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Frontiers in Immunology 2022Hookworms infect more that 400 million people and cause significant socio-economic burden on endemic countries. The lack of efficient vaccines and the emergence of...
Hookworms infect more that 400 million people and cause significant socio-economic burden on endemic countries. The lack of efficient vaccines and the emergence of anthelminthic drug resistance are of major concern. Free-living hookworm larvae infect their hosts the skin and live as adult worms in the small intestine where they feed on host tissue and blood. Excretory/secretory (E/S) products, released by helminths as they migrate through their host, are thought to play a key role in facilitating infection and successful establishment of parasitism. However, E/S products can also elicit protective immune responses that might be harnessed for vaccine development. By performing Western blots with serum of (Nb) infected mice as a model for human hookworm infection, we identified a largely overlapping set of IgG1- and IgE-reactive antigens in E/S from infective L3 stage larvae. Mass spectrometry analysis led to the identification of a new protein family with 6 paralogues in the Nb genome which we termed Nb-LSA1 for " larval secreted protein 1". The recombinantly expressed 17 kDa family member Nb-LSA1a was recognized by antibodies in the serum of Nb immune mice. Immunization of mice with Nb-LSA1a in alum elicited a strong IgG1 response but no detectable antigen-specific IgE. Most importantly, immunized mice were largely protected against a challenge Nb infection. This effect was dependent on the presence of basophils and occurred before the parasites reached the intestine. Therefore, basophils appear to play a critical role for rapid control of infection with L3 stage larvae in mice immunized with a single secreted larval protein. A better understanding of basophil-mediated protective immunity and identification of potent larval antigens of human hookworms could help to develop promising vaccination strategies.
Topics: Ancylostomatoidea; Animals; Antigens, Helminth; Basophils; Humans; Immunoglobulin E; Immunoglobulin G; Larva; Mice; Nippostrongylus
PubMed: 36091065
DOI: 10.3389/fimmu.2022.979491 -
Journal of Leukocyte Biology Dec 2008Most of our understanding of the development and phenotype of alternatively activated macrophages (AAMs) has been obtained from studies investigating the response of...
Most of our understanding of the development and phenotype of alternatively activated macrophages (AAMs) has been obtained from studies investigating the response of bone marrow- and peritoneal-derived cells to IL-4 or IL-13 stimulation. Comparatively little is known about the development of AAMs in the lungs, and how the complex signals associated with pulmonary inflammation influence the AAM phenotype. Here, we use Nippostrongylus brasiliensis to initiate AAM development and define the dynamics of surface molecules, gene expression, and cell function of macrophages isolated from lung tissue at different times postinfection (PI). Initially, lung macrophages take on a foamy phenotype, up-regulate MHC and costimulatory molecules, express reduced levels of TNF and IL-12, and undergo proliferation. Cells isolated between days 8 and 15 PI adopt a dense, granular phenotype and exhibit reduced levels of costimulatory molecules and elevated levels of programmed death ligand-1 (PDL-1) and PDL-2 and an increase in IL-10 expression. Functionally, AAMs isolated on days 13-15 PI demonstrate an enhanced capacity to take up and sequester antigen. However, these same cells did not mediate antigen-specific T cell proliferation and dampened the proliferation of CD3/CD28-activated CD4+ T cells. These data indicate that the alternative activation of macrophages in the lungs, although initiated by IL-4/IL-13, is a dynamic process that is likely to be influenced by other immune and nonimmune factors in the pulmonary environment.
Topics: Animals; Bronchoalveolar Lavage Fluid; CD28 Antigens; CD3 Complex; CD4 Antigens; CD4-Positive T-Lymphocytes; Cell Proliferation; Flow Cytometry; Gene Expression Profiling; Immunity, Innate; Immunoenzyme Techniques; Interleukin-10; Interleukin-12; Lymphocyte Activation; Macrophage Activation; Macrophages, Alveolar; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Monocytes; Nippostrongylus; Oligonucleotide Array Sequence Analysis; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Strongylida Infections; T-Lymphocytes
PubMed: 18719016
DOI: 10.1189/jlb.0308199 -
The Korean Journal of Parasitology Feb 2018Some small mammals occur as household pests and harbour a number of parasites that could be of public health importance. This study profiled the helminth and protozoan...
Some small mammals occur as household pests and harbour a number of parasites that could be of public health importance. This study profiled the helminth and protozoan parasites in trapped small mammals within and around human dwelling places (houses) located across 4 major towns (Auchi, Benin, Ekpoma, and Uromi) and environs in Edo state, Nigeria. Six genera ( sp., sp., , , sp., and sp.) were identified from 502 trapped small mammals. Overall, (71.9%) and (20.1%) were the most frequently trapped. In total, on examination of blood, gastrointestinal contents, and brain tissues, 12 helminth taxa ( sp., sp., sp., sp., sp., sp., and sp.), and 6 protozoan parasites ( sp., sp., sp., sp., and ) were isolated. Most prevalent helminths with relatively heavy mean intensity were sp. and , while , and were the most prevalent protozoan parasites. Generally, intrinsic factors like sex and age had marginal influence on the rate and burden of infection in and . Although the infection rate and prevalence of zoonotic parasites were low, they were largely recovered in rodents from Ekpoma. This study elucidates the public health implication of the presence of zoonotic parasites in these small mammals.
