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1.
Cell Rep ; 30(8): 2512-2525.e9, 2020 02 25.
Article in English | MEDLINE | ID: mdl-32101732

ABSTRACT

Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4+ T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4+ T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4+ T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients.


Subject(s)
Immunity/drug effects , Interferon Type I/pharmacology , Leishmaniasis, Visceral/immunology , Leishmaniasis, Visceral/parasitology , Parasites/immunology , Amphotericin B/pharmacology , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Cytokines/metabolism , Dendritic Cells/drug effects , Dendritic Cells/immunology , Epitopes , Humans , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/pharmacology , Mice, Inbred C57BL , Nitriles , Parasites/drug effects , Pyrazoles/pharmacology , Pyrimidines , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/metabolism , Signal Transduction/drug effects
2.
J Immunol ; 200(4): 1443-1456, 2018 02 15.
Article in English | MEDLINE | ID: mdl-29321276

ABSTRACT

Differentiation of CD4+ Th cells is critical for immunity to malaria. Several innate immune signaling pathways have been implicated in the detection of blood-stage Plasmodium parasites, yet their influence over Th cell immunity remains unclear. In this study, we used Plasmodium-reactive TCR transgenic CD4+ T cells, termed PbTII cells, during nonlethal P. chabaudi chabaudi AS and P. yoelii 17XNL infection in mice, to examine Th cell development in vivo. We found no role for caspase1/11, stimulator of IFN genes, or mitochondrial antiviral-signaling protein, and only modest roles for MyD88 and TRIF-dependent signaling in controlling PbTII cell expansion. In contrast, IFN regulatory factor 3 (IRF3) was important for supporting PbTII expansion, promoting Th1 over T follicular helper (Tfh) differentiation, and controlling parasites during the first week of infection. IRF3 was not required for early priming by conventional dendritic cells, but was essential for promoting CXCL9 and MHC class II expression by inflammatory monocytes that supported PbTII responses in the spleen. Thereafter, IRF3-deficiency boosted Tfh responses, germinal center B cell and memory B cell development, parasite-specific Ab production, and resolution of infection. We also noted a B cell-intrinsic role for IRF3 in regulating humoral immune responses. Thus, we revealed roles for IRF3 in balancing Th1- and Tfh-dependent immunity during nonlethal infection with blood-stage Plasmodium parasites.


Subject(s)
Cell Differentiation/immunology , Interferon Regulatory Factor-3/immunology , Malaria/immunology , T-Lymphocytes, Helper-Inducer/immunology , Th1 Cells/immunology , Animals , Female , Germinal Center/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Spleen/immunology
3.
Int J Parasitol ; 47(14): 913-922, 2017 12.
Article in English | MEDLINE | ID: mdl-28864033

ABSTRACT

The artemisinins are the first-line therapy for severe and uncomplicated malaria, since they cause rapid declines in parasitemia after treatment. Despite this, in vivo mechanisms underlying this rapid decline remain poorly characterised. The overall decline in parasitemia is the net effect of drug inhibition of parasites and host clearance, which competes against any ongoing parasite proliferation. Separating these mechanisms in vivo was not possible through measurements of total parasitemia alone. Therefore, we employed an adoptive transfer approach in which C57BL/6J mice were transfused with Plasmodium berghei ANKA strain-infected, fluorescent red blood cells, and subsequently drug-treated. This approach allowed us to distinguish between the initial drug-treated generation of parasites (Gen0), and their progeny (Gen1). Artesunate efficiently impaired maturation of Gen0 parasites, such that a sufficiently high dose completely arrested maturation after 6h of in vivo exposure. In addition, artesunate-affected parasites were cleared from circulation with a half-life of 6.7h. In vivo cell depletion studies using clodronate liposomes revealed an important role for host phagocytes in the removal of artesunate-affected parasites, particularly ring and trophozoite stages. Finally, we found that a second antimalarial drug, mefloquine, was less effective than artesunate at suppressing parasite maturation and driving host-mediated parasite clearance. Thus, we propose that in vivo artesunate treatment causes rapid decline in parasitemia by arresting parasite maturation and encouraging phagocyte-mediated clearance of parasitised RBCs.


