20 results on '"Saljoughian, Noushin"'
Search Results
2. Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells
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Varikuti, Sanjay, Singh, Bhawana, Volpedo, Greta, Ahirwar, Dinesh K., Jha, Bijay K., Saljoughian, Noushin, Viana, Agostinho G., Verma, Chaitenya, Hamza, Omar, Halsey, Gregory, Holcomb, Erin A., Maryala, Ritvik J., Oghumu, Steve, Ganju, Ramesh K., and Satoskar, Abhay R.
- Published
- 2020
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3. A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing
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Zhang, Wen-Wei, Karmakar, Subir, Gannavaram, Sreenivas, Dey, Ranadhir, Lypaczewski, Patrick, Ismail, Nevien, Siddiqui, Abid, Simonyan, Vahan, Oliveira, Fabiano, Coutinho-Abreu, Iliano V., DeSouza-Vieira, Thiago, Meneses, Claudio, Oristian, James, Serafim, Tiago D., Musa, Abu, Nakamura, Risa, Saljoughian, Noushin, Volpedo, Greta, Satoskar, Monika, Satoskar, Sanika, Dagur, Pradeep K., McCoy, J. Philip, Kamhawi, Shaden, Valenzuela, Jesus G., Hamano, Shinjiro, Satoskar, Abhay R., Matlashewski, Greg, and Nakhasi, Hira L.
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- 2020
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4. Pseudomonas aeruginosa pulmonary infection results in S100A8/A9-dependent cardiac dysfunction.
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Kumar, Naresh, Pestrak, Matthew J., Wu, Qian, Ahumada, Omar Santiagonunez, Dellos-Nolan, Sheri, Saljoughian, Noushin, Shukla, Rajni Kant, Mitchem, Cortney F., Nagareddy, Prabhakara R., Ganesan, Latha P., William, Lafuse P., Wozniak, Daniel J., and Rajaram, Murugesan V. S.
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HEART diseases ,RECEPTOR for advanced glycation end products (RAGE) ,PSEUDOMONAS aeruginosa infections ,COMMUNITY-acquired pneumonia ,PNEUMONIA-related mortality ,LUNG infections - Abstract
Pseudomonas aeruginosa (P.a.) infection accounts for nearly 20% of all cases of hospital acquired pneumonia with mortality rates >30%. P.a. infection induces a robust inflammatory response, which ideally enhances bacterial clearance. Unfortunately, excessive inflammation can also have negative effects, and often leads to cardiac dysfunction with associated morbidity and mortality. However, it remains unclear how P.a. lung infection causes cardiac dysfunction. Using a murine pneumonia model, we found that P.a. infection of the lungs led to severe cardiac left ventricular dysfunction and electrical abnormalities. More specifically, we found that neutrophil recruitment and release of S100A8/A9 in the lungs activates the TLR4/RAGE signaling pathways, which in turn enhance systemic inflammation and subsequent cardiac dysfunction. Paradoxically, global deletion of S100A8/A9 did not improve but aggravated cardiac dysfunction and mortality likely due to uncontrolled bacterial burden in the lungs and heart. Our results indicate that P.a. infection induced release of S100A8/9 is double-edged, providing increased risk for cardiac dysfunction yet limiting P.a. growth. Author summary: Over 5 million people develop pneumonia annually in the United States and is the 8
th leading cause of death worldwide. Surprisingly, up to 30% of patients admitted to the hospital for community acquired pneumonia develop cardiovascular complications but the mechanisms are not clearly understood. Pseudomonas aeruginosa infection is very common in hospital settings and accounts for up to 20% of all cases of hospital-acquired pneumonia with a mortality rate of ~30%. P. aeruginosa infection and severe lung and systemic inflammation increases levels of S100A8/9 (calprotectin) in the blood stream. Systemic inflammation or dissemination of pathogens into heart tissue can induce cardiac inflammation, cardiomyocyte death and cardiac dysfunction. We found that P. aeruginosa infection increases infiltration of inflammatory immune cells in the heart, leading to arrhythmia and left ventricular dysfunction. Our study provides evidence that S100A8/9 provides protection against bacterial infection yet when its production is uncontrolled it activates host immune responses leading to severe cardiovascular complications. [ABSTRACT FROM AUTHOR]- Published
- 2023
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5. Development of a novel immunoFET technology‐based POC assay for detection of Leishmania donovani and Leishmania major.
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Yentur Doni, Nebiye, Bertani, Paul J., Volpedo, Greta, Saljoughian, Noushin, Varikuti, Sanjay, Matlashewski, Greg, Lu, Wu, and Satoskar, Abhay R.
