Publications by authors named "Sanjay Varikuti"

52 Publications

Scavenger Receptor BI Attenuates IL-17A-dependent Neutrophilic Inflammation in Asthma.

Am J Respir Cell Mol Biol 2021 Mar 1. Epub 2021 Mar 1.

East Carolina University, 3627, Greenville, North Carolina, United States.

Asthma is a common respiratory disease currently affecting more than 300 million worldwide and is characterized by airway inflammation, hyperreactivity, and remodeling. It is a heterogeneous disease consisting of corticosteroid-sensitive Th2-driven eosinophilic and corticosteroid-resistant Th17-driven neutrophilic phenotypes. One pathway recently described to regulate asthma pathogenesis is cholesterol trafficking. Scavenger receptors, in particular scavenger receptor class B type I (SR-BI), are known to direct cellular cholesterol uptake and efflux. We recently defined SR-BI functions in pulmonary host defense, however, the function of SR-BI in asthma pathogenesis is unknown. To elucidate the role of SR-BI in allergic asthma, SR-BI sufficient (SR-BI+/+) and deficient (SR-BI-/-) mice were sensitized (days 0, 7) and then challenged (days 14, 15, 16) with HDM (house dust mite) by oropharyngeal aspiration. Airway inflammation and cytokine production were quantified on day 17. When compared to SR-BI+/+ mice, HDM-challenged SR-BI-/- mice had increased bronchoalveolar lavage (BAL) neutrophils and pulmonary IL-17A production. This augmented IL-17A production in SR-BI-/- mice originated from a non-T cell source including neutrophils and alveolar macrophages. Given that SR-BI regulates adrenal steroid hormone production, we tested if the changes in SR-BI-/- mice were glucocorticoid-dependent. Indeed, SR-BI-/- mice were adrenally insufficient during HDM challenge and corticosterone replacement decreased pulmonary neutrophilia and IL-17A production in SR-BI-/- mice. Taken together, these data indicate that SR-BI dampens pulmonary neutrophilic inflammation and IL-17A production in allergic asthma at least in part by maintaining adrenal function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2020-0007OCDOI Listing
March 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 Feb 2. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2021.01.012DOI 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.20517/2574-1209.2020.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575144PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaccine.2020.06.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788512PMC
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2020.05.029DOI Listing
July 2020

The IL-33/ST2 Axis in Immune Responses Against Parasitic Disease: Potential Therapeutic Applications.

Front Cell Infect Microbiol 2020 17;10:153. Epub 2020 Apr 17.

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

Parasitic infections pose a wide and varying threat globally, impacting over 25% of the global population with many more at risk of infection. These infections are comprised of, but not limited to, toxoplasmosis, malaria, leishmaniasis and any one of a wide variety of helminthic infections. While a great deal is understood about the adaptive immune response to each of these parasites, there remains a need to further elucidate the early innate immune response. Interleukin-33 is being revealed as one of the earliest players in the cytokine milieu responding to parasitic invasion, and as such has been given the name "alarmin." A nuclear cytokine, interleukin-33 is housed primarily within epithelial and fibroblastic tissues and is released upon cellular damage or death. Evidence has shown that interleukin-33 seems to play a crucial role in priming the immune system toward a strong T helper type 2 immune response, necessary in the clearance of some parasites, while disease exacerbating in the context of others. With the possibility of being a double-edged sword, a great deal remains to be seen in how interleukin-33 and its receptor ST2 are involved in the immune response different parasites elicit, and how those parasites may manipulate or evade this host mechanism. In this review article we compile the current cutting-edge research into the interleukin-33 response to toxoplasmosis, malaria, leishmania, and helminthic infection. Furthermore, we provide insight into directions interleukin-33 research may take in the future, potential immunotherapeutic applications of interleukin-33 modulation and how a better clarity of early innate immune system responses involving interleukin-33/ST2 signaling may be applied in development of much needed treatment options against parasitic invaders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2020.00153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180392PMC
April 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.03095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974475PMC
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366342PMC
March 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4155/fmc-2018-0439DOI Listing
August 2019

Cutting Edge: CXCR3 Escapes X Chromosome Inactivation in T Cells during Infection: Potential Implications for Sex Differences in Immune Responses.