Subject(s)
Antimalarials/pharmacology , Malaria/drug therapy , Parasitemia/drug therapy , Plasmodium berghei/drug effects , Plasmodium yoelii/drug effects , Adoptive Transfer , Animals , Antimalarials/administration & dosage , Artemisinins/administration & dosage , Artemisinins/pharmacology , Artesunate , Dose-Response Relationship, Drug , Erythrocytes/parasitology , Female , Flow Cytometry , Malaria/parasitology , Mefloquine/administration & dosage , Mefloquine/pharmacology , Mice , Mice, Inbred C57BL , Parasitemia/parasitology , Phagocytes , Plasmodium berghei/growth & development , Plasmodium yoelii/growth & development
4.
Proc Natl Acad Sci U S A ; 114(29): 7701-7706, 2017 07 18.
Article in English | MEDLINE | ID: mdl-28673996

ABSTRACT

Severe malaria and associated high parasite burdens occur more frequently in humans lacking robust adaptive immunity to Plasmodium falciparum Nevertheless, the host may partly control blood-stage parasite numbers while adaptive immunity is gradually established. Parasite control has typically been attributed to enhanced removal of parasites by the host, although in vivo quantification of this phenomenon remains challenging. We used a unique in vivo approach to determine the fate of a single cohort of semisynchronous, Plasmodium berghei ANKA- or Plasmodium yoelii 17XNL-parasitized red blood cells (pRBCs) after transfusion into naive or acutely infected mice. As previously shown, acutely infected mice, with ongoing splenic and systemic inflammatory responses, controlled parasite population growth more effectively than naive controls. Surprisingly, however, this was not associated with accelerated removal of pRBCs from circulation. Instead, transfused pRBCs remained in circulation longer in acutely infected mice. Flow cytometric assessment and mathematical modeling of intraerythrocytic parasite development revealed an unexpected and substantial slowing of parasite maturation in acutely infected mice, extending the life cycle from 24 h to 40 h. Importantly, impaired parasite maturation was the major contributor to control of parasite growth in acutely infected mice. Moreover, by performing the same experiments in rag1-/- mice, which lack T and B cells and mount weak inflammatory responses, we revealed that impaired parasite maturation is largely dependent upon the host response to infection. Thus, impairment of parasite maturation represents a host-mediated, immune system-dependent mechanism for limiting parasite population growth during the early stages of an acute blood-stage Plasmodium infection.


Subject(s)
Host-Parasite Interactions , Malaria, Falciparum/immunology , Malaria, Falciparum/parasitology , Plasmodium berghei/physiology , Plasmodium falciparum/physiology , Adaptive Immunity , Animals , Cytokines/metabolism , Erythrocytes/parasitology , Female , Flow Cytometry , Green Fluorescent Proteins/metabolism , Homeodomain Proteins/genetics , Immune System , Inflammation , Malaria , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Theoretical , Plasmodium yoelii/physiology
5.
PLoS Pathog ; 12(11): e1005999, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27812214

ABSTRACT

Parasite-specific antibodies protect against blood-stage Plasmodium infection. However, in malaria-endemic regions, it takes many months for naturally-exposed individuals to develop robust humoral immunity. Explanations for this have focused on antigenic variation by Plasmodium, but have considered less whether host production of parasite-specific antibody is sub-optimal. In particular, it is unclear whether host immune factors might limit antibody responses. Here, we explored the effect of Type I Interferon signalling via IFNAR1 on CD4+ T-cell and B-cell responses in two non-lethal murine models of malaria, P. chabaudi chabaudi AS (PcAS) and P. yoelii 17XNL (Py17XNL) infection. Firstly, we demonstrated that CD4+ T-cells and ICOS-signalling were crucial for generating germinal centre (GC) B-cells, plasmablasts and parasite-specific antibodies, and likewise that T follicular helper (Tfh) cell responses relied on B cells. Next, we found that IFNAR1-signalling impeded the resolution of non-lethal blood-stage infection, which was associated with impaired production of parasite-specific IgM and several IgG sub-classes. Consistent with this, GC B-cell formation, Ig-class switching, plasmablast and Tfh differentiation were all impaired by IFNAR1-signalling. IFNAR1-signalling proceeded via conventional dendritic cells, and acted early by limiting activation, proliferation and ICOS expression by CD4+ T-cells, by restricting the localization of activated CD4+ T-cells adjacent to and within B-cell areas of the spleen, and by simultaneously suppressing Th1 and Tfh responses. Finally, IFNAR1-deficiency accelerated humoral immune responses and parasite control by boosting ICOS-signalling. Thus, we provide evidence of a host innate cytokine response that impedes the onset of humoral immunity during experimental malaria.