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LEISHMANIA ,LEISHMANIA donovani ,LEISHMANIA major ,ALUMINUM gallium nitride ,FIELD-effect transistors ,GALLIUM nitride ,FREEZE-thaw cycles - Abstract
Leishmaniasis is considered as one of the 20 neglected tropical diseases. Current methods of leishmanial diagnosis depend on conventional laboratory‐based techniques, which are time‐consuming, costly and require special equipment and trained personnel. In this context, we aimed to provide an immuno field effect transistors (ImmunoFET) biosensor that matches the conventional standards for point‐of‐care (POC) monitoring and detection of Leishmania (L.) donovani/Leishmania major. Crude antigens prepared by repeated freeze thawing of L. donovani/L. major stationary phase promastigotes were used for ELISA and ImmunoFETs. Lesishmania‐specific antigens were serially diluted in 1× PBS from a concentration of 106–102 parasites/mL. A specific polyclonal antibody‐based sandwich ELISA was established for the detection of Leishmania antigens. An immunoFET technology‐based POC novel assay was constructed for the detection of Leishmania antigens. Interactions between antigen–antibody at the gate surface generate an electrical signal that can be measured by semiconductor field‐effect principles. Sensitivity was considered and measured as the change in current divided by the initial current. The final L. donovani/L. major crude antigen protein concentrations were measured as 1.50 mg/mL. Sandwich ELISA against the Leishmania 40S ribosomal protein detected Leishmania antigens could detect as few as 100 L. donovani/L. major parasites. An immunoFET biosensor was constructed based on the optimization of aluminium gallium nitride/gallium nitride (AlGaN/GaN) surface oxidation methods. The device surface was composed by an AlGaN/GaN wafer with a 23 nm AlGaN barrier layer, a 2 μm GaN layer on the silicon carbide (SiC) substrate for Leishmania binding, and coated with a specific antibody against the Leishmania 40S ribosomal protein, which was successfully detected at concentrations from 106 to 102 parasites/mL in 1× PBS. At the concentration of 104 parasites, the immunoFETs device sensitivities were 13% and 0.052% in the sub‐threshold regime and the saturation regime, respectively. Leishmania parasites were successfully detected by the ImmunoFET biosensor at a diluted concentration as low as 150 ng/mL. In this study, the developed ImmunoFET biosensor performed well. ImmunoFET biosensors can be used as an alternative diagnostic method to ELISA. Increasing the sensitivity and optimization of immuno‐FET biosensors might allow earlier and faster detection of leishmaniasis. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Immunological comparison of DNA vaccination using two delivery systems against canine leishmaniasis
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Shahbazi, Mehdi, Zahedifard, Farnaz, Saljoughian, Noushin, Doroud, Delaram, Jamshidi, Shahram, Mahdavi, Niousha, Shirian, Sadegh, Daneshbod, Yahya, Hamid Zarkesh-Esfahani, Sayyed, Papadopoulou, Barbara, and Rafati, Sima
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- 2015
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7. Psychological stress creates an immune suppressive environment in the lung that increases susceptibility of aged mice to Mycobacterium tuberculosis infection.
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Lafuse, William P., Qian Wu, Kumar, Naresh, Saljoughian, Noushin, Sunkum, Shrayes, Ahumada, Omar Santiagonunez, Turner, Joanne, and Rajaram, Murugesan V. S.
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MYCOBACTERIUM tuberculosis ,PSYCHOLOGICAL stress ,MYCOBACTERIAL diseases ,REGULATORY T cells ,PSYCHONEUROIMMUNOLOGY ,ALVEOLAR macrophages ,PERITONEAL macrophages - Abstract
Age is a major risk factor for chronic infections, including tuberculosis (TB). Elderly TB patients also suffer from elevated levels of psychological stress. It is not clear how psychological stress impacts immune response to Mycobacterium tuberculosis (M.tb). In this study, we used social disruption stress (SDR) to investigate effects of psychological stress in young and old mice. Unexpectedly, we found that SDR suppresses lung inflammation in old mice as evidenced by lower pro-inflammatory cytokine levels in bronchial lavage fluid and decreased cytokine mRNA expression by alveolar macrophages. To investigate effects of stress on M.tb infection, mice were subjected to SDR and then infected with M.tb. As previously reported, old mice were better at controlling infection at 30 days than young mice. This control was transient as CFUs at 60 days were higher in old control mice compared to young mice. Consistently, SDR significantly increased M. tb growth at 60 days in old mice compared to young mice. In addition, SDR in old mice resulted in accumulation of IL-10 mRNA and decreased IFN-g mRNA at 60 days. Also, confocal microscopy of lung sections from old SDR mice showed increased number of CD4 T cells which express LAG3 and CD49b, markers of IL-10 secreting regulatory T cells. Further, we also demonstrated that CD4 T cells from old SDR mice express IL-10. Thus, we conclude that psychological stress in old mice prior to infection, increases differentiation of IL-10 secreting T cells, which over time results in loss of control of the infection. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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8. CRISPR Gene Editing of Human Primary NK and T Cells for Cancer Immunotherapy.
