scholarly journals Transgenic Expression of CXCR3 on T Cells Enhances Susceptibility to Cutaneous Leishmania major Infection by Inhibiting Monocyte Maturation and Promoting a Th2 Response

2014 ◽  
Vol 83 (1) ◽  
pp. 67-76 ◽  
Author(s):  
Steve Oghumu ◽  
James C. Stock ◽  
Sanjay Varikuti ◽  
Ran Dong ◽  
Cesar Terrazas ◽  
...  
Keyword(s):  
T Cells ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Critical Role ◽  
Sand Fly ◽  
Interleukin 4 ◽  
Th2 Response ◽  
Content Type ◽  
Transgenic Expression ◽  
Inflammatory Monocytes

Cutaneous leishmaniasis, caused mainly byLeishmania major, an obligate intracellular parasite, is a disfiguring disease characterized by large skin lesions and is transmitted by a sand fly vector. We previously showed that the chemokine receptor CXCR3 plays a critical role in mediating resistance to cutaneous leishmaniasis caused byLeishmania major. Furthermore, T cells fromL. major-susceptible BALB/c but notL. major-resistant C57BL/6 mice fail to efficiently upregulate CXCR3 upon activation. We therefore examined whether transgenic expression of CXCR3 on T cells would enhance resistance toL. majorinfection in susceptible BALB/c mice. We generated BALB/c and C57BL/6 transgenic mice, which constitutively overexpressed CXCR3 under a CD2 promoter, and then examined the outcomes withL. majorinfection. Contrary to our hypothesis, transgenic expression of CXCR3 (CXCR3Tg) on T cells of BALB/c mice resulted in increased lesion sizes and parasite burdens compared to wild-type (WT) littermates afterL. majorinfection. Restimulated lymph node cells fromL. major-infected BALB/c-CXCR3Tgmice produced more interleukin-4 (IL-4) and IL-10 and less gamma interferon (IFN-γ). Cells in draining lymph nodes from BALB/c-CXCR3Tgmice showed enhanced Th2 and reduced Th1 cell accumulation associated with increased neutrophils and inflammatory monocytes. However, monocytes displayed an immature phenotype which correlated with increased parasite burdens. Interestingly, transgenic expression of CXCR3 on T cells did not impact the outcome ofL. majorinfection in C57BL/6 mice, which mounted a predominantly Th1 response and spontaneously resolved their infection similar to WT littermates. Our findings demonstrate that transgenic expression of CXCR3 on T cells increases susceptibility of BALB/c mice toL. major.

scholarly journals Deletion of Interleukin-4 Receptor Alpha-Responsive Keratinocytes in BALB/c Mice Does Not Alter Susceptibility to Cutaneous Leishmaniasis

2018 ◽  
Vol 86 (12) ◽  
Author(s):  
Melissa Govender ◽  
Ramona Hurdayal ◽  
Berenice Martinez-Salazar ◽  
Kaya Gqada ◽  
Shandre Pillay ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Interleukin 4 ◽  
High Dose ◽  
Littermate Control ◽  
Content Type ◽  
Receptor Alpha ◽  
Th2 Immune Response

ABSTRACTThe skin microenvironment at the site of infection plays a role in the early events that determine protective T helper 1/type 1 immune responses during cutaneous leishmaniasis (CL) infection. During CL in nonhealing BALB/c mice, early interleukin-4 (IL-4) can instruct dendritic cells for protective Th1 immunity. Additionally, keratinocytes, which are the principal cell type in the skin epidermis, have been shown to secrete IL-4 early afterLeishmania majorinfection. Here, we investigated whether IL-4/IL-13 signaling via the common IL-4 receptor alpha chain (IL-4Rα) on keratinocytes contributes to susceptibility during experimental CL. To address this, keratinocyte-specific IL-4Rα-deficient (KRT14creIL-4Rα−/lox) mice on a BALB/c genetic background were generated by gene targeting and site-specific recombination (Cre/loxP) under the control of the keratinocyte-specifickrt14locus. Following high-dose infection withL. majorIL-81 and LV39 promastigotes subcutaneously in the footpad, footpad swelling, parasite burden, IFN-γ/IL-4/IL-13 cytokine production, and type 1 and type 2 antibody responses were similar between KRT14creIL-4Rα−/loxand littermate control IL-4Rα−/loxBALB/c mice. An intradermal infection with low-doseL. majorIL-81 and LV39 promastigotes in the ear showed results in infected KRT14creIL-4Rα−/loxBALB/c mice similar to those of littermate control IL-4Rα−/loxBALB/c mice, with the exception of a significant decrease observed in parasite burden only at the site of LV39 infection in the ear. Collectively, our results show that autocrine and paracrine signaling of IL-4/IL-13 through the IL-4Rα chain on keratinocytes does not influence the establishment of a nonhealing Th2 immune response in BALB/c mice duringL. majorinfection.