Topics: Animals; Blood; Brain; Female; Gastrointestinal Tract; Helminths; Housing; Male; Mice; Nigeria; Parasites; Parasitic Diseases, Animal; Prevalence; Rats; Rodent Diseases; Zoonoses
PubMed: 29529857
DOI: 10.3347/kjp.2018.56.1.93 -
ELife Aug 2022Th2 cells provide effector functions in type 2 immune responses to helminths and allergens. Despite knowledge about molecular mechanisms of Th2 cell differentiation,...
Th2 cells provide effector functions in type 2 immune responses to helminths and allergens. Despite knowledge about molecular mechanisms of Th2 cell differentiation, there is little information on Th2 cell heterogeneity and clonal distribution between organs. To address this, we performed combined single-cell transcriptome and T-cell receptor (TCR) clonotype analysis on murine Th2 cells in mesenteric lymph nodes (MLNs) and lung after infection with (Nb) as a human hookworm infection model. We find organ-specific expression profiles, but also populations with conserved migration or effector/resident memory signatures that unexpectedly cluster with potentially regulatory cells. A substantial MLN subpopulation with an interferon response signature suggests a role for interferon signaling in Th2 differentiation or diversification. Further RNA-inferred developmental directions indicate proliferation as a hub for differentiation decisions. Although the TCR repertoire is highly heterogeneous, we identified expanded clones and CDR3 motifs. Clonal relatedness between distant organs confirmed effective exchange of Th2 effector cells, although locally expanded clones dominated the response. We further cloned an Nb-specific TCR from an expanded clone in the lung effector cluster and describe surface markers that distinguish transcriptionally defined clusters. These results provide insights in Th2 cell subset diversity and clonal relatedness in distant organs.
Topics: Animals; Cells, Cultured; Humans; Interferons; Mice; Nippostrongylus; Receptors, Antigen, T-Cell; Th2 Cells
PubMed: 35950748
DOI: 10.7554/eLife.74183 -
Nature Communications Jun 2016Th2-eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2-eosinophil responses in counteracting...
Th2-eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2-eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis.
Topics: Animals; Arthritis; Biomarkers; Cell Count; Eosinophilia; Eosinophils; Humans; Inflammation; Interleukin-13; Interleukin-4; Joints; Macrophages; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Nippostrongylus; STAT6 Transcription Factor; Strongylida Infections; Th2 Cells; Tumor Necrosis Factor-alpha
PubMed: 27273006
DOI: 10.1038/ncomms11596 -
Immunology Jun 2016Cellular and molecular investigation of parasitic helminth infections has greatly accelerated the understanding of type 2 immune responses. However, there remains... (Review)
Review
Cellular and molecular investigation of parasitic helminth infections has greatly accelerated the understanding of type 2 immune responses. However, there remains considerable debate regarding the specific leucocytes that kill parasites and whether these mechanisms are distinct from those responsible for tissue repair. Herein, we chronicle discoveries over the past decade highlighting current paradigms in type 2 immunity with a particular emphasis upon how CD4(+) T helper type 2 cells, type 2 innate lymphoid cells and alternatively activated macrophages coordinately control helminth-induced parasitism. Primarily, this review will draw from studies of the murine nematode parasite Nippostrongylus brasiliensis, which bears important similarities to the human hookworms Ancylostoma duodenale and Necator americanus. Given that one or more hookworm species currently infect millions of individuals across the globe, we propose that vaccine and/or pharmaceutical-based cure strategies targeting these affected human populations should incorporate the conceptual advances outlined herein.
Topics: Ancylostoma; Ancylostomiasis; Animals; Antigens, Helminth; Cell Differentiation; Complement Pathway, Alternative; Humans; Immunity, Innate; Macrophage Activation; Macrophages; Necator americanus; Necatoriasis; Nippostrongylus; Strongylida Infections; Th2 Cells
PubMed: 26928141
DOI: 10.1111/imm.12601 -
Journal of Nematology Jan 1986Chemical signals released by one organism and perceived by another organism are classified as semiochemicals. Semiochemicals are divided into pheromones, which elicit...
Chemical signals released by one organism and perceived by another organism are classified as semiochemicals. Semiochemicals are divided into pheromones, which elicit intraspecific responses, and allelochemics, which elicit interspecific responses. Nematodes utilize and (or) recognize signals from both categories of semiochemicals. The existence of pheromones, specifically sex and aggregation pheromones, has been demonstrated in numerous plant and animal parasitic and free-living nematodes. Sex pheromones have been isolated and purified from Nippostrongylus brasiliensis and Heterodera glycines, and epidietic pheromones have been shown to be responsible for initiation of dauer juvenile formation in Caenorhabditis elegans. Allelochemics cause interspecific responses in insects and other invertebrates but are only postulated to occur in nematodes. Food-finding behavior of nematodes is almost certainly caused by host-released allelochemic messengers. Understanding of the behavioral responses and the chemical messengers that affect bioregulation of various processes in nematodes will influence future management strategies.