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Elmas, Ezgi, Saljoughian, Noushin, de Souza Fernandes Pereira, Marcelo, Tullius, Brian P., Sorathia, Kinnari, Nakkula, Robin J., Lee, Dean A., and Naeimi Kararoudi, Meisam
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KILLER cells ,T cells ,GENOME editing ,CRISPRS ,CANCER cells - Abstract
Antitumor activity of immune cells such as T cells and NK cells has made them auspicious therapeutic regimens for adaptive cancer immunotherapy. Enhancing their cytotoxic effects against malignancies and overcoming their suppression in tumor microenvironment (TME) may improve their efficacy to treat cancers. Clustered, regularly interspaced short palindromic repeats (CRISPR) genome editing has become one of the most popular tools to enhance immune cell antitumor activity. In this review we highlight applications and practicability of CRISPR/Cas9 gene editing and engineering strategies for cancer immunotherapy. In addition, we have reviewed several approaches to study CRISPR off-target effects. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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9. Comparison of Protective Potency of DNA and Live Vaccines Expressing A2-CPA-CPB-CTE Antigens against Visceral Leishmaniasis in Syrian Hamster as Preliminary Study.
- Author
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TASLIMI, Yasaman, ZAHEDIFARD, Farnaz, TAHERI, Tahereh, DOROUD, Delaram, LATIF DIZAJI, Sakineh, SALJOUGHIAN, Noushin, and RAFATI, Sima
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GOLDEN hamster ,VISCERAL leishmaniasis ,CATIONIC lipids ,DNA vaccines ,HUMORAL immunity ,BODY burden - Abstract
Background: Visceral leishmaniasis is the most severe form of leishmaniasis caused by Leishmania (L.) donovani complex. Drug-resistant strains have been developed as a consequence of the current chemotherapeutic interventions, which has increased the need for advanced preventive and therapeutic strategies. A2-CPA-CPB
-CTE -recombinant strain of L. tarentolae, which is non-pathogenic to humans, was shown protective in live vaccine as well as its DNA vaccine counter-part in both murine and canine models. Methods: We evaluated the effectiveness of these DNA and live vaccination harboring A2-CPA-CPB-CTE in protecting hamsters against L. infantum infection using prime-boost regimens, namely DNA/DNA and Live/Live (n=9 hamsters per group). Cationic solid lipid nanoparticles (cSLN) were utilized as an adjuvant for DNA priming and electroporation for boosting DNA. At different time points post-challenge, parasite burden and body weight as well as humoral immune responses were measured. Results: Both immunization strategies partially protect hamsters against L. infantum challenge. This protective immunity is associated with remarkable decrease in parasite load in liver and spleen of vaccinated hamsters eight weeks after challenge compared to control group. Conclusion: Both test groups (DNA/DNA and Live/Live) elicited high levels of IgG2 and total IgG as humoral immune responses and lower level of parasite propagation in both liver and spleen. [ABSTRACT FROM AUTHOR]- Published
- 2020
10. Effect of Mycobacterium tuberculosis Enhancement of Macrophage P-Glycoprotein Expression and Activity on Intracellular Survival During Antituberculosis Drug Treatment.
