelial dysfunction and cell death. METHODS: Abdominal subcutaneous adipose arterioles from 14 non-AL subjects were cannulated; dilator response to acetylcholine and papaverine were measured at baseline and following 1-hour exposure to LC (20 µg/mL, 2 purified from AL subjects' urine, 1 from human recombinant LC [AL-09]) ± NL (phosphatidylcholine/cholesterol/phosphatidic acid 70/25/5 molar ratio) or NL alone. Human aortic artery endothelial cells (HAEC) were exposed to Oregon Green-labeled LC ± NL for 24 hours and intracellular LC and apoptosis (Hoechst stain) were measured. Circular dichroism spectroscopy was performed on AL-09 LC ± NL to follow changes in secondary structure and protein thermal stability. RESULTS: LC caused impaired dilation to acetylcholine that was restored by NL (control - 94.0 ± 1.8%, LC - 65.0 ± 7.1%, LC + NL - 95.3 ± 1.8%, p ≤ 0.001 LC versus control or LC + NL). NL protection was inhibited by L-NG-nitroarginine methyl ester. NL increased the beta sheet structure of LC, reduced endothelial cell internalization of LC and protected against LC-induced endothelial cell death. CONCLUSIONS: LC induced human adipose arteriole endothelial dysfunction and endothelial cell death, which were reversed by co-treatment with NL. This protection may partly be due to enhancing LC protein structure and reducing LC internalization. Nanoliposomes represent a promising new class of agents to ameliorate tissue injury from protein misfolding diseases such as AL.


Subject(s)
Amyloid/chemistry , Amyloidosis/drug therapy , Endothelium/drug effects , Liposomes/therapeutic use , Nanoparticles/therapeutic use , Aged , Apoptosis/drug effects , Endothelium/injuries , Endothelium/pathology , Heart Failure/drug therapy , Heart Failure/pathology , Humans , Liposomes/chemistry , Male , Middle Aged , Nanoparticles/chemistry , Proteostasis Deficiencies/drug therapy
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