J Immunol 2019 08 28;203(4):789-794. Epub 2019 Jun 28.

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

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 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 infection. These results demonstrate that XCI escape by CXCR3 potentially contributes to the sex-associated bias observed during infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1800931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684832PMC
August 2019

MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection.

Infect Immun 2019 08 23;87(8). Epub 2019 Jul 23.

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

CD4 T helper 1 (Th1) cells producing interferon gamma (IFN-γ) are critical for the resolution of visceral leishmaniasis (VL). MicroRNA 155 (miR155) promotes CD4 Th1 responses and IFN-γ production by targeting suppressor of cytokine signaling-1 (SOCS1) and Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP-1) and therefore could play a role in the resolution of VL. To determine the role of miR155 in VL, we monitored the course of infection in miR155 knockout (miR155KO) and wild-type (WT) C57BL/6 mice. miR155KO mice displayed significantly higher liver and spleen parasite loads than WT controls and showed impaired hepatic granuloma formation. However, parasite growth eventually declined in miR155KO mice, suggesting the induction of a compensatory miR155-independent antileishmanial pathway. antigen-stimulated splenocytes from miR155KO mice produced significantly lower levels of Th1-associated IFN-γ than controls. Interestingly, at later time points, levels of Th2-associated interleukin-4 (IL-4) and IL-10 were also lower in miR155KO splenocyte supernatants than in WT mice. On the other hand, miR155KO mice displayed significantly higher levels of , , and gene transcripts in their livers than WT mice, indicating that distinct organ-specific antiparasitic mechanisms were involved in control of infection in miR155KO mice. Throughout the course of infection, organs of miR155KO mice showed significantly more PDL1-expressing Ly6C inflammatory monocytes than WT mice. Conversely, blockade of Ly6C inflammatory monocyte recruitment in miR155KO mice significantly reduced parasitic loads, indicating that these cells contributed to disease susceptibility. In conclusion, we found that miR155 contributes to the control of but is not essential for infection resolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00307-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652779PMC
August 2019

Mannosylated thiolated paromomycin-loaded PLGA nanoparticles for the oral therapy of visceral leishmaniasis.

Nanomedicine (Lond) 2019 02 28;14(4):387-406. Epub 2019 Jan 28.

Department of Pharmacy, Quaid-I-Azam University, Islamabad 44000, Pakistan.

Aim: The present study evaluates the efficacy of paromomycin (PM)-loaded mannosylated thiomeric nanoparticles for the targeted delivery to pathological organs for the oral therapy of visceral leishmaniasis.

Materials & Methods: Mannosylated thiolated chitosan (MTC)-coated PM-loaded PLGA nanoparticles (MTC-PLGA-PM) were synthesized and evaluated for morphology, drug release, permeation enhancing and antileishmanial potential.

Results: MTC-PLGA-PM were spherical in shape with a size of 391.24 ± 6.91 nm and an encapsulation efficiency of 67.16 ± 14%. Ex vivo permeation indicated 12.73-fold higher permeation of PM with MTC-PLGA-PM against the free PM. Flow cytometry indicated enhanced macrophage uptake and parasite killing in Leishmania donovani infected macrophage model. In vitro antileishmanial activity indicated 36-fold lower IC for MTC-PLGA-PM as compared with PM. The in vivo studies indicated 3.6-fold reduced parasitic burden in the L. donovani infected BALB/c mice model.

Conclusion: The results encouraged the concept of MTC-PLGA-PM nanoparticles as promising strategy for visceral leishmaniasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/nnm-2018-0038DOI Listing
February 2019

Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites.

Front Microbiol 2018 30;9:2655. Epub 2018 Nov 30.