scholarly journals T-Cell Responses to Immunodominant LACK Antigen Do Not Play a Critical Role in Determining Susceptibility of BALB/c Mice toLeishmania mexicana

2001 ◽  
Vol 69 (1) ◽  
pp. 617-621 ◽  
Author(s):  
Fabiola Aguilar Torrentera ◽  
Nicolas Glaichenhaus ◽  
Jon D. Laman ◽  
Yves Carlier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leishmania Major ◽  
Critical Role ◽  
Interleukin 4 ◽  
Hybridoma Cells ◽  
Leishmania Mexicana ◽  
Wild Type ◽  
Cell Responses ◽  
Early Production

ABSTRACT Although BALB/c mice develop lesions when infected withLeishmania mexicana, the mechanisms which are responsible for susceptibility to this parasite have not been elucidated. In contrast, susceptibility of BALB/c mice to Leishmania majorhas been shown to depend on the early production of interleukin-4 (IL-4) by T cells which react to the parasitic LACK antigen. Here, we demonstrate that the lesions induced by L. mexicana are delayed compared to those induced by L. major but rapidly develop at later time points. Interestingly, while LACK-tolerant BALB/c-derived IE-LACK transgenic mice were resistant to L. major, they were susceptible to L. mexicana and developed lesions similar to those observed in wild-type BALB/c mice. The latter result was observed despite the fact that (i) LACK was expressed by L. mexicana, (ii) splenocytes from BALB/c mice were able to stimulate LACK-specific T-cell hybridoma cells when incubated with live L. mexicana promastigotes, and (iii) LACK-specific T cells contributed to IL-4 production in L. mexicana-infected BALB/c mice. Thus, in contrast to what was observed for L. major-infected mice, LACK-specific T cells do not play a critical role in determining susceptibility to L. mexicana. Although BALB/c mice are susceptible to both L. major and L. mexicana, the mechanisms which are responsible for susceptibility to these parasites are likely to be different.

scholarly journals Repeated Exposure to Aspergillus fumigatus Conidia Results in CD4+T Cell-Dependent and -Independent Pulmonary Arterial Remodeling in a Mixed Th1/Th2/Th17 Microenvironment That Requires Interleukin-4 (IL-4) and IL-10

2011 ◽  
Vol 80 (1) ◽  
pp. 388-397 ◽  
Author(s):  
Andrew B. Shreiner ◽  
Benjamin J. Murdock ◽  
Amir A. Sadighi Akha ◽  
Nicole R. Falkowski ◽  
Paul J. Christensen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Aspergillus Fumigatus ◽  
Pulmonary Arteries ◽  
Interleukin 4 ◽  
Arterial Remodeling ◽  
Th2 Response ◽  
Content Type ◽  
Inflammatory Microenvironment ◽  
Pulmonary Arterial

