Publications by authors named "Winter A Okoth"

5 Publications

  • Page 1 of 1

CD47 blockade reduces the pathologic features of experimental cerebral malaria and promotes survival of hosts with infection.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;

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 , 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 ANKA () murine model. In vitro we tested the effect of anti-CD47 mAb on infected RBC phagocytosis and found that anti-CD47 treatment significantly increased clearance of -infected RBCs. Infection of C57BL/6 mice with 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1907653118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980459PMC
March 2021

TCRβ-expressing macrophages induced by a pathogenic murine malaria correlate with parasite burden and enhanced phagocytic activity.

PLoS One 2018 25;13(7):e0201043. Epub 2018 Jul 25.

Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States of America.

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 TCRβ. This population expands dramatically during a Plasmodium berghei ANKA infection and sequesters in the brain during experimental cerebral malaria. Importantly, measurement of TCRβ 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 TCRβ on brain sequestered macrophages undergoes productive gene rearrangements and shows preferential Vβ usage. Remarkably, there is a significant correlation in the proportion of macrophages that express TCRβ and peripheral parasitemia. In addition, presence of TCRβ 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 TCRβ expression by the macrophage. Expansion of TCRβ-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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201043PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059462PMC
January 2019

Superior Pyronaridine Single-Dose Pharmacodynamics Compared to Artesunate, Chloroquine, and Amodiaquine in a Murine Malaria Luciferase Model.

Antimicrob Agents Chemother 2018 09 27;62(9). Epub 2018 Aug 27.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

Many previous and 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 single-dose pharmacodynamic properties of artesunate and the 4-aminoquinolines pyronaridine, chloroquine, and amodiaquine in a 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 than artesunate, chloroquine, and amodiaquine during the initial decline in parasites and cure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.00394-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125524PMC
September 2018

TCRβ Combinatorial Immunoreceptor Expression by Neutrophils Correlates with Parasite Burden and Enhanced Phagocytosis during a Plasmodium berghei ANKA Malaria Infection.

Infect Immun 2018 07 21;86(7). Epub 2018 Jun 21.

Laboratory of Mucosal Pathogens and Cellular Immunology, Division of Bacterial, Parasitic, and Allergenic Products, Office of Vaccine Research and Review, Food and Drug Administration, Silver Spring, Maryland, USA

Recent studies have demonstrated that a subpopulation of neutrophils express the TCRαβ combinatorial immunoreceptor in humans and mice. Here, we report that a ANKA murine malaria infection induces expansion of TCRβ expressing CD11b Ly6G neutrophils in the spleen during the early phase of infection. Measurement of TCRβ transcript and protein levels of neutrophils in wild-type versus nude and 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 TCRβ and peripheral blood parasite burden. In addition, TCRβ neutrophils phagocytose parasitized erythrocytes with 4-fold greater efficiency than TCRβ 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00899-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013678PMC
July 2018

Nanoliposomes protect against AL amyloid light chain protein-induced endothelial injury.

J Liposome Res 2014 Mar 15;24(1):69-73. Epub 2013 Nov 15.

Phoenix Veterans Affairs , Phoenix, AZ , USA .

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/08982104.2013.838258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925072PMC
March 2014