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

The neglected tropical diseases (NTDs) caused by protozoan parasites are responsible for significant morbidity and mortality worldwide. Current treatments using anti-parasitic drugs are toxic and prolonged with poor patient compliance. In addition, emergence of drug-resistant parasites is increasing worldwide. Hence, there is a need for safer and better therapeutics for these infections. Host-directed therapy using drugs that target host pathways required for pathogen survival or its clearance is a promising approach for treating infections. This review will give a summary of the current status and advances of host-targeted therapies for treating NTDs caused by protozoa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2018.02655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284052PMC
November 2018

The Potent ITK/BTK Inhibitor Ibrutinib Is Effective for the Treatment of Experimental Visceral Leishmaniasis Caused by Leishmania donovani.

J Infect Dis 2019 01;219(4):599-608

Department of Pathology, Ohio State University Medical Center, Ohio State University, Columbus.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiy552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784510PMC
January 2019

Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation.

Oncogene 2018 08 3;37(32):4428-4442. Epub 2018 May 3.

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

The chemokine CXCL12 has been shown to regulate breast tumor growth, however, its mechanism in initiating distant metastasis is not well understood. Here, we generated a novel conditional allele of Cxcl12 in mice and used a fibroblast-specific Cre transgene along with various mammary tumor models to evaluate CXCL12 function in the breast cancer metastasis. Ablation of CXCL12 in stromal fibroblasts of mice significantly delayed the time to tumor onset and inhibited distant metastasis in different mouse models. Elucidation of mechanisms using in vitro and in vivo model systems revealed that CXCL12 enhances tumor cell intravasation by increasing vascular permeability and expansion of a leaky tumor vasculature. Furthermore, our studies revealed CXCL12 enhances permeability by recruiting endothelial precursor cells and decreasing endothelial tight junction and adherence junction proteins. High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels confers poorer patient survival compared to individual protein level. However, no correlation was observed between epithelial CXCL12 and patient survival or blood vessel density. Our findings describe the novel interactions between fibroblasts-derived CXCL12 and endothelial cells in facilitating tumor cell intrvasation, leading to distant metastasis. Overall, our studies indicate that cross-talk between fibroblast-derived CXCL12 and endothelial cells could be used as novel biomarker and strategy for developing tumor microenvironment based therapies against aggressive and metastatic breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-018-0263-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063845PMC
August 2018

Inhibitors of elastase stimulate murine B lymphocyte differentiation into IgG- and IgA-producing cells.

Eur J Immunol 2018 08 5;48(8):1295-1301. Epub 2018 Jul 5.

Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.

It is well established that dendritic cells and macrophages play a role in antigen presentation to B and T cells and in shaping B and T cell responses via cytokines they produce. We have previously reported that depletion of neutrophils improves the production of mucosal IgA after sublingual immunization with Bacillus anthracis edema toxin as adjuvant. These past studies also demonstrated that an inverse correlation exists between the number of neutrophils and production of IgA by B cells. Using specific inhibitors of elastase, we addressed whether the elastase activity of neutrophil could be the factor that interferes with production of IgA and possibly other immunoglobulin isotypes. We found that murine splenocytes and mesenteric lymph node cells cultured for 5 days in the presence of neutrophil elastase inhibitors secreted higher levels of IgG and IgA than cells cultured in the absence of inhibitors. The effect of the inhibitors was dose-dependent and was consistent with increased frequency of CD138 cells expressing IgG or IgA. Finally, neutrophil elastase inhibitors increased transcription of mRNA for AID, IL-10, BAFF and APRIL, factors involved in B cell differentiation. These findings identify inhibitors of elastase as potential adjuvants for increasing production of antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/eji.201747264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447050PMC
August 2018

IL-27 gene therapy induces depletion of Tregs and enhances the efficacy of cancer immunotherapy.

JCI Insight 2018 04 5;3(7). Epub 2018 Apr 5.

Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Tumor-induced expansion of Tregs is a significant obstacle to cancer immunotherapy. However, traditional approaches to deplete Tregs are often inefficient, provoking autoimmunity. We show here that administration of IL-27-expressing recombinant adeno-associated virus (AAV-IL-27) significantly inhibits tumor growth and enhances T cell responses in tumors. Strikingly, we found that AAV-IL-27 treatment causes rapid depletion of Tregs in peripheral blood, lymphoid organs, and - most pronouncedly - tumor microenvironment. AAV-IL-27-mediated Treg depletion is dependent on IL-27 receptor and Stat1 in Tregs and is a combined result of CD25 downregulation in Tregs and inhibition of IL-2 production by T cells. In combination with a GM-CSF vaccine, AAV-IL-27 treatment not only induced nearly complete tumor rejection, but also resulted in amplified neoantigen-specific T cell responses. AAV-IL-27 also dramatically increased the efficacy of anti-PD-1 therapy, presumably due to induction of PD-L1 in T cells and depletion of Tregs. Importantly, AAV-IL-27 therapy did not induce significant adverse events, partially due to its induction of IL-10. In a plasmacytoma mouse model, we found that IL-10 was required for AAV-IL-27-mediated tumor rejection. Thus, our study demonstrates the potential of AAV-IL-27 as an independent cancer therapeutic and as an efficient adjuvant for cancer immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.98745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928864PMC
April 2018

STAT1 gene deficient mice develop accelerated breast cancer growth and metastasis which is reduced by IL-17 blockade.

Oncoimmunology 2017;6(11):e1361088. Epub 2017 Aug 14.

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

Signal transducer and activator of transcription 1 (STAT1) mediates interferon gamma signaling which activates the expression of various genes related to apoptosis, inflammation, cell cycle and angiogenesis. Several experimental and clinical studies have investigated the role of STAT1 in primary tumor growth in breast cancer; however, its role in tumor metastasis remains to be determined. To determine the role of STAT1 in breast cancer metastasis, we analyzed growth and metastasis in WT or STAT1 mice orthotopically implanted with metastatic 4T1.2 cells. Primary tumor development was faster in STAT1 mice and these mice developed significantly bigger primary tumors and displayed more lung metastasis compared with WT counterparts. STAT1 mice showed elevated Ly6GCD11b granulocytic MDSC infiltration in their primary tumors and spleens with concomitant upregulation of and expression in tumors compared with WT counterparts. Blockade of IL-17A in primary tumor-bearing STAT1 mice suppressed accumulation of Ly6GCD11b cells and markedly reduced lung metastasis. These data show that STAT1 is an important suppressor of primary breast tumor growth and metastasis. Importantly, we found anti-IL-17 treatment can rescue STAT1 deficient animals from developing exacerbated metastasis to the lungs which could be important for immunotherapies for immunocompromised breast cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2017.1361088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674966PMC
August 2017

Ly6C inflammatory monocytes promote susceptibility to Leishmania donovani infection.

Sci Rep 2017 10 31;7(1):14693. Epub 2017 Oct 31.

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

Ly6C inflammatory monocytes (iMO) are critical for host defense against toxoplasmosis and malaria but their role in leishmaniasis is unclear. In this study, we report a detrimental role of Ly6C iMOs in visceral leishmaniasis (VL) caused by Leishmania donovani. We demonstrate that Ly6C iMOs are continuously recruited into the spleen and liver during L. donovani infection and they are preferential targets for the parasite. Using microarray-based gene expression profiling, we show that Ly6C iMOs isolated from the infected liver and spleen have distinct phenotypic and activation profiles. Furthermore, we demonstrate that blocking the recruitment of Ly6C iMOs into the liver and spleen during L. donovani infection using a CCR2 antagonist reduces the frequency of the pathogenic IFN-γ/IL10 dual producer CD4+ T cells in the spleen and leads to a significant reduction in parasite loads in the liver and spleen. Using STAT1-/- mice we show that STAT1 is critical for mediating the recruitment of Ly6C iMOs into organs during L. donovani infection, and adaptive transfer of wild type Ly6C iMOs into STAT1-/- recipients renders them susceptible to disease. Our findings reveal an unexpected pathogenic role for Ly6C iMOs in promoting parasite survival in VL and open the possibility of targeting this population for host-directed therapy during VL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-14935-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665970PMC
October 2017

Pentalinonsterol, a Constituent of Pentalinon andrieuxii, Possesses Potent Immunomodulatory Activity and Primes T Cell Immune Responses.