ABSTRACTPulmonary arterial remodeling is a pathological process seen in a number of clinical disease states, driven by inflammatory cells and mediators in the remodeled artery microenvironment. In murine models, Th2 cell-mediated immune responses to inhaled antigens, such as purifiedAspergillusallergen, have been reported to induce remodeling of pulmonary arteries. We have previously shown that repeated intranasal exposure of healthy C57BL/6 mice to viable, restingAspergillus fumigatusconidia leads to the development of chronic pulmonary inflammation and the coevolution of Th1, Th2, and Th17 responses in the lungs. Our objective was to determine whether repeated intranasal exposure toAspergillusconidia would induce pulmonary arterial remodeling in this mixed Th inflammatory microenvironment. Using weekly intranasal conidial challenges, mice developed robust pulmonary arterial remodeling after eight exposures (but not after two or four). The process was partially mediated by CD4+T cells and by interleukin-4 (IL-4) production, did not require eosinophils, and was independent of gamma interferon (IFN-γ) and IL-17. Furthermore, remodeling could occur even in the presence of strong Th1 and Th17 responses. Rather than serving an anti-inflammatory function, IL-10 was required for the development of the Th2 response toA. fumigatusconidia. However, in contrast to previous studies of pulmonary arterial remodeling driven by theA. fumigatusallergen, viable conidia also stimulated pulmonary arterial remodeling in the absence of CD4+T cells. Remodeling was completely abrogated in IL-10−/−mice, suggesting that a second, CD4+T cell-independent, IL-10-dependent pathway was also driving pulmonary arterial remodeling in response to repeated conidial exposure.

scholarly journals Antileishmanial Effects of Synthetic EhPIb Analogs Derived from the Entamoeba histolytica Lipopeptidephosphoglycan

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Helena Fehling ◽  
Siew Ling Choy ◽  
Frederic Ting ◽  
Dirk Landschulze ◽  
Hannah Bernin ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Entamoeba Histolytica ◽  
Murine Model ◽  
Leishmania Major ◽  
Interleukin 4 ◽  
Intestinal Protozoan ◽  
Cutaneous Lesions ◽  
Content Type ◽  
Arginase 1

ABSTRACT With an estimated number of new cases annually of approximately 1.4 million, leishmaniasis belongs to the most important parasitic diseases in the world. Nevertheless, existing drugs against leishmaniasis in general have several drawbacks that urgently necessitate new drug development. A glycolipid molecule of the intestinal protozoan parasite Entamoeba histolytica and its synthetic analogs previously showed considerable immunotherapeutic effects against Leishmania major infection. Here, we designed and synthesized a series of new immunostimulatory compounds derived from the phosphatidylinositol b anchor of Entamoeba histolytica (EhPIb) subunit of the native compound and investigated their antileishmanial activity in vitro and in vivo in a murine model of cutaneous leishmaniasis. The new synthetic EhPIb analogs showed almost no toxicity in vitro. Treatment with the analogs significantly decreased the parasite load in murine and human macrophages in vitro. In addition, topical application of the EhPIb analog Eh-1 significantly reduced cutaneous lesions in the murine model, correlating with an increase in the production of selected Th1 cytokines. In addition, we could show in in vitro experiments that treatment with Eh-1 led to a decrease in mRNA expression of arginase-1 (Arg1) and interleukin 4 (IL-4), which are required by the parasites to circumvent their elimination by the immune response. The use of the host-targeting synthetic EhPIb compounds, either alone or in combination therapy with antiparasitic drugs, shows promise for treating cutaneous leishmaniasis and therefore might improve the current unsatisfactory status of chemotherapy against this infectious disease.

scholarly journals Identification of Two Distinct Subpopulations of Leishmania major-Specific T Helper 2 Cells

2002 ◽  
Vol 70 (10) ◽  
pp. 5512-5520 ◽  
Author(s):  
Pascale Kropf ◽  
Shanti Herath ◽  
Rita Tewari ◽  
Nelofer Syed ◽  
Roman Klemenz ◽  
...  
Keyword(s):  
T Cells ◽  
Leishmania Major ◽  
Lymphoid Organs ◽  
Cytokine Profile ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Th2 Response ◽  
T Helper 2