Subject(s)
Antibodies, Protozoan/immunology , Immunity, Humoral/immunology , Inducible T-Cell Co-Stimulator Protein/immunology , Malaria/immunology , Receptor, Interferon alpha-beta/immunology , Animals , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Confocal , Plasmodium chabaudi/immunology , Plasmodium yoelii/immunology , Signal Transduction/immunology
6.
Cell Rep ; 17(2): 399-412, 2016 10 04.
Article in English | MEDLINE | ID: mdl-27705789

ABSTRACT

The development of immunoregulatory networks is important to prevent disease. However, these same networks allow pathogens to persist and reduce vaccine efficacy. Here, we identify type I interferons (IFNs) as important regulators in developing anti-parasitic immunity in healthy volunteers infected for the first time with Plasmodium falciparum. Type I IFNs suppressed innate immune cell function and parasitic-specific CD4+ T cell IFNγ production, and they promoted the development of parasitic-specific IL-10-producing Th1 (Tr1) cells. Type I IFN-dependent, parasite-specific IL-10 production was also observed in P. falciparum malaria patients in the field following chemoprophylaxis. Parasite-induced IL-10 suppressed inflammatory cytokine production, and IL-10 levels after drug treatment were positively associated with parasite burdens before anti-parasitic drug administration. These findings have important implications for understanding the development of host immune responses following blood-stage P. falciparum infection, and they identify type I IFNs and related signaling pathways as potential targets for therapies or vaccine efficacy improvement.


Subject(s)
Host-Parasite Interactions/immunology , Immunity, Innate/genetics , Interferon Type I/genetics , Malaria, Falciparum/immunology , Antiparasitic Agents/administration & dosage , CD4-Positive T-Lymphocytes/immunology , Healthy Volunteers , Humans , Interferon Type I/immunology , Interferon-gamma/genetics , Interleukin-10/genetics , Interleukin-10/immunology , Malaria, Falciparum/drug therapy , Malaria, Falciparum/genetics , Plasmodium falciparum/immunology , Plasmodium falciparum/pathogenicity , Th1 Cells/immunology , Th1 Cells/metabolism
8.
PLoS Negl Trop Dis ; 10(2): e0004415, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26872334

ABSTRACT

Chronic disease caused by infections, cancer or autoimmunity can result in profound immune suppression. Immunoregulatory networks are established to prevent tissue damage caused by inflammation. Although these immune checkpoints preserve tissue function, they allow pathogens and tumors to persist, and even expand. Immune checkpoint blockade has recently been successfully employed to treat cancer. This strategy modulates immunoregulatory mechanisms to allow host immune cells to kill or control tumors. However, the utility of this approach for controlling established infections has not been extensively investigated. Here, we examined the potential of modulating glucocorticoid-induced TNF receptor-related protein (GITR) on T cells to improve anti-parasitic immunity in blood and spleen tissue from visceral leishmaniasis (VL) patients infected with Leishmania donovani. We found little effect on parasite growth or parasite-specific IFNγ production. However, this treatment reversed the improved anti-parasitic immunity achieved by IL-10 signaling blockade. Further investigations using an experimental VL model caused by infection of C57BL/6 mice with L. donovani revealed that this negative effect was prominent in the liver, dependent on parasite burden and associated with an accumulation of Th1 cells expressing high levels of KLRG-1. Nevertheless, combined anti-IL-10 and anti-GITR mAb treatment could improve anti-parasitic immunity when used with sub-optimal doses of anti-parasitic drug. However, additional studies with VL patient samples indicated that targeting GITR had no overall benefit over IL-10 signaling blockade alone at improving anti-parasitic immune responses, even with drug treatment cover. These findings identify several important factors that influence the effectiveness of immune modulation, including parasite burden, target tissue and the use of anti-parasitic drug. Critically, these results also highlight potential negative effects of combining different immune modulation strategies.