J Nat Prod 2017 09 6;80(9):2515-2523. Epub 2017 Sep 6.

College of Public Health, §College of Pharmacy, and ∥Department of Microbiology, The Ohio State University , Columbus, Ohio 43210, United States.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.7b00445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731641PMC
September 2017

Interleukin-27 signalling induces stem cell antigen-1 expression in T lymphocytes in vivo.

Immunology 2017 12 23;152(4):638-647. Epub 2017 Aug 23.

Department of Pathology and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.

Stem cell antigen-1 (Sca-1/Ly6A/E) is a cell surface glycoprotein that is often used as a biomarker for stem cells and cell stemness. However, it is not clear what factors can directly induce the expression of Sca-1/Ly6A/E in T lymphocytes in vivo, and if induction of Sca-1 is associated with T cell stemness. In this study, we show that interleukin-27 (IL-27), a member of the IL-12 family of cytokines, directly induces Sca-1 expression in T cells in vivo. We found that mice-deficient for IL-27 (either P28 or EBI3) or its signalling (IL-27Rα) had profound reduction of Sca-1 expression in naive (CD62L  CD44 ), memory (CD62L  CD44 ) and effector (CD62L  CD44 ) T cells. In contrast, in vivo delivery of IL-27 using adeno-associated viral vectors strongly induced the expression of Sca-1 in naive and memory/effector T-cell populations in an IL-27 receptor- or signal transducer and activator of transcription 1-dependent manner. Interestingly, IL-27-induced Sca-1 T cells do not express or up-regulate classic stem cell-associated genes such as Nanog, Oct4, Sox2 and Ctnnb1. However, IL-27-induced Sca-1 T cells had increased expression of effector/memory-associated transcription factor T-bet, Eomes and Blimp1. Hence, IL-27 signalling directly induces the expression of Sca-1/Ly6A/E expression in T cells. Direct expansion of Sca-1  CD62L  CD44 T memory stem cells may explain why IL-27 enhances T-cell memory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.12805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680066PMC
December 2017

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.

Acta Trop 2017 Sep 9;173:102-108. Epub 2017 Jun 9.

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

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actatropica.2017.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731240PMC
September 2017

STAT4 is required for the generation of Th1 and Th2, but not Th17 immune responses during monophosphoryl lipid A adjuvant activity.

Int Immunol 2016 11 30;28(11):565-570. Epub 2016 Aug 30.

Department of Pathology, Ohio State University Medical Center, 1645 Neil Avenue, Columbus, OH 43210, USA

STAT4 is critical for the production of IFN-γ during the generation of T1 immune responses. We investigated the role of STAT4 in mediating T1-inducing activity of a vaccine adjuvant monophosphoryl lipid A (MPL-A) using the standard antigen ovalbumin (OVA) in STAT4KO mice. Our results show that splenocytes from STAT4KO mice displayed lower OVA-specific T-cell proliferation and IL-2 production compared with wild-type (WT) mice. Further, IFN-γ production was diminished in STAT4KO-derived splenocytes but the levels of IL-12 and TNF-α were similar compared with WT mice. Interestingly, STAT4 deficiency also led to a decrease in IL-10 and T2 cytokines such as IL-4 and IL-13 upon MPL-A immunization, although IL-17 production was similar between WT- and STAT4KO-derived splenocytes. Our observations for defective T1 and T2 responses in STAT4KO mice were further supported by the low levels of T1-associated IgG2a and T2-associated IgG1 in the sera of these mice. Taken together, our results show that STAT4 plays a critical role in mediating both T1 and T2 responses upon immunization with MPL-A. Our study provides a better understanding of how MPL-A mediates T-cell activation which will be critical for future vaccine development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/intimm/dxw038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018885PMC
November 2016