Publications by authors named "Abhay R Satoskar"

181 Publications

Surfactant free synthesis of cationic nano-vesicles: A safe triple drug loaded vehicle for the topical treatment of cutaneous leishmaniasis.

Nanomedicine 2021 Nov 5;40:102490. Epub 2021 Nov 5.

Nanomedicine Research Group, School of Pharmacy, University of Lahore-Islamabad campus, Islamabad, Pakistan. Electronic address:

The basic aim of the study was to develop and evaluate the triple drug loaded cationic nano-vesicles (cNVs), where miltefosine was used as a replacement of surfactant (apart from its anti-leishmanial role), in addition to meglumine antimoniate (MAM) and imiquimod (Imq), as a combination therapy for the topical treatment of cutaneous leishmaniasis (CL). The optimized formulation was nano-sized (86.2 ± 2.7 nm) with high entrapment efficiency (63.8 ± 2.1% (MAM) and 81.4 ± 2.3% (Imq)). In-vivo skin irritation assay showed reduced irritation potential and a decrease in the cytotoxicity of cNVs as compared to conventional NVs (having sodium deoxycholate as a surfactant). A synergistic interaction between drugs was observed against intracellular amastigotes, whereas the in-vivo antileishmanial study presented a significant reduction in the parasitic burden. The results suggested the potential of surfactant free, triple drug loaded cNVs as an efficient vehicle for the safe topical treatment of CL.
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http://dx.doi.org/10.1016/j.nano.2021.102490DOI Listing
November 2021

Determinants of Innate Immunity in Visceral Leishmaniasis and Their Implication in Vaccine Development.

Front Immunol 2021 12;12:748325. Epub 2021 Oct 12.

Laboratory of Emerging Pathogens, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.

Leishmaniasis is endemic to the tropical and subtropical regions of the world and is transmitted by the bite of an infected sand fly. The multifaceted interactions between , the host innate immune cells, and the adaptive immunity determine the severity of pathogenesis and disease development. parasites establish a chronic infection by subversion and attenuation of the microbicidal functions of phagocytic innate immune cells such as neutrophils, macrophages and dendritic cells (DCs). Other innate cells such as inflammatory monocytes, mast cells and NK cells, also contribute to resistance and/or susceptibility to infection. In addition to the cytokine/chemokine signals from the innate immune cells, recent studies identified the subtle shifts in the metabolic pathways of the innate cells that activate distinct immune signal cascades. The nexus between metabolic pathways, epigenetic reprogramming and the immune signaling cascades that drive the divergent innate immune responses, remains to be fully understood in pathogenesis. Further, development of safe and efficacious vaccines against Leishmaniasis requires a broader understanding of the early interactions between the parasites and innate immune cells. In this review we focus on the current understanding of the specific role of innate immune cells, the metabolomic and epigenetic reprogramming and immune regulation that occurs during visceral leishmaniasis, and the strategies used by the parasite to evade and modulate host immunity. We highlight how such pathways could be exploited in the development of safe and efficacious vaccines.
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http://dx.doi.org/10.3389/fimmu.2021.748325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546207PMC
December 2021

STAT1-Dependent Recruitment of Ly6CCCR2 Inflammatory Monocytes and M2 Macrophages in a Helminth Infection.

Pathogens 2021 Oct 6;10(10). Epub 2021 Oct 6.

Unidad de Biomedicina, Facultad de Estudios Superiores (FES)-Iztacala, Universidad Nacional Autónoma de Mexico (UNAM), Av. De Los Barrios, Los Reyes Iztacala, Tlalnepantla 54090, Edo. de Mexico, Mexico.

Signal Transducer and Activator of Transcription (STAT) 1 signaling is critical for IFN-γ-mediated immune responses and resistance to protozoan and viral infections. However, its role in immunoregulation during helminth parasitic infections is not fully understood. Here, we used STAT1 mice to investigate the role of this transcription factor during a helminth infection caused by the cestode and show that STAT1 is a central molecule favoring susceptibility to this infection. STAT1 mice displayed lower parasite burdens at 8 weeks post-infection compared to STAT1 mice. STAT1 mediated the recruitment of inflammatory monocytes and the development of alternatively activated macrophages (M2) at the site of infection. The absence of STAT1 prevented the recruitment of CD11bLy6CLy6G monocytic cells and therefore their suppressive activity. This failure was associated with the defective expression of CCR2 on CD11bLy6CLy6G cells. Importantly, CD11bLy6CLy6G cells highly expressed PDL-1 and suppressed T-cell proliferation elicited by anti-CD3 stimulation. PDL-1 cells were mostly absent in STAT1 mice. Furthermore, only STAT1 mice developed M2 macrophages at 8 weeks post-infection, although macrophages from both -infected STAT1 and STAT1 mice responded to IL-4 in vitro, and both groups of mice were able to produce the Th2 cytokine IL-13. This suggests that CD11bCCR2Ly6CLy6G cells give rise to M2 macrophages in this infection. In summary, a lack of STAT1 resulted in impaired recruitment of CD11bCCR2Ly6CLy6G cells, failure to develop M2 macrophages, and increased resistance against infection.
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http://dx.doi.org/10.3390/pathogens10101287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540143PMC
October 2021

From infection to vaccination: reviewing the global burden, history of vaccine development, and recurring challenges in global leishmaniasis protection.

Expert Rev Vaccines 2021 Nov 15;20(11):1431-1446. Epub 2021 Sep 15.

Departments of Pathology and Microbiology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.

Introduction: Leishmaniasis is a major public health problem and the second most lethal parasitic disease in the world due to the lack of effective treatments and vaccines. Even when not lethal, leishmaniasis significantly affects individuals and communities through life-long disabilities, psycho-sociological trauma, poverty, and gender disparity in treatment.