Subject(s)
Immunotherapy , Leishmania donovani/physiology , Leishmaniasis, Visceral/immunology , Leishmaniasis, Visceral/therapy , Animals , Cytokines/immunology , Female , Humans , Interleukin-10/immunology , Leishmaniasis, Visceral/parasitology , Mice , Mice, Inbred C57BL , Spleen/immunology , Spleen/parasitology , Th1 Cells/immunology
9.
PLoS Pathog ; 12(1): e1005398, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26765224

ABSTRACT

Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4+ T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation.


Subject(s)
Inflammation/immunology , Interleukin-10/biosynthesis , Leishmaniasis, Visceral/immunology , Repressor Proteins/immunology , Th1 Cells/immunology , Tumor Necrosis Factor-alpha/immunology , Animals , Disease Models, Animal , Female , Flow Cytometry , Humans , Inflammation/pathology , Interleukin-10/immunology , Leishmaniasis, Visceral/pathology , Malaria/immunology , Malaria/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Microscopy, Fluorescence , Positive Regulatory Domain I-Binding Factor 1 , T-Lymphocytes, Regulatory/immunology
10.
J Immunol ; 195(12): 5707-17, 2015 Dec 15.
Article in English | MEDLINE | ID: mdl-26538396

ABSTRACT

Intracellular infections, such as those caused by the protozoan parasite Leishmania donovani, a causative agent of visceral leishmaniasis (VL), require a potent host proinflammatory response for control. IL-17 has emerged as an important proinflammatory cytokine required for limiting growth of both extracellular and intracellular pathogens. However, there are conflicting reports on the exact roles for IL-17 during parasitic infections and limited knowledge about cellular sources and the immune pathways it modulates. We examined the role of IL-17 in an experimental model of VL caused by infection of C57BL/6 mice with L. donovani and identified an early suppressive role for IL-17 in the liver that limited control of parasite growth. IL-17-producing γδ T cells recruited to the liver in the first week of infection were the critical source of IL-17 in this model, and CCR2(+) inflammatory monocytes were an important target for the suppressive effects of IL-17. Improved parasite control was independent of NO generation, but associated with maintenance of superoxide dismutase mRNA expression in the absence of IL-17 in the liver. Thus, we have identified a novel inhibitory function for IL-17 in parasitic infection, and our results demonstrate important interactions among γδ T cells, monocytes, and infected macrophages in the liver that can determine the outcome of parasitic infection.


Subject(s)
Interleukin-17/metabolism , Leishmania donovani/immunology , Leishmaniasis, Visceral/immunology , Liver/immunology , T-Lymphocytes/immunology , Animals , Disease Models, Animal , Humans , Immunosuppression Therapy , Leishmania donovani/growth & development , Liver/parasitology , Mice , Mice, Inbred C57BL , Monocytes/immunology , Monocytes/parasitology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, CCR2/metabolism , Superoxide Dismutase/metabolism , T-Lymphocytes/parasitology
11.
Sci Rep ; 5: 9412, 2015 May 06.
Article in English | MEDLINE | ID: mdl-25944649

ABSTRACT

The best correlate of malaria severity in human Plasmodium falciparum (Pf) infection is the total parasite load. Pf-infected humans could control parasite loads by two mechanisms, either decreasing parasite multiplication, or increasing parasite clearance. However, few studies have directly measured these two mechanisms in vivo. Here, we have directly quantified host clearance of parasites during Plasmodium infection in mice. We transferred labelled red blood cells (RBCs) from Plasmodium infected donors into uninfected and infected recipients, and tracked the fate of donor parasites by frequent blood sampling. We then applied age-based mathematical models to characterise parasite clearance in the recipient mice. Our analyses revealed an increased clearance of parasites in infected animals, particularly parasites of a younger developmental stage. However, the major decrease in parasite multiplication in infected mice was not mediated by increased clearance alone, but was accompanied by a significant reduction in the susceptibility of RBCs to parasitisation.