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Wu, Qian, Hossfeld, Austin, Gerberick, Abigail, Saljoughian, Noushin, Tiwari, Charu, Mehra, Smriti, Ganesan, Latha Prabha, Wozniak, Daniel J, and Rajaram, Murugesan V S
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MYCOBACTERIUM tuberculosis ,P-glycoprotein ,MYCOBACTERIUM smegmatis ,HEAT shock factors - Abstract
Background: Tuberculosis is caused by Mycobacterium tuberculosis. Recent emergence of multidrug-resistant (MDR) tuberculosis strains seriously threatens tuberculosis control and prevention. However, the role of macrophage multidrug resistance gene MDR1 on intracellular M. tuberculosis survival during antituberculosis drug treatment is not known.Methods: We used the human monocyte-derived macrophages to study the role of M. tuberculosis in regulation of MDR1 and drug resistance.Results: We discovered that M. tuberculosis infection increases the expression of macrophage MDR1 to extrude various chemical substances, including tuberculosis drugs, resulting in enhanced survival of intracellular M. tuberculosis. The pathway of regulation involves M. tuberculosis infection of macrophages and suppression of heat shock factor 1, a transcriptional regulator of MDR1 through the up-regulation of miR-431. Notably, nonpathogenic Mycobacterium smegmatis did not increase MDR1 expression, indicating active secretion of virulence factors in pathogenic M. tuberculosis contributing to this phenotype. Finally, inhibition of MDR1 improves antibiotic-mediated killing of M. tuberculosis.Conclusion: We report a novel finding that M. tuberculosis up-regulates MDR1 during infection, which limits the exposure of M. tuberculosis to sublethal concentrations of antimicrobials. This condition promotes M. tuberculosis survival and potentially enhances the emergence of resistant variants. [ABSTRACT FROM AUTHOR]- Published
- 2019
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11. Potent ITK/BTK Inhibitor Ibrutinib Is Effective for the Treatment of Experimental Visceral Leishmaniasis Caused by Leishmania donovani.
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Varikuti, Sanjay, Volpedo, Greta, Saljoughian, Noushin, Hamza, Omar M, Halsey, Gregory, Ryan, Nathan M, Sedmak, Bren E, Seidler, Gabriella R, Papenfuss, Tracey L, Oghumu, Steve, and Satoskar, Abhay R
- Abstract
Background New drugs are needed for leishmaniasis because current treatments such as pentavalent antimonials are toxic and require prolonged administration, leading to poor patient compliance. Ibrutinib is an anticancer drug known to modulate T-helper type 1 (Th1)/Th2 responses and has the potential to regulate immunity against infectious disease. Methods In this study, we evaluated the efficacy of oral ibrutinib as a host-targeted treatment for visceral leishmaniasis (VL) caused by Leishmania donovani using an experimental mouse model. Results We found that oral ibrutinib was significantly more effective than the pentavalent antimonial sodium stibogluconate (70 mg/kg) for the treatment of VL caused by L. donovani. Ibrutinib treatment increased the number of interleukin 4– and interferon γ–producing natural killer T cells in the liver and spleen and enhanced granuloma formation in the liver. Further, ibrutinib treatment reduced the influx of Ly6C
hi inflammatory monocytes, which mediate susceptibility to L. donovani. Finally, ibrutinib treatment was associated with the increased production of the cytokines interferon γ, tumor necrosis factor α, interleukin 4, and interleukin 13 in the liver and spleen, which are associated with protection against L. donovani. Conclusions Our findings show that oral ibrutinib is highly effective for the treatment of VL caused by L. donovani and mediates its antileishmanial activity by promoting host immunity. Therefore, ibrutinib could be a novel host-targeted drug for the treatment of VL. [ABSTRACT FROM AUTHOR]- Published
- 2019
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12. Design of mannosylated oral amphotericin B nanoformulation: efficacy and safety in visceral leishmaniasis.
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Sarwar, Hafiz Shoaib, Sohail, Muhammad Farhan, Saljoughian, Noushin, Rehman, Anees Ur, Akhtar, Sohail, Nadhman, Akhtar, Yasinzai, Masoom, Gendelman, Howard E., Satoskar, Abhay R., and Shahnaz, Gul
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AMPHOTERICIN B ,ORAL drug administration ,DRUG efficacy ,MEDICATION safety ,VISCERAL leishmaniasis - Abstract
The aim of this study was to evaluate mannose-anchored thiolated chitosan (MTC) based nanocarriers (NCs) for enhanced permeability, improved oral bioavailability and anti-parasitic potential of amphotericin B (AmB). Transgenic Leishmania donovani parasites expressing red fluorescent protein DsRed2 and imaging-flow cytometry was used to investigate parasitic burdens inside bone marrow-derived macrophages ex vivo. Cytokine estimation revealed that MTC nanocarriers activated the macrophages to impart an explicit immune response by higher production of TNF-α and IL-12 as compared to control. Cells treated with MTC NCs showed a significantly higher magnitude of nitrite and propidium iodide (PI) fluorescence intensity in contrast to cells treated with AmB. Concerning to apparent permeability coefficient (P
app ) results, the MTC NCs formulation displayed more specific permeation across the Caco-2 cell monolayer as compared to AmB. The half-life of MTC NCs was about 3.3-fold persistent than oral AmB used as positive control. Also, t oral bioavailability of AmB was increased to 6.4-fold for MTC NCs compared to AmB for positive control. Acute oral evaluation indicated that MTC NCs were significantly less toxic compared to the AmB. Based on these findings, MTC NCs seems to be promising for significant oral absorption and improved oral bioavailability of AmB in leishmaniasis chemotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2018
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13. Topical treatment with nanoliposomal Amphotericin B reduces early lesion growth but fails to induce cure in an experimental model of cutaneous leishmaniasis caused by Leishmania mexicana.