Areas Covered: This review discusses the most relevant and recent research available on Pubmed and GoogleScholar highlighting leishmaniasis' global impact, pathogenesis, treatment options, and lack of effective control strategies. An effective vaccine is necessary to prevent morbidity and mortality, lower health care costs, and reduce the economic burden of leishmaniasis for endemic low- and middle-income countries. Since there are several forms of leishmaniasis, a pan- vaccine without geographical restrictions is needed. This review also focuses on recent advances and common challenges in developing prophylactic strategies against leishmaniasis.

Expert Opinion: Despite advances in pre-clinical vaccine research, approval of a human leishmaniasis vaccine still faces major challenges - including manufacturing of candidate vaccines under Good Manufacturing Practices, developing well-designed clinical trials suitable in endemic countries, and defined correlates of protection. In addition, there is a need to explore Challenge Human Infection Model to avoid large trials because of fluctuating incidence and prevalence of leishmanasis.
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http://dx.doi.org/10.1080/14760584.2021.1969231DOI Listing
November 2021

Pentalinonsterol, a Phytosterol from Pentalinon andrieuxii, is Immunomodulatory through Phospholipase A in Macrophages toward its Antileishmanial Action.

Cell Biochem Biophys 2021 Aug 13. Epub 2021 Aug 13.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Our earlier in vitro and in vivo studies have revealed that the phytosterol, pentalinonsterol (cholest-4,20,24-trien-3-one) (PEN), isolated from the roots of Pentalinon andrieuxii, possesss immunomodulatory properties in macrophages and dendritic cells. Leishmaniasis, caused by the infection of Leishmania spp. (a protozoan parasite), is emerging as the second-leading cause of mortality among the tropical diseases and there is an unmet need for a pharmacological intervention of leishmaniasis. Given the beneficial immunomodulatory actions and lipophilic properties of PEN, the objective of this study was to elucidate the mechanism(s) of action of the immunomodulatory action(s) of PEN in macrophages through the modulation of phospholipase A (PLA) activity that might be crucial in the antileishmanial action of PEN. Therefore, in this study, we investigated whether PEN would modulate the activity of PLA in RAW 264.7 macrophages and mouse bone marrow-derived primary macrophages (BMDMs) in vitro and further determined how the upstream PLA activation would regulate the downstream cytokine release in the macrophages. Our current results demonstrated that (i) PEN induced PLA activation (arachidonic acid release) in a dose- and time-dependent manner that was regulated upstream by the mitogen-activated protein kinases (MAPKs); (ii) the PEN-induced activation of PLA was attenuated by the cPLA-specific pharmacological inhibitors; and (iii) the cPLA-specific pharmacological inhibitors attenuated the release of inflammatory cytokines from the macrophages. For the first time, our current study demonstrated that PEN exhibited its immunomodulatory actions through the activation of cPLA in the macrophages, which potentially could be used in the development of a pharmacological intervention against leishmaniasis.
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http://dx.doi.org/10.1007/s12013-021-01030-8DOI Listing
August 2021

Inhibition of elastase enhances the adjuvanticity of alum and promotes anti-SARS-CoV-2 systemic and mucosal immunity.

Proc Natl Acad Sci U S A 2021 08;118(34)

Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210;

Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses. However, it fails to induce secretory immunoglobulin (Ig) A (SIgA) in mucosal tissues and is poor in inducing Th1 and cell-mediated immunity. Alum stimulates interleukin 1 (IL-1) and the recruitment of myeloid cells, including neutrophils. We investigated whether neutrophil elastase regulates the adjuvanticity of alum, and whether a strategy targeting neutrophil elastase could improve responses to injected vaccines. Mice coadministered a pharmacological inhibitor of elastase, or lacking elastase, developed high-affinity serum IgG and IgA antibodies after immunization with alum-adsorbed protein vaccines, including the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). These mice also developed broader antigen-specific CD4 T cell responses, including high Th1 and T follicular helper (Tfh) responses. Interestingly, in the absence of elastase activity, mucosal SIgA responses were induced after systemic immunization with alum as adjuvant. Importantly, lack or suppression of elastase activity enhanced the magnitude of anti-SARS-CoV-2 spike subunit 1 (S1) antibodies, and these antibodies reacted with the same epitopes of spike 1 protein as sera from COVID-19 patients. Therefore, suppression of neutrophil elastase could represent an attractive strategy for improving the efficacy of alum-based injected vaccines for the induction of broad immunity, including mucosal immunity.
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http://dx.doi.org/10.1073/pnas.2102435118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403952PMC
August 2021

MicroRNA-21 Deficiency Promotes the Early Th1 Immune Response and Resistance toward Visceral Leishmaniasis.

J Immunol 2021 09 2;207(5):1322-1332. Epub 2021 Aug 2.

Department of Pathology, The Ohio State University Medical Center, Columbus, OH;

MicroRNA-21 (miR-21) inhibits IL-12 expression and impairs the Th1 response necessary for control of infection. Recent studies have shown that infection induces miR-21 expression in dendritic cells and macrophages, and inhibition of miR-21 restores IL-12 expression. Because miR-21 is known to be expressed due to inflammatory stimuli in a wide range of hematopoietic cells, we investigated the role of miR-21 in regulating immune responses during visceral leishmaniasis (VL) caused by infection. We found that miR-21 expression was significantly elevated in dendritic cells, macrophages, inflammatory monocytes, polymorphonuclear neutrophils, and in the spleen and liver tissues after infection, concomitant with an increased expression of disease exacerbating IL-6 and STAT3. Bone marrow dendritic cells from miR-21 knockout (miR-21KO) mice showed increased IL-12 production and decreased production of IL-10. On infection, miR-21KO mice exhibited significantly greater numbers of IFN-γ- and TNF-α-producing CD4 and CD8 T cells in their organs that was associated with increased production of Th1-associated IFN-γ, TNF-α, and NO from the splenocytes. Finally, miR-21KO mice displayed significantly more developing and mature hepatic granulomas leading to reduction in organ parasitic loads compared with wild type counterparts. Similar results were noted in -infected wild type mice after transient miR-21 depletion. These observations indicate that miR-21 plays a critical role in pathogenesis of VL by suppressing IL-12- and Th1-associated IFN-γ and also inducing disease-promoting induction of the IL-6 and STAT-3 signaling pathway. miR-21 could therefore be used as a potential target for developing host-directed treatment for VL.
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http://dx.doi.org/10.4049/jimmunol.2001099DOI Listing
September 2021

Mechanisms of Immunopathogenesis in Cutaneous Leishmaniasis And Post Kala-azar Dermal Leishmaniasis (PKDL).