PubMed: 19294130
DOI: No ID Found -
Cannabis and Cannabinoid Research Jun 2021Over 1 billion humans carry infectious helminth parasites that can lead to chronic comorbidities such as anemia and growth retardation in children. Helminths induce a...
Over 1 billion humans carry infectious helminth parasites that can lead to chronic comorbidities such as anemia and growth retardation in children. Helminths induce a T-helper type 2 (Th2) immune response in the host and can cause severe tissue damage and fibrosis if chronic. We recently reported that mice infected with the soil-transmitted helminth, , displayed elevated levels of endocannabinoids (eCBs) in the lung and intestine. eCBs are lipid-signaling molecules that control inflammation; however, their function in infection is not well defined. A combination of pharmacological approaches and genetic mouse models was used to investigate roles for the eCB system in inflammatory responses and lung injury in mice during parasitic infection with . Hemorrhaging of lung tissue in mice infected with was exacerbated by inhibiting peripheral cannabinoid receptor subtype-1 (CBRs) with the peripherally restricted CBR antagonist, AM6545. In addition, these mice exhibited an increase in nonfunctional alveolar space and prolonged airway eosinophilia compared to vehicle-treated infected mice. In contrast to mice treated with AM6545, infected cannabinoid receptor subtype-2-null mice (Cnr2) did not display any changes in these parameters compared to wild-type mice. Roles for the eCB system in Th2 immune responses are not well understood; however, increases in its activity in response to infection suggest an immunomodulatory role. Moreover, these findings suggest a role for eCB signaling at CBRs but not cannabinoid receptor subtypes-2 in the resolution of Th2 inflammatory responses, which become host destructive over time.
Topics: Animals; Endocannabinoids; Eosinophilia; Hemorrhage; Lung; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Nippostrongylus; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Strongylida Infections; Th2 Cells
PubMed: 33998896
DOI: 10.1089/can.2020.0167 -
The Journal of Allergy and Clinical... Jul 2021Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the...
BACKGROUND
Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent.
OBJECTIVE
We sought to investigate the role of CYLD in Treg cell function and T2 cell immune responses under steady-state conditions and during helminth infection.
METHODS
Foxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays.
RESULTS
Treg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation.
CONCLUSIONS
Our findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into T2 cell-like effector cells, which potentiates parasite resistance.
Topics: Animals; Cell Plasticity; Deubiquitinating Enzyme CYLD; Helminthiasis; Helminths; Immunity; Inflammation; Interleukin-4; MAP Kinase Kinase Kinases; Mice; Mice, Knockout; NF-kappa B; Nippostrongylus; Signal Transduction; T-Lymphocytes, Regulatory; Th2 Cells; Up-Regulation
PubMed: 33309741
DOI: 10.1016/j.jaci.2020.10.042 -
Proceedings of the National Academy of... Aug 2009Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine, mainly expressed by epithelial cells, and key to the development of allergic responses. The...
Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine, mainly expressed by epithelial cells, and key to the development of allergic responses. The well-documented involvement of TSLP in allergy has led to the conviction that TSLP promotes the development of inflammatory Th2 cell responses. However, we now report that the interaction of TSLP with its receptor (TSLPR) has no functional impact on the development of protective Th2 immune responses after infection with 2 helminth pathogens, Heligmosomoides polygyrus and Nippostrongylus brasiliensis. Mice deficient in the TSLP binding chain of the TSLPR (TSLPR(-/-)) exhibited normal Th2 cell differentiation, protective immunity and memory responses against these two distinct rodent helminths. In contrast TSLP was found to be necessary for the development of protective Th2 responses upon infection with the helminth Trichuris muris (T. muris). TSLP inhibited IL-12p40 production in response to T. muris infection, and treatment of TSLPR(-/-) animals with neutralizing anti-IL-12p40 monoclonal antibody (mAb) was able to reverse susceptibility and attenuate IFN-gamma production. We additionally demonstrated that excretory-secretory (ES) products from H. polygyrus and N. brasiliensis, but not T. muris, were capable of directly suppressing dendritic cell (DC) production of IL-12p40, thus bypassing the need for TSLP. Taken together, our data show that the primary function of TSLP is to directly suppress IL-12 secretion, thus supporting Th2 immune responses.
Topics: Animals; Antibodies, Monoclonal; Cytokines; Dendritic Cells; Immune System; Interferon-gamma; Interleukin-12 Subunit p40; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Models, Biological; Nippostrongylus; Strongylida Infections; Th2 Cells; Trichuriasis; Trichuris; Thymic Stromal Lymphopoietin
PubMed: 19666528
DOI: 10.1073/pnas.0906367106