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Varikuti, Sanjay, Saljoughian, Noushin, Pioso, Marissa S., Sedmak, Bren E, Satoskar, Abhay R., Oghumu, Steve, and Khamesipour, Ali
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LEISHMANIA mexicana , *AMPHOTERICIN B - Abstract
Leishmania mexicana infection causes localized skin lesions that can lead to tissue damage and permanent disfigurement if not resolved. Currently, recommended treatments include intravenous administration of Amphotericin B, which is undesirable due to the associated cost and patient burden related to receiving regular injections. In this study, we evaluated the effect of topical treatment with a nanoliposomal formulation of Amphotericin B that is penetrable to the skin (SinaAmphoLeish 0.4%) in mice infected with L. mexicana by using ulcerated (BALB/c) and non-ulcerated (129SVE) models. BALB/c mice received a 4 week treatment following ulcerated lesion development, while 129SVE mice received a 10 week treatment beginning at week 5 post-infection. Although mice from both models showed comparable susceptibility to L. mexicana infection after topical treatment with SinaAmphoLeish relative to controls, 129SVE mice displayed a transient decrease in lesion sizes which eventually became similar to control mice. On other hand this treatment resulted in no reduction in the lesion sizes in BALB/c mice. 129SVE treated mice exhibited greater IFN-γ, IL-4, and IL-10 cytokine levels and higher T-cell proliferation in re-stimulated draining lymph node cells. BALB/c mice showed no differences in cytokine responses between treated and control mice. These findings indicate that topical SinaAmphoLeish treatment is not likely to be effective in the treatment of cutaneous leishmaniasis caused by L. mexicana. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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14. Live vaccination tactics: possible approaches for controlling visceral leishmaniasis.
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Saljoughian, Noushin, Taheri, Tahareh, and Rafati, Sima
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VACCINATION ,LEISHMANIASIS ,INFECTION ,ANTIGENS ,PATHOGENIC microorganisms - Abstract
Vaccination with durable immunity is the main goal and fundamental to control leishmaniasis. To stimulate the immune response, small numbers of parasites are necessary to be presented in the mammalian host. Similar to natural course of infection, strategy using live vaccine is more attractive when compared to other approaches. Live vaccines present the whole spectrum of antigens to the host immune system in the absence of any adjuvant. Leishmanization was the first effort for live vaccination and currently used in a few countries against cutaneous leishmaniasis, in spite of their obstacle and safety. Then, live attenuated vaccines developed with similar promotion of creating long-term immunity in the host with lower side effect. Different examples of attenuated strains are generated through long-term in vitro culturing, culturing under drug pressure, temperature sensitivity, and chemical mutagenesis, but none is safe enough and their revision to virulent form is possible. Attenuation through genetic manipulation and disruption of virulence factors or essential enzymes for intracellular survival are among other approaches that are intensively under study. Other designs to develop live vaccines for visceral form of leishmaniasis are utilization of live avirulent microorganisms such as Lactococcus lactis, Salmonella enterica, and Leishmania tarentolae called as vectored vaccine. Apparently, these vaccines are intrinsically safer and can harbor the candidate antigens in their genome through different genetic manipulation and create more potential to control Leishmania parasite as an intracellular pathogen. [ABSTRACT FROM AUTHOR]
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- 2014
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15. Development of Novel Prime-Boost Strategies Based on a Tri-Gene Fusion Recombinant L. tarentolae Vaccine against Experimental Murine Visceral Leishmaniasis.