Front Cell Infect Microbiol 2021 8;11:685296. Epub 2021 Jun 8.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Leishmaniasis is a neglected tropical disease that affects 12 million people worldwide. The disease has high morbidity and mortality rates and is prevalent in over 80 countries, leaving more than 300 million people at risk of infection. Of all of the manifestations of this disease, cutaneous leishmaniasis (CL) is the most common form and it presents as ulcerating skin lesions that can self-heal or become chronic, leading to disfiguring scars. This review focuses on the different pathologies and disease manifestations of CL, as well as their varying degrees of severity. In particular, this review will discuss self-healing localized cutaneous leishmaniasis (LCL), leishmaniasis recidivans (LR), mucocutaneous leishmaniasis (MCL), anergic diffuse cutaneous leishmaniasis (ADCL), disseminated leishmaniasis (DL), and Post Kala-azar Dermal Leishmaniasis (PKDL), which is a cutaneous manifestation observed in some visceral leishmaniasis (VL) patients after successful treatment. The different clinical manifestations of CL are determined by a variety of factors including the species of the parasites and the host's immune response. Specifically, the balance between the pro and anti-inflammatory mediators plays a vital role in the clinical presentation and outcome of the disease. Depending upon the immune response, infection can also transition from one form of the disease to another. In this review, different forms of cutaneous infections and their immunology are described.
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http://dx.doi.org/10.3389/fcimb.2021.685296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217655PMC
July 2021

Molecular characterization and genetic diversity of cutaneous leishmaniasis from North Eastern Pakistan.

Acta Trop 2021 Sep 21;221:105964. Epub 2021 May 21.

Department of Zoology, Faculty of Biological Science, Quaid-i-Azam University Islamabad 45320, Pakistan. Electronic address:

The genetic diversity of Leishmania spp. in North Eastern Pakistan remains undetermined despite increased cases of cutaneous leishmaniasis (CL). This study was designed to decipher the molecular characterization and genetic diversity of Leishmania spp. in North Eastern Pakistan. Out of 13761 CL suspected cases, 567 cases were microscopically positive and confirmed as Leishmania spp. by internal transcribed spacer (ITS) gene amplification through the PCR- RFLP technique. Further, isolates were directly sequenced to conduct phylogenetic analysis for genetic diversity. Among suspected CL cases, Mirpur showed the highest proportion of CL infection with 4.85% (118/2431) of the cases, while the Neelum district showed the lowest percentage at 3.29% (9/273). The slide positivity rate, annual blood examination rate, and annual parasite incidence rate were 3.84, 0.27, and 0.01% respectively, and the incidence of CL in the age group 1-20 years old was higher in males (50.92%) than females (25.75%). The RFLP analysis and sequencing confirmed the occurrence of Leishmania tropica, Leishmania major, and Leishmania infantum. Leishmania tropica (p = 0.02) confirmed significantly higher nucleotides variation than L. major (p = 0.05). Current findings confirmed the prior assumption that anthroponotic CL is the primary CL form present in North Eastern Pakistan. Moreover, this is the first report based on molecular identification of L. major, and L. infantum from North Eastern Pakistan. This remarkable heterogeneity in the Leishmania spp. is the leading cause of treatment failure and emergence of new haplotypes. Therefore more extensive investigations are recommended from all geographical regions of North Eastern Pakistan, especially those using a large sample size.
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http://dx.doi.org/10.1016/j.actatropica.2021.105964DOI Listing
September 2021

MicroRNA155 Plays a Critical Role in the Pathogenesis of Cutaneous Leishmania major Infection by Promoting a Th2 Response and Attenuating Dendritic Cell Activity.

Am J Pathol 2021 05 2;191(5):809-816. Epub 2021 Feb 2.

Department of Pathology, The Ohio State University Medical Center, Columbus, Ohio; Department of Microbiology, The Ohio State University, Columbus, Ohio. Electronic address:

Interferon (IFN)-γ is indispensable in the resolution of cutaneous leishmaniasis (CL), while the Th2 cytokines IL-4, IL-10, and IL-13 mediate susceptibility. A recent study found that miR155, which promotes CD4 Th1 response and IFN-γ production, is dispensable in the control of Leishmania donovani infection. Here, the role of miR155 in CL caused by L. major was investigated using miR155-deficient (miR155) mice. Infection was controlled significantly quicker in the miR155 mice than in their wild-type (WT) counterparts, indicating that miR155 contributes to the pathogenesis of CL. Faster resolution of infection in miR155 mice was associated with increased levels of Th1-associated IL-12 and IFN-γ and reduced production of Th2- associated IL-4, IL-10, and IL-13. Concentrations of IFN-γCD8 T cells and natural killer cells in draining lymph nodes were significantly higher in the L. major-infected miR155 mice than in the infected WT mice, as indicated by flow-cytometry. After in vitro IFN-γ stimulation, nitric oxide and IL-12 production were increased, IL-10 production was decreased, and parasite clearance was enhanced in L. major-infected miR155 DCs compared to those in WT DCs. Furthermore, IFN-γ production from activated miR155 T cells was significantly enhanced in L. major-infected miR155 DCs. Together, these findings demonstrate that miR155 promotes susceptibility to CL caused by L. major by promoting Th2 response and inhibiting DC function.
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http://dx.doi.org/10.1016/j.ajpath.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132173PMC
May 2021

Understanding the immune responses involved in mediating protection or immunopathology during leishmaniasis.

Biochem Soc Trans 2021 02;49(1):297-311

Department of Pathology, College of Medicine, The Ohio State University, Columbus, Ohio 43210, U.S.A.