ABSTRACT It is widely accepted that a strong Th2 response is responsible for nonhealing Leishmania major infections in BALB/c mice. This Th2 response has been thoroughly documented by measuring the levels of Th2 cytokines produced by CD4+ T cells present in the lymphoid organs by enzyme-linked immunosorbent assay and PCR. However, the cytokine profile of L. major-specific Th2 cells has never been determined. In this study, we used the recently described Th2 marker T1/ST2 to characterize Th2 cells during the course of nonhealing L. major infection. We analyzed the intracellular cytokine profile of CD4+ T1/ST2+ T cells and showed that they clearly displayed a Th2 phenotype, as they expressed interleukin 4 (IL-4), IL-10, and IL-5. In addition, we detected another population of Th2 cells among the CD4+ T1/ST2− T cells that expressed IL-4 and IL-10 but excluded IL-5. In summary, we show here that two type 2 subpopulations are present in the lymphoid organs of L. major-infected BALB/c mice; Th2 cells from both subsets expressed IL-4 and IL-10, but they could be distinguished by their expression of IL-5 and T1/ST2.

scholarly journals A Listeria monocytogenes-Based Vaccine That Secretes Sand Fly Salivary Protein LJM11 Confers Long-Term Protection against Vector-Transmitted Leishmania major

2014 ◽  
Vol 82 (7) ◽  
pp. 2736-2745 ◽  
Author(s):  
Delbert S. Abi Abdallah ◽  
Alan Pavinski Bitar ◽  
Fabiano Oliveira ◽  
Claudio Meneses ◽  
Justin J. Park ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Salivary Protein ◽  
Sand Fly ◽  
Sand Flies ◽  
Content Type ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACTCutaneous leishmaniasis is a sand fly-transmitted disease characterized by skin ulcers that carry significant scarring and social stigmatization. Over the past years, there has been cumulative evidence that immunity to specific sand fly salivary proteins confers a significant level of protection against leishmaniasis. In this study, we used an attenuated strain ofListeria monocytogenesas a vaccine expression system for LJM11, a sand fly salivary protein identified as a good vaccine candidate. We observed that mice were best protected against an intradermal needle challenge withLeishmania majorand sand fly saliva when vaccinated intravenously. However, this protection was short-lived. Importantly, groups of vaccinated mice were protected long term when challenged with infected sand flies. Protection correlated with smaller lesion size, fewer scars, and better parasite control between 2 and 6 weeks postchallenge compared to the control group of mice vaccinated with the parentL. monocytogenesstrain not expressing LJM11. Moreover, protection correlated with high numbers of CD4+, gamma interferon-positive (IFN-γ+), tumor necrosis factor alpha-positive/negative (TNF-α+/−), interleukin-10-negative (IL-10−) cells and low numbers of CD4+IFN-γ+/−TNF-α−IL-10+T cells at 2 weeks postchallenge. Overall, our data indicate that delivery of LJM11 byListeriais a promising vaccination strategy against cutaneous leishmaniasis inducing long-term protection against ulcer formation following a natural challenge with infected sand flies.

scholarly journals Establishment of Chronic Typhoid Infection in a Mouse Carriage Model Involves a Type 2 Immune Shift and T and B Cell Recruitment to the Gallbladder

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Juan F. González ◽  
Jonathan Kurtz ◽  
David L. Bauer ◽  
Regan Hitt ◽  
James Fitch ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Response ◽  
Salmonella Enterica ◽  
Systemic Disease ◽  
Interleukin 4 ◽  
Th2 Response ◽  
Content Type ◽  
Chronic Carriage ◽  
Anti Inflammatory