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Saljoughian, Noushin, Taheri, Tahereh, Zahedifard, Farnaz, Taslimi, Yasaman, Doustdari, Fatemeh, Bolhassani, Azam, Doroud, Delaram, Azizi, Hiva, Heidari, Kazem, Vasei, Mohammad, Namvar Asl, Nabiollah, Papadopoulou, Barbara, and Rafati, Sima
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CATIONIC lipids , *VISCERAL leishmaniasis , *HUMORAL immunity , *LEISHMANIA mexicana , *CYSTEINE proteinases , *VECTOR-borne diseases , *OPPORTUNISTIC infections , *COMBINED vaccines - Abstract
Visceral leishmaniasis (VL) is a vector-borne disease affecting humans and domestic animals that constitutes a serious public health problem in many countries. Although many antigens have been examined so far as protein- or DNA-based vaccines, none of them conferred complete long-term protection. The use of the lizard non-pathogenic to humans Leishmania (L.) tarentolae species as a live vaccine vector to deliver specific Leishmania antigens is a recent approach that needs to be explored further. In this study, we evaluated the effectiveness of live vaccination in protecting BALB/c mice against L. infantum infection using prime-boost regimens, namely Live/Live and DNA/Live. As a live vaccine, we used recombinant L. tarentolae expressing the L. donovani A2 antigen along with cysteine proteinases (CPA and CPB without its unusual C-terminal extension (CPB-CTE)) as a tri-fusion gene. For DNA priming, the tri-fusion gene was encoded in pcDNA formulated with cationic solid lipid nanoparticles (cSLN) acting as an adjuvant. At different time points post-challenge, parasite burden and histopathological changes as well as humoral and cellular immune responses were assessed. Our results showed that immunization with both prime-boost A2-CPA-CPB-CTE-recombinant L. tarentolae protects BALB/c mice against L. infantum challenge. This protective immunity is associated with a Th1-type immune response due to high levels of IFN-γ production prior and after challenge and with lower levels of IL-10 production after challenge, leading to a significantly higher IFN-γ/IL-10 ratio compared to the control groups. Moreover, this immunization elicited high IgG1 and IgG2a humoral immune responses. Protection in mice was also correlated with a high nitric oxide production and low parasite burden. Altogether, these results indicate the promise of the A2-CPA-CPB-CTE-recombinant L. tarentolae as a safe live vaccine candidate against VL. Author Summary: Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and has emerged as an opportunistic infection in HIV-1 infected patients in many parts of the world. Drug-resistant forms have developed so emergence and increased the need for advanced preventive strategies. Using live avirulent organisms as a vaccine has been proven to be more effective than other regimens. The lizard protozoan parasite Leishmania tarentolae is considered as nonpathogenic to humans. In our previous work, a recombinant L. tarentolae strain expressing the amastigote-specific L. donovani A2 antigen as a vaccine candidate elicited protection against L. infantum challenge in mice. Furthermore, combinations of CPA/CPB cysteine proteinases were more protective against visceral and cutaneous Leishmania infections than the individual forms. Herein, we used DNA/Live and Live/Live prime-boost vaccination strategies against visceral leishmaniasis in BALB/c mice consisting of the A2-CPA-CPB-CTE tri-fusion genes formulated with cationic solid lipid nanoparticles and a recombinant L. tarentolae expressing the tri-fusion. Assessments of cytokine production, humoral responses, parasite burden and histopathological studies support that the recombinant L. tarentolae A2-CPA-CPB-CTE candidate vaccine elicits a protective response against visceral leishmaniasis in mice and represents an important step forward in the development of new vaccine combinations against Leishmania infections. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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16. The Potent ITK/BTK Inhibitor Ibrutinib Is Effective for the Treatment of Experimental Visceral Leishmaniasis Caused by Leishmania donovani.
- Author
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Varikuti, Sanjay, Volpedo, Greta, Saljoughian, Noushin, Hamza, Omar M, Halsey, Gregory, Ryan, Nathan M, Sedmak, Bren E, Seidler, Gabriella R, Papenfuss, Tracey L, Oghumu, Steve, and Satoskar, Abhay R
- Subjects
ANIMAL experimentation ,BIOLOGICAL models ,CELLULAR immunity ,COMPARATIVE studies ,CYTOKINES ,HETEROCYCLIC compounds ,IMMUNOLOGICAL adjuvants ,LEISHMANIA ,LEISHMANIASIS ,RESEARCH methodology ,MEDICAL cooperation ,MICE ,ORAL drug administration ,RESEARCH ,EVALUATION research ,TREATMENT effectiveness ,PROTEIN kinase inhibitors - Abstract
Background: New drugs are needed for leishmaniasis because current treatments such as pentavalent antimonials are toxic and require prolonged administration, leading to poor patient compliance. Ibrutinib is an anticancer drug known to modulate T-helper type 1 (Th1)/Th2 responses and has the potential to regulate immunity against infectious disease.Methods: In this study, we evaluated the efficacy of oral ibrutinib as a host-targeted treatment for visceral leishmaniasis (VL) caused by Leishmania donovani using an experimental mouse model.Results: We found that oral ibrutinib was significantly more effective than the pentavalent antimonial sodium stibogluconate (70 mg/kg) for the treatment of VL caused by L. donovani. Ibrutinib treatment increased the number of interleukin 4- and interferon γ-producing natural killer T cells in the liver and spleen and enhanced granuloma formation in the liver. Further, ibrutinib treatment reduced the influx of Ly6Chi inflammatory monocytes, which mediate susceptibility to L. donovani. Finally, ibrutinib treatment was associated with the increased production of the cytokines interferon γ, tumor necrosis factor α, interleukin 4, and interleukin 13 in the liver and spleen, which are associated with protection against L. donovani.Conclusions: Our findings show that oral ibrutinib is highly effective for the treatment of VL caused by L. donovani and mediates its antileishmanial activity by promoting host immunity. Therefore, ibrutinib could be a novel host-targeted drug for the treatment of VL. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
17. Cutting Edge: CXCR3 Escapes X Chromosome Inactivation in T Cells during Infection: Potential Implications for Sex Differences in Immune Responses.