Leishmaniasis is a vector-borne Neglected Tropical Disease (NTD) transmitted by the sand fly and is a major public health problem worldwide. Infections caused by Leishmania clinically manifest as a wide range of diseases, such as cutaneous (CL), diffuse cutaneous (DCL), mucosal (MCL) and visceral leishmaniasis (VL). The host innate and adaptative immune responses play critical roles in the defense against leishmaniasis. However, Leishmania parasites also manipulate the host immune response for their survival and replication. In addition, other factors such as sand fly salivary proteins and microbiota also promote disease susceptibility and parasite spread by modulating local immune response. Thus, a complex interplay between parasite, sand fly and the host immunity governs disease severity and outcome. In this review, we discuss the host immune response during Leishmania infection and highlight the factors associated with resistance or susceptibility.
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http://dx.doi.org/10.1042/BST20200606DOI Listing
February 2021

The role of vascular endothelium and exosomes in human protozoan parasitic diseases.

Vessel Plus 2020 27;4. Epub 2020 Sep 27.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH 43201, USA.

The vascular endothelium is a vital component in maintaining the structure and function of blood vessels. The endothelial cells (ECs) mediate vital regulatory functions such as the proliferation of cells, permeability of various tissue membranes, and exchange of gases, thrombolysis, blood flow, and homeostasis. The vascular endothelium also regulates inflammation and immune cell trafficking, and ECs serve as a replicative niche for many bacterial, viral, and protozoan infectious diseases. Endothelial dysfunction can lead to vasodilation and pro-inflammation, which are the hallmarks of many severe diseases. Exosomes are nanoscale membrane-bound vesicles that emerge from cells and serve as important extracellular components, which facilitate communication between cells and maintain homeostasis during normal and pathophysiological states. Exosomes are also involved in gene transfer, inflammation and antigen presentation, and mediation of the immune response during pathogenic states. Protozoa are a diverse group of unicellular organisms that cause many infectious diseases in humans. In this regard, it is becoming increasingly evident that many protozoan parasites (such as , , , and ) utilize exosomes for the transfer of their virulence factors and effector molecules into the host cells, which manipulate the host gene expression, immune responses, and other biological activities to establish and modulate infection. In this review, we discuss the role of the vascular endothelium and exosomes in and their contribution to pathogenesis in malaria, African sleeping sickness, Chagas disease, and leishmaniasis and toxoplasmosis with an emphasis on their actions on the innate and adaptive immune mechanisms of resistance.
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http://dx.doi.org/10.20517/2574-1209.2020.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575144PMC
September 2020

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance.

Parasit Vectors 2020 Oct 12;13(1):510. Epub 2020 Oct 12.

Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China.

Background: Leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Emerging drug resistance of Leishmania species poses threaten to the effective control and elimination programme of this neglected tropical disease.

Methods: In this work, we conducted drug-resistance testing, whole genome resequencing and proteome profiling for a recently reported clinical isolate with supposed drug resistance (HCZ), and two reference sensitive strains (DD8 and 9044) of Leishmania donovani, to explore molecular mechanisms underlying drug resistance in this parasite.

Results: With reference to DD8 and 9044 strains, HCZ isolate showed higher-level virulence and clear resistance to antimonials in promastigote culture, infected macrophages and animal experiment. Pairwise genomic comparisons revealed genetic variations (86 copy number variations, 271 frameshift mutations in protein-coding genes and two site mutations in non-coding genes) in HCZ isolate that were absent from the reference sensitive strains. Proteomic analysis indicated different protein expression between HCZ isolate and reference strains, including 69 exclusively detected proteins and 82 consistently down-/upregulated molecules in the HCZ isolate. Integrative analysis showed linkage of 12 genomic variations (gene duplication, insertion and deletion) and their protein expression changes in HCZ isolate, which might be associated with pathogenic and antimony-resistant phenotype. Functional annotation analyses further indicated that molecules involved in nucleotide-binding, fatty acid metabolism, oxidation-reduction and transport might play a role in host-parasite interaction and drug-resistance.

Conclusions: This comprehensive integrative work provided novel insights into the genetic basis underlying virulence and resistance, suggesting new aspects to be investigated for a better intervention against L. donovani and associated diseases.
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http://dx.doi.org/10.1186/s13071-020-04397-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552375PMC
October 2020

Macrophage migration inhibitory factor inhibition as a novel therapeutic approach against triple-negative breast cancer.

Cell Death Dis 2020 09 17;11(9):774. Epub 2020 Sep 17.

Department of Pathology, Ohio State University, Columbus, OH, 43210, USA.

Triple-negative breast cancer (TNBC), defined as loss of estrogen, progesterone, and Her2 receptors, is a subtype of highly aggressive breast cancer with worse prognosis and poor survival rate. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine aberrantly expressed in many solid tumors and known to promote tumor progression and metastasis. However, its role in TNBC progression and metastasis is unexplored. Here we have shown that in TNBC patients, MIF expression was significantly enriched in the tumor compared to adjacent normal tissue. Using publically available patient datasets, we showed that MIF overexpression correlates with worse survival in TNBC compared to other hormonal status. Orthotopic implantation of TNBC cells into MIF knockout mice showed reduced tumor growth compared to wild-type mice. In addition, we have shown that MIF downregulation inhibits TNBC growth and progression in a syngeneic mouse model. We further showed that CPSI-1306, a small-molecule MIF inhibitor, inhibits the growth of TNBC cells in vitro. Mechanistic studies revealed that CPSI-1306 induces intrinsic apoptosis by alteration in mitochondrial membrane potential, cytochrome c (Cyt c) release, and activation of different caspases. In addition, CPSI-1306 inhibits the activation of cell survival and proliferation-related molecules. CPSI-1306 treatment also reduced the tumor growth and metastasis in orthotopic mouse models of mammary carcinoma. CPSI-1306 treatment of tumor-bearing mice significantly inhibited TNBC growth and pulmonary metastasis in a dose-dependent manner. Histological analysis of xenograft tumors revealed a higher number of apoptotic cells in CPSI-1306-treated tumors compared to vehicle controls. Our studies, for the first time, show that MIF overexpression in TNBC enhances growth and metastasis. Taken together, our results indicate that using small molecular weight MIF inhibitors could be a promising strategy to inhibit TNBC progression and metastasis.
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http://dx.doi.org/10.1038/s41419-020-02992-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498597PMC
September 2020

A listeriolysin O subunit vaccine is protective against Listeria monocytogenes.