ABSTRACT Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S. Typhi), is a life-threatening systemic disease responsible for significant morbidity and mortality worldwide. Three to 5% of individuals infected with S. Typhi become chronic carriers due to bacterial persistence in the gallbladder. We have demonstrated that Salmonella forms biofilms on gallstones to establish gallbladder carriage. However, an in-depth molecular understanding of chronic carriage in the gallbladder, from the perspective of both the pathogen and host, is poorly defined. To examine the dynamics of the gallbladder in response to Salmonella infection, we performed transcriptional profiling in the mouse gallbladder at early (7 days) and chronic (21 days) time points. Transcriptome sequencing (RNA-Seq) revealed a shift from a Th1 proinflammatory response at 7 days postinfection (dpi) toward an anti-inflammatory Th2 response by 21 dpi, characterized by increased levels of immunoglobulins and the Th2 master transcriptional regulator, GATA3. Additionally, bioinformatic analysis predicted the upstream regulation of characteristic Th2 markers, including interleukin-4 (IL-4) and Stat6. Immunohistochemistry and fluorescence-activated cell sorter (FACS) analysis confirmed a significant increase in lymphocytes, including T and B cells, at 21 dpi in mice with gallstones. Interestingly, the levels of Salmonella-specific CD4 T cells were 10-fold higher in the gallbladder of mice with gallstones at 21 dpi. We speculate that the biofilm state allows Salmonella to resist the initial onslaught of the Th1 inflammatory response, while yet undefined events influence a switch in the host immunity toward a more permissive type 2 response, enabling the establishment of chronic infection. IMPORTANCE The existence of chronic typhoid carriers has been in the public eye for over 100 years in part because of the publicity around Typhoid Mary. Additionally, it has been known for decades that the gallbladder is the main site of persistence and recently that gallstones play a key role. Despite this, very little is known about the physiological conditions that allow Salmonella enterica serovar Typhi to persist in the gallbladder. In this study, we analyze the transcriptional profile of the gallbladder in a mouse model of chronic carriage. We found a shift from an early proinflammatory immune response toward a later anti-inflammatory response, which could explain the stalemate that allows Salmonella persistence. Interestingly, we found a 10-fold increase in the number of Salmonella-specific T cells in mice with gallstones. This work moves us closer to understanding the mechanistic basis of chronic carriage, with a goal toward eradication of the disease.

scholarly journals Prediction of IL4 Inducing Peptides

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Sandeep Kumar Dhanda ◽  
Sudheer Gupta ◽  
Pooja Vir ◽  
G. P. S. Raghava
Keyword(s):  
Mhc Class Ii ◽  
Critical Role ◽  
Interleukin 4 ◽  
Th2 Response ◽  
Data Set ◽  
T Helper 2 ◽  
Cell Responses ◽  
Antibody Class ◽  
First Time ◽  
Motif Information

The secretion of Interleukin-4 (IL4) is the characteristic of T-helper 2 responses. IL4 is a cytokine produced by CD4+ T cells in response to helminthes and other extracellular parasites. It has a critical role in guiding antibody class switching, hematopoiesis and inflammation, and the development of appropriate effector T-cell responses. In this study, it is the first time an attempt has been made to understand whether it is possible to predict IL4 inducing peptides. The data set used in this study comprises 904 experimentally validated IL4 inducing and 742 noninducing MHC class II binders. Our analysis revealed that certain types of residues are preferred at certain positions in IL4 inducing peptides. It was also observed that IL4 inducing and noninducing epitopes differ in compositional and motif pattern. Based on our analysis we developed classification models where the hybrid method of amino acid pairs and motif information performed the best with maximum accuracy of 75.76% and MCC of 0.51. These results indicate that it is possible to predict IL4 inducing peptides with reasonable precession. These models would be useful in designing the peptides that may induce desired Th2 response.

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

2019 ◽  
Vol 87 (8) ◽  
Author(s):  
Sanjay Varikuti ◽  
Gayathri Natarajan ◽  
Greta Volpedo ◽  
Bhawana Singh ◽  
Omar Hamza ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Interleukin 4 ◽  
Cytokine Signaling ◽  
T Helper 1 ◽  
Content Type ◽  
Inflammatory Monocytes ◽  
Organ Specific ◽  
Src Homology ◽  
Ifn Γ ◽  
Src Homology 2 Domain

ABSTRACT 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 Leishmania donovani 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. Leishmania 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 IFN-γ, iNOS, and TNF-α gene transcripts in their livers than WT mice, indicating that distinct organ-specific antiparasitic mechanisms were involved in control of L. donovani infection in miR155KO mice. Throughout the course of infection, organs of miR155KO mice showed significantly more PDL1-expressing Ly6Chi inflammatory monocytes than WT mice. Conversely, blockade of Ly6Chi 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 L. donovani but is not essential for infection resolution.

Sign in / Sign up

Export Citation Format

Share Document