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Oghumu, Steve, Varikuti, Sanjay, Stock, James C., Volpedo, Greta, Saljoughian, Noushin, Terrazas, Cesar A., and Satoskar, Abhay R.
- Subjects
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X chromosome , *T cells , *IMMUNE response , *LEISHMANIA mexicana , *GENDER - Abstract
CXCR3, an X-linked gene, is subject to X chromosome inactivation (XCI), but it is unclear whether CXCR3 escapes XCI in immune cells. We determined whether CXCR3 escapes XCI in vivo, evaluated the contribution of allelic CXCR3 expression to the phenotypic properties of T cells during experimental infection with Leishmania, and examined the potential implications to sex differences in immune responses. We used a bicistronic CXCR3 dual-reporter mouse, with each CXCR3 allele linked to a green or red fluorescent reporter without affecting endogenous CXCR3 expression. Our results show that CXCR3 escapes XCI, biallelic CXCR3-expressing T cells produce more CXCR3 protein than monoallelic CXCR3-expressing cells, and biallelic CXCR3-expressing T cells produce more IFN-γ, IL-2, and CD69 compared with T cells that express CXCR3 from one allele during Leishmania mexicana infection. These results demonstrate that XCI escape by CXCR3 potentially contributes to the sex-associated bias observed during infection. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
18. Comparison of Protective Potency of DNA and Live Vaccines Expressing A2-CPA-CPB -CTE Antigens against Visceral Leishmaniasis in Syrian Hamster as Preliminary Study.
- Author
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Taslimi Y, Zahedifard F, Taheri T, Doroud D, Latif Dizaji S, Saljoughian N, and Rafati S
- Abstract
Background: Visceral leishmaniasis is the most severe form of leishmaniasis caused by Leishmania ( L. ) donovani complex. Drug-resistant strains have been developed as a consequence of the current chemotherapeutic interventions, which has increased the need for advanced preventive and therapeutic strategies. A2-CPA-CPB
-CTE -recombinant strain of L. tarentolae , which is non-pathogenic to humans, was shown protective in live vaccine as well as its DNA vaccine counterpart in both murine and canine models., Methods: We evaluated the effectiveness of these DNA and live vaccination harboring A2-CPA-CPB-CTE in protecting hamsters against L. infantum infection using prime-boost regimens, namely DNA/DNA and Live/Live (n=9 hamsters per group). Cationic solid lipid nanoparticles (cSLN) were utilized as an adjuvant for DNA priming and electroporation for boosting DNA. At different time points post-challenge, parasite burden and body weight as well as humoral immune responses were measured., Results: Both immunization strategies partially protect hamsters against L. infantum challenge. This protective immunity is associated with remarkable decrease in parasite load in liver and spleen of vaccinated hamsters eight weeks after challenge compared to control group., Conclusion: Both test groups (DNA/DNA and Live/Live) elicited high levels of IgG2 and total IgG as humoral immune responses and lower level of parasite propagation in both liver and spleen., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest., (Copyright© Iranian Society of Parasitology & Tehran University of Medical Sciences.)- Published
- 2020
- Full Text
- View/download PDF
19. The Potent ITK/BTK Inhibitor Ibrutinib Is Effective for the Treatment of Experimental Visceral Leishmaniasis Caused by Leishmania donovani.