Vaccine 2020 08 17;38(36):5803-5813. Epub 2020 Jul 17.

Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; Department of Microbiology, The Ohio State University, The Ohio State University, Columbus, OH, USA. Electronic address:

Listeria monocytogenes is a facultative intracellular pathogen responsible for the life-threatening disease listeriosis. The pore-forming toxin listeriolysin O (LLO) is a critical virulence factor that plays a major role in the L. monocytogenes intracellular lifecycle and is indispensable for pathogenesis. LLO is also a dominant antigen for T cells involved in sterilizing immunity and it was proposed that LLO acts as a T cell adjuvant. In this work, we generated a novel full-length LLO toxoid (LLO) in which the cholesterol-recognition motif, a threonine-leucine pair located at the tip of the LLO C-terminal domain, was substituted with two glycine residues. We showed that LLO lost its ability to bind cholesterol and to form pores. Importantly, LLO retained binding to the surface of epithelial cells and macrophages, suggesting that it could efficiently be captured by antigen-presenting cells. We then determined if LLO can be used as an antigen and adjuvant to protect mice from L. monocytogenes infection. Mice were immunized with LLO alone or together with cholera toxin or Alum as adjuvants. We found that mice immunized with LLO alone or in combination with the Th2-inducing adjuvant Alum were not protected against L. monocytogenes. On the other hand, mice immunized with LLO along with the experimental adjuvant cholera toxin, were protected against L. monocytogenes, as evidenced by a significant decrease in bacterial burden in the liver and spleen three days post-infection. This immunization regimen elicited mixed Th1, Th2, and Th17 responses, as well as the generation of LLO-neutralizing antibodies. Further, we identified T cells as being required for immunization-induced reductions in bacterial burden, whereas B cells were dispensable in our model of non-pregnant young mice. Overall, this work establishes that LLO is a promising vaccine antigen for the induction of protective immunity against L. monocytogenes by subunit vaccines containing Th1-driving adjuvants.
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http://dx.doi.org/10.1016/j.vaccine.2020.06.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788512PMC
August 2020

A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing.

Nat Commun 2020 07 10;11(1):3461. Epub 2020 Jul 10.

Division of Emerging and Transfusion Transmitted Diseases, CBER, FDA, Silver Spring, MD, 20993, USA.

Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa transmitted by infected sand flies. Vaccination through leishmanization with live Leishmania major has been used successfully but is no longer practiced because it resulted in occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain (LmCen). Notably, LmCen is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen have no visible lesions following challenge with L. major-infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen immunization results in protection and an immune response comparable to leishmanization. LmCen is safe since it is unable to cause disease in immunocompromised mice, induces robust host protection against vector sand fly challenge and because it is marker free, can be advanced to human vaccine trials.
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http://dx.doi.org/10.1038/s41467-020-17154-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351751PMC
July 2020

Cutaneous Leishmaniasis due to Three Leishmania Species Among Syrian Refugees in Sanliurfa, Southeastern Turkey.

Acta Parasitol 2020 Dec 16;65(4):936-948. Epub 2020 Jun 16.

Ministry of Health, Health Sciences University, Van Training and Research Hospital, Dermatology Clinic, Van, Turkey.

Sanliurfa, a city in southeastern Turkey, is host to 477,166 Syrian refugees. The incidence of cutaneous leishmaniasis (CL) may be on the rise in areas affected by a refugee crisis, like Sanliurfa; thus, consequently, local uncommon species of Leishmania may be encountered in these regions. This might potentially make diagnosis and treatment more challenging over time. In this study, it was aimed to identify the causative agents of CL in clinical samples. A total of 154 patients (60 Syrian and 94 Turkish) who were diagnosed with CL via microscopical examination and PCR were enrolled this study. All of the samples were analyzed using internal transcribed spacer 1 genes, restriction fragment length polymorphism, DNA-sequencing, and phylogenetic analyses. In this study, Leishmania tropica was determined to be the predominant species in 140 of the patients (90.9%), followed by Leishmania major in 12 patients (7.8%), and Leishmania infantum in 2 patients (1.3%). Of the 94 Turkish patients, 94.7% were infected with L. tropica and 5.3% were infected with L. major, while none were infected with L. infantum. However, of the 60 Syrian patients, 85% were infected with L. tropica, 11.7% were infected with L. major, and 3.3% were infected with L. infantum. There was a significant association between the Leishmania species and the nations (Turkish-Syrian) (P < 0.001). The sequences were numbered from MH347941 to MH347953 and submitted to GenBank. This study confirmed that L. tropica, L. major, and L. infantum coexisted in Sanliurfa. This was the first time that the species L. infantum was reported among recent immigrants from Syria in Sanliurfa. Therefore, it is necessary to discriminate the Leishmania species for diagnosis, treatment, and controlled studies in hyper-endemic regions.
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http://dx.doi.org/10.2478/s11686-020-00227-wDOI Listing
December 2020

Oral delivery and enhanced efficacy of antimonal drug through macrophage-guided multifunctional nanocargoes against visceral Leishmaniasis.

Eur J Pharm Biopharm 2020 Jul 30;152:307-317. Epub 2020 May 30.

Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address:

The present study aimed on the site specific delivery and enhanced in-vivo efficacy of antimonial drugs against the visceral leishmaniasis via macrophage targeted mannose anchored thiomer based nanoparticles. Mannose anchored thiolated nanoformulation [M-(CS-g-PEI)-TGA] was developed and evaluated in terms particle size, zeta-potential and entrapment efficacy. The TEM and EDX analysis was carried out to evaluate the morphology and successful entrapment of antimonial drug. Mucodhesion, permeation enhancement, oral pharmacokinetics, and in-vivo anti-leishmanial activity were carried out. The M-(CS-g-PEI)-TGA were found to be spherical having particle size of 287 ± 20 nm. Ex-vivo permeation indicated a 7.39-fold enhanced permeation of Meglumine Antimoniate with M-(CS-g-PEI)-TGA across Caco-2 cells compared to the Glucantime. Evaluation of in-vitro reduction in the parasitic burden via flow cytometric analysis indicated a 5.7-fold lower IC for M-(CS-g-PEI)-TGA compared to Glucantime. A 6.1-fold improvement in the oral bioavailability and 5.2-fold reduced parasitic burden in the L. donovani infected BALB/c mice model was observed with M-(CS-g-PEI)-TGA compared to Glucantime. The results encouraged the concept of M-(CS-g-PEI)-TGA nanoformulations as a promising strategy for oral therapy against visceral leishmaniasis.
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http://dx.doi.org/10.1016/j.ejpb.2020.05.029DOI Listing
July 2020

MicroRNA-155 Deficiency Exacerbates Trypanosoma cruzi Infection.

Infect Immun 2020 06 22;88(7). Epub 2020 Jun 22.

Division of Infectious Diseases, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA

Chagas disease, caused by the intracellular protozoan parasite , is a public health problem affecting 6 to 8 million people, mainly in Latin America. The role of microRNAs in the pathogenesis of Chagas disease has not been well described. Here, we investigate the role of microRNA-155 (miR-155), a proinflammatory host innate immune regulator responsible for T helper type 1 and type 17 (Th1 and Th17) development and macrophage responses during infection. For this, we compared the survival and parasite growth and distribution in miR-155 and wild-type (WT) C57BL/6 mice. The lack of miR-155 caused robust parasite infection and diminished survival of infected mice, while WT mice were resistant to infection. Immunological analysis of infected mice indicated that, in the absence of miR-155, there was decreased interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. In addition, we found that there was a significant reduction of CD8-positive (CD8) T cells, natural killer (NK) cells, and NK-T cells and increased accumulation of neutrophils and inflammatory monocytes in miR-155 mice. Collectively, these data indicate that miR-155 is an important immune regulatory molecule critical for the control of infection.
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http://dx.doi.org/10.1128/IAI.00948-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309613PMC
June 2020

Nano-elastic liposomes as multidrug carrier of sodium stibogluconate and ketoconazole: A potential new approach for the topical treatment of cutaneous Leishmaniasis.

Eur J Pharm Sci 2020 Mar 4;145:105256. Epub 2020 Feb 4.

Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address:

The present study evaluates the efficacy of sodium stibogluconate (SSG) co-loaded with ketoconazole (KTZ) in nano-elastic liposomes (NELs) for the topical treatment of cutaneous leishmaniasis (CL). SSG-KTZ co-loaded NELs were developed and assessed for various physicochemical properties and anti-leishmanial potential. The optimized nano-vesicles have an average size of 212.8 ± 3.1 nm and entrapment efficiency of 61.2 ± 2.9%. SSG-KTZ co-loaded NELs displayed 5.37-fold higher skin permeation of SSG as compared to drug solution. SSG and KTZ displayed a synergistic interaction and flow cytometry revealed enhanced killing of DsRed Leishmania mexicana in infected macrophages. In-vitro and in-vivo anti-leishmanial studies indicated a 10.67-fold lower IC value and a 35.33-fold reduced parasitic burden as compared with plain SSG solution, respectively. SSG-KTZ co-loaded NELs were found to be a promising approach for the topical treatment of CL.
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http://dx.doi.org/10.1016/j.ejps.2020.105256DOI Listing
March 2020

Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells.

Br J Cancer 2020 03 6;122(7):1005-1013. Epub 2020 Feb 6.

Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA.

Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK) inhibitor used for treating chronic lymphocytic leukaemia (CLL) and other cancers. Although ibrutinib is known to inhibit the growth of breast cancer cell growth in vitro, its impact on the treatment and metastasis of breast cancer is unclear.

Methods: Using an orthotopic mouse breast cancer model, we show that ibrutinib inhibits the progression and metastasis of breast cancer.

Results: Ibrutinib inhibited proliferation of cancer cells in vitro, and Ibrutinib-treated mice displayed significantly lower tumour burdens and metastasis compared to controls. Furthermore, the spleens and tumours from Ibrutinib-treated mice contained more mature DCs and lower numbers of myeloid-derived suppressor cells (MDSCs), which promote disease progression and are linked to poor prognosis. We also confirmed that ex vivo treatment of MDSCs with ibrutinib switched their phenotype to mature DCs and significantly enhanced MHCII expression. Further, ibrutinib treatment promoted T cell proliferation and effector functions leading to the induction of antitumour T1 and CTL immune responses.

Conclusions: Ibrutinib inhibits tumour development and metastasis in breast cancer by promoting the development of mature DCs from MDSCs and hence could be a novel therapeutic agent for the treatment of breast cancer.
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http://dx.doi.org/10.1038/s41416-020-0743-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109110PMC
March 2020

Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC.