- Author
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Varikuti S, Volpedo G, Saljoughian N, Hamza OM, Halsey G, Ryan NM, Sedmak BE, Seidler GR, Papenfuss TL, Oghumu S, and Satoskar AR
- Subjects
- Adenine analogs & derivatives, Administration, Oral, Animals, Cytokines metabolism, Disease Models, Animal, Female, Immunity, Cellular, Mice, Mice, Inbred BALB C, Piperidines, Treatment Outcome, Immunologic Factors administration & dosage, Leishmania donovani growth & development, Leishmaniasis, Visceral drug therapy, Protein Kinase Inhibitors administration & dosage, Pyrazoles administration & dosage, Pyrimidines administration & dosage
- Abstract
Background: New drugs are needed for leishmaniasis because current treatments such as pentavalent antimonials are toxic and require prolonged administration, leading to poor patient compliance. Ibrutinib is an anticancer drug known to modulate T-helper type 1 (Th1)/Th2 responses and has the potential to regulate immunity against infectious disease., Methods: In this study, we evaluated the efficacy of oral ibrutinib as a host-targeted treatment for visceral leishmaniasis (VL) caused by Leishmania donovani using an experimental mouse model., Results: We found that oral ibrutinib was significantly more effective than the pentavalent antimonial sodium stibogluconate (70 mg/kg) for the treatment of VL caused by L. donovani. Ibrutinib treatment increased the number of interleukin 4- and interferon γ-producing natural killer T cells in the liver and spleen and enhanced granuloma formation in the liver. Further, ibrutinib treatment reduced the influx of Ly6Chi inflammatory monocytes, which mediate susceptibility to L. donovani. Finally, ibrutinib treatment was associated with the increased production of the cytokines interferon γ, tumor necrosis factor α, interleukin 4, and interleukin 13 in the liver and spleen, which are associated with protection against L. donovani., Conclusions: Our findings show that oral ibrutinib is highly effective for the treatment of VL caused by L. donovani and mediates its antileishmanial activity by promoting host immunity. Therefore, ibrutinib could be a novel host-targeted drug for the treatment of VL.
- Published
- 2019
- Full Text
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20. Pentalinonsterol, a Constituent of Pentalinon andrieuxii, Possesses Potent Immunomodulatory Activity and Primes T Cell Immune Responses.
- Author
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Oghumu S, Varikuti S, Saljoughian N, Terrazas C, Huntsman AC, Parinandi NL, Fuchs JR, Kinghorn AD, and Satoskar AR
- Subjects
- Adjuvants, Immunologic chemistry, Animals, Cytokines biosynthesis, Mice, Mice, Inbred BALB C, Molecular Structure, NF-kappa B metabolism, Ovalbumin chemistry, Sterols chemistry, T-Lymphocytes, Tumor Necrosis Factor-alpha chemistry, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha metabolism, Adjuvants, Immunologic pharmacology, Apocynaceae chemistry, Cytokines immunology, Interleukin-12 immunology, NF-kappa B immunology, Ovalbumin immunology, Sterols isolation & purification, Sterols pharmacology, Tumor Necrosis Factor-alpha pharmacology
- Abstract
The use of natural products as adjuvants has emerged as a promising approach for the development of effective vaccine formulations. Pentalinonsterol (PEN) is a recently isolated compound from the roots of Pentalinon andrieuxii and has been shown to possess antileishmanial activity against Leishmania spp. The objective of this study was to examine the immunomodulatory properties of PEN and evaluate its potential as an adjuvant. Macrophages and bone-marrow-derived dendritic cells (BMDCs) were stimulated with PEN and tested for gene expression, cytokine production, and their ability to activate T cells in vitro. PEN was also evaluated for its ability to generate antigen-specific Th1 and Th2 responses in vivo, following ovalbumin (OVA) immunization using PEN as an adjuvant. The results obtained demonstrate that PEN enhances the expression of NF-κB and AP1 transcription factors, promotes gene expression of Tnfα, Il6, Nos2, and Arg1, and upregulates MHCII, CD80, and CD86 in macrophages. PEN also enhanced IL-12 production in BMDCs and promoted BMDC-mediated production of IFN-γ by T cells. Further, mice immunized with OVA and PEN showed enhanced antigen-specific Th1 and Th2 cytokines in their splenocytes and lymph node cells, as well as increased levels of IgG1 and IgG2 in their sera. Taken together, this study demonstrates that PEN is a potent immunomodulatory compound and potentially can be used as an adjuvant for vaccine development against infectious diseases.
- Published
- 2017
- Full Text
- View/download PDF
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