Front Immunol 2019 15;10:3095. Epub 2020 Jan 15.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Head and neck squamous cell carcinoma (HNSCC) is a prevalent form of cancer with 5-years survival rates around 57%, and metastasis is a leading cause of mortality. Host-derived immunological factors that affect HNSCC tumor development and metastasis are not completely understood. We investigated the role of host-derived signal transducer and activator of transcription 4 (STAT4) during experimental HNSCC using an aggressive and metastatic HNSCC cell line, LY2, which was orthotopically injected into the buccal sulcus of wild type (WT) and STAT4 deficient ( ) BALB/c mice. Necropsies performed at terminal sacrifice revealed that mice displayed comparable primary tumor growth to the WT mice. However, the rate and extent of lymph node and lung metastasis among mice was significantly higher. Downstream analyses performed on primary tumors, draining lymph nodes, spleens and bone marrow revealed significant upregulation of lymphocytic immunosuppressive biomarkers as well as an accumulation of granulocytic MDSC subpopulations in draining lymph nodes of metastatic mice. Further, we observed a significant decrease in T1, T17, and cytotoxic activity in tumor bearing compared to WT mice. Our results demonstrate that STAT4 mediates resistance to HNSCC metastasis, and activation of STAT4 could potentially mitigate lymphatic metastasis in HNSCC patients.
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http://dx.doi.org/10.3389/fimmu.2019.03095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974475PMC
October 2020

Development and evaluation of novel miltefosine-polyphenol co-loaded second generation nano-transfersomes for the topical treatment of cutaneous leishmaniasis.

Expert Opin Drug Deliv 2020 01 6;17(1):97-110. Epub 2019 Dec 6.

Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.

: To test the hypothesis that miltefosine (MTF)-polyphenol co-loaded second-generation nano-transfersomes (SGNTs) can be an effective approach for the topical treatment of cutaneous leishmaniasis (CL).: The co-loaded SGNTs with various MTF-polyphenol combinations were developed, evaluated and compared for the entrapment efficiency, vesicle size, deformability index, permeation, cytotoxicity, and anti-leishmanial potential, using both and models.: The co-loaded SGNTs were spherical in shape, with an average size of 119 ± 1.5 nm and a high entrapment efficiency of 73.7 ± 3.7%. The study displayed a 3.2-fold higher permeation of MTF when entrapped in co-loaded SGNTs, whereas cytotoxicity potential of co-loaded SGNTs was 43.2% higher than the MTF solution. A synergistic interaction was observed between MTF and apigenin (APG) among all polyphenols and an 8.0-fold lower IC was found against amastigotes of DsRed , compared with the plain MTF solution. Moreover, the studies displayed a 9.5-fold reduced parasitic burden in the infected BALB/c mice treated with MTF-APG co-loaded SGNTs gel.: The potential of MTF-APG co-loaded SGNTs topical formulation is established for the first time as an effective drug delivery strategy against CL.
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http://dx.doi.org/10.1080/17425247.2020.1700227DOI Listing
January 2020

Topical treatment of cutaneous leishmaniasis with novel amphotericin B-miltefosine co-incorporated second generation ultra-deformable liposomes.

Int J Pharm 2020 Jan 22;573:118900. Epub 2019 Nov 22.

Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address:

The present study aims to optimize and evaluate amphotericin B (AmB) and miltefosine (MTF) co-loaded second generation ultra-deformable liposomes (SGUDLs) for the topical treatment of cutaneous leishmaniasis (CL). The development of an effective topical drug formulation against CL is desirable because of its non-invasive nature, which may potentially enhance the patient adherence and treatment accessibility. AmB-MTF co-loaded SGUDLs were prepared and characterized for size, entrapment efficiency (EE) and elasticity. The optimized formulation was then subjected to ex-vivo permeation studies in addition to cytotoxicity and anti-leishmanial assays. The co-loaded SGUDLs had an average size of 139.7 ± 1.7 nm and high EE of 77.8 ± 3.9% with respect to AmB. The ex-vivo permeation of co-loaded SGUDLs exhibited 6.15-fold higher permeation of AmB. A synergistic interaction was observed between AmB and MTF, and anti-leishmanial activity of co-loaded SGUDLs against amastigotes of Lesihmania mexicana indicated 8.62 and 6.12-fold lower IC values of AmB and MTF as compared to plain drug solutions, respectively. The results of the in-vivo study displayed a significant reduction in the parasitic burden in an infected BALB/c experimental model of CL. In conclusion, AmB-MTF co-loaded SGUDLs could be an effective topical treatment option against CL.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118900DOI Listing
January 2020

Lymphocytes influence Leishmania major pathogenesis in a strain-dependent manner.

PLoS Negl Trop Dis 2019 11 18;13(11):e0007865. Epub 2019 Nov 18.

Doctoral Leadership Program, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.

Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis and is caused by several species of Leishmania parasite. Clinical presentation of CL varies from a self-healing infection to a chronic form of the disease determined by the virulence of infecting Leishmania species and host immune responses to the parasite. Mouse models of CL show contradictory roles of lymphocytes in pathogenesis, while acquired immune responses are responsible for host protection from diseases. To reconcile the inconclusive roles of acquired immune responses in pathogenesis, we infected mice from various genetic backgrounds with two pathogenic strains of Leishmania major, Friedlin or 5ASKH, and assessed the outcome of the infections. Our findings showed that the genetic backgrounds of L. major determine the impact of lymphocytes for pathogenesis. In the absence of lymphocytes, L. major Friedlin induced the lowest inflammatory reaction and pathology at the site of infection, while 5ASKH infection induced a strong inflammatory reaction and severe pathology. Lymphocytes ameliorated 5ASKH mediated pathology, while it exacerbated pathology during Friedlin infection. Excess inflammatory reactions, like the recruitment of macrophages, neutrophils, eosinophils and production of pro-inflammatory cytokines, together with uncontrolled parasite growth in the absence of lymphocytes during 5ASKH infection may induce severe pathology development. Taken together our study provides insight into the impact of differences in the genetic background of Leishmania on CL pathogenesis.
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http://dx.doi.org/10.1371/journal.pntd.0007865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886877PMC
November 2019

STAT1 inhibits T-cell exhaustion and myeloid derived suppressor cell accumulation to promote antitumor immune responses in head and neck squamous cell carcinoma.

Int J Cancer 2020 03 29;146(6):1717-1729. Epub 2019 Nov 29.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH.

Cancers of the oral cavity remain the sixth most diagnosed cancer worldwide, with high rates of recurrence and mortality. We determined the role of STAT1 during oral carcinogenesis using two orthotopic models in mice genetically deficient for Stat1. Metastatic (LY2) and nonmetastatic (B4B8) head and neck squamous cell carcinoma (HNSCC) cell lines were injected into the oral cavity of Stat1 deficient (Stat1 ) and Stat1 competent (Stat1 ) mice. Stat1 mice displayed increased tumor growth and metastasis compared to Stat1 mice. Mechanistically, Stat1 mice displayed impaired CD4+ and CD8+ T-cell expansion compared to Stat1 mice. This was associated with enhanced T-cell exhaustion, and severely attenuated T-cell antitumor effector responses including reduced expression of IFN-γ and perforin at the tumor site. Interestingly, tumor necrosis factor (TNF)-α production by T cells in tumor-bearing mice was suppressed by Stat1 deficiency. This deficiency in T-cell expansion and functional responses in mice was linked to PD-1 and CD69 overexpression in T cells of Stat1 mice. In contrast, we observed increased accumulation of CD11b+ Ly6G+ myeloid derived suppressor cells in tumors, draining lymph nodes, spleens and bone marrow of tumor-bearing Stat1 mice, resulting in a protumorigenic microenvironment. Our data demonstrates that STAT1 is an essential mediator of the antitumor response through inhibition of myeloid derived suppressor cell accumulation and promotion of T-cell mediated immune responses in murine head and neck squamous cell carcinoma. Selective induction of STAT1 phosphorylation in HNSCC patients could potentially improve oral tumor outcomes and response to therapy.
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http://dx.doi.org/10.1002/ijc.32781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366342PMC
March 2020

MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages.

JCI Insight 2019 11 1;4(21). Epub 2019 Nov 1.

Judy and Bernard Briskin Center for Multiple Myeloma Research, Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope Medical Center, Duarte, California, USA.

High levels of circulating miR-16 in the serum of multiple myeloma (MM) patients are independently associated with longer survival. Although the tumor suppressor function of intracellular miR-16 in MM plasma cells (PCs) has been elucidated, its extracellular role in maintaining a nonsupportive cancer microenvironment has not been fully explored. Here, we show that miR-16 is abundantly released by MM cells through extracellular vesicles (EVs) and that differences in its intracellular expression as associated with chromosome 13 deletion (Del13) are correlated to extracellular miR-16 levels. We also demonstrate that EVs isolated from MM patients and from the conditioned media of MM-PCs carrying Del13 more strongly differentiate circulating monocytes to M2-tumor supportive macrophages (TAMs), compared with MM-PCs without this chromosomal aberration. Mechanistically, our data show that miR-16 directly targets the IKKα/β complex of the NF-κB canonical pathway, which is critical not only in supporting MM cell growth, but also in polarizing macrophages toward an M2 phenotype. By using a miR-15a-16-1-KO mouse model, we found that loss of the miR-16 cluster supports polarization to M2 macrophages. Finally, we demonstrate the therapeutic benefit of miR-16 overexpression in potentiating the anti-MM activity by a proteasome inhibitor in the presence of MM-resident bone marrow TAM.
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http://dx.doi.org/10.1172/jci.insight.129348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948777PMC
November 2019

Evaluation of synergy between host and pathogen-directed therapies against intracellular Leishmania donovani.

Int J Parasitol Drugs Drug Resist 2019 08 21;10:125-132. Epub 2019 Aug 21.

Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address:

Visceral leishmaniasis (VL) is associated with treatment complications due to the continued growth of resistant parasites toward currently available pathogen-directed therapeutics. To limit the emergence and combat resistant parasites there is a need to develop new anti-leishmanial drugs and alternative treatment approaches, such as host-directed therapeutics (HDTs). Discovery of new anti-leishmanial drugs including HDTs requires suitable in vitro assay systems. Herein, we modified and evaluated a series of resazurin assays against different life-stages of the VL causing parasite, Leishmania donovani to identify novel HDTs. We further analyzed the synergy of combinatorial interactions between traditionally used pathogen-directed drugs and HDTs for clearance of intracellular L. donovani. The inhibitory concentration at 50% (IC) of the five evaluated therapies [amphotericin B (AMB), miltefosine, paromomycin, DNER-4, and AR-12 (OSU-03012)] was determined against promastigotes, extracellular amastigotes, and intracellular amastigotes of L. donovani via a resazurin-based assay and compared to image-based microscopy. Using the resazurin-based assay, all evaluated therapies showed reproducible anti-leishmanial activity against the parasite's different life-stages. These results were consistent to the traditional image-based technique. The gold standard of therapy, AMB, showed the highest potency against intracellular L. donovani, and was further evaluated for combinatorial effects with the HDTs. Among the combinations analyzed, pathogen-directed AMB and host-directed AR-12 showed a synergistic reduction of intracellular L. donovani compared to individual treatments. The modified resazurin assay used in this study demonstrated a useful technique to measure new anti-leishmanial drugs against both intracellular and extracellular parasites. The synergistic interactions between pathogen-directed AMB and host-directed AR-12 showed a great promise to combat VL, with the potential to reduce the emergence of drug-resistant strains.
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http://dx.doi.org/10.1016/j.ijpddr.2019.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731340PMC
August 2019

Host-directed therapies for parasitic diseases.

Future Med Chem 2019 08 8;11(15):1999-2018. Epub 2019 Aug 8.

Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.

Parasitic infections are responsible for significant morbidity and mortality throughout the world. Management strategies rely primarily on antiparasitic drugs that have side effects and risk of drug resistance. Therefore, novel strategies are needed for treatment of parasitic infections. Host-directed therapy (HDT) is a viable alternative, which targets host pathways responsible for parasite invasion/survival/pathogenicity. Recent innovative combinations of genomics, proteomics and computational biology approaches have led to discovery of several host pathways that could be promising targets for HDT for treating parasitic infections. Herein, we review major advances in HDT for parasitic disease with regard to core regulatory pathways and their interactions.
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http://dx.doi.org/10.4155/fmc-2018-0439DOI Listing
August 2019
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