Subject(s)
Erythrocytes/parasitology , Host-Pathogen Interactions , Malaria, Falciparum/parasitology , Parasite Load/methods , Plasmodium falciparum/growth & development , Plasmodium falciparum/pathogenicity , Animals , Computer Simulation , Disease Susceptibility , Female , Malaria, Falciparum/blood , Mice , Mice, Inbred C57BL , Models, Biological , Plasmodium falciparum/cytology , Severity of Illness Index
12.
Clin Vaccine Immunol ; 22(5): 477-83, 2015 May.
Article in English | MEDLINE | ID: mdl-25716232

ABSTRACT

Acute lower respiratory tract infections (ALRTI) are the leading cause of global childhood mortality, with human respiratory syncytial virus (hRSV) being a major cause of viral ALRTI in young children worldwide. In sub-Saharan Africa, many young children experience severe illnesses due to hRSV or Plasmodium infection. Although the incidence of malaria in this region has decreased in recent years, there remains a significant opportunity for coinfection. Recent data show that febrile young children infected with Plasmodium are often concurrently infected with respiratory viral pathogens but are less likely to suffer from pneumonia than are non-Plasmodium-infected children. Here, we hypothesized that blood-stage Plasmodium infection modulates pulmonary inflammatory responses to a viral pathogen but does not aid its control in the lung. To test this, we established a novel coinfection model in which mice were simultaneously infected with pneumovirus of mice (PVM) (to model hRSV) and blood-stage Plasmodium chabaudi chabaudi AS (PcAS) parasites. We found that PcAS infection was unaffected by coinfection with PVM. In contrast, PVM-associated weight loss, pulmonary cytokine responses, and immune cell recruitment to the airways were substantially reduced by coinfection with PcAS. Importantly, PcAS coinfection facilitated greater viral dissemination throughout the lung. Although Plasmodium coinfection induced low levels of systemic interleukin-10 (IL-10), this regulatory cytokine played no role in the modulation of lung inflammation or viral dissemination. Instead, we found that Plasmodium coinfection drove an early systemic beta interferon (IFN-ß) response. Therefore, we propose that blood-stage Plasmodium coinfection may exacerbate viral dissemination and impair inflammation in the lung by dysregulating type I IFN-dependent responses to respiratory viruses.


Subject(s)
Bronchiolitis, Viral/immunology , Coinfection , Interferon-beta/immunology , Lung/virology , Malaria/immunology , Pneumovirus Infections/immunology , Pneumovirus/immunology , Animals , Bronchiolitis, Viral/virology , Disease Models, Animal , Female , Inflammation/immunology , Inflammation/parasitology , Inflammation/virology , Interferon-beta/blood , Interleukin-10/immunology , Lung/immunology , Malaria/complications , Plasmodium chabaudi , Pneumovirus/pathogenicity , Pneumovirus/physiology , Pneumovirus Infections/complications , Respiratory Syncytial Virus, Human/pathogenicity , Viral Load , Weight Loss
13.
Eur J Immunol ; 45(1): 130-41, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25319247

ABSTRACT

Type I IFN signaling suppresses splenic T helper 1 (Th1) responses during blood-stage Plasmodium berghei ANKA (PbA) infection in mice, and is crucial for mediating tissue accumulation of parasites and fatal cerebral symptoms via mechanisms that remain to be fully characterized. Interferon regulatory factor 7 (IRF7) is considered to be a master regulator of type I IFN responses. Here, we assessed IRF7 for its roles during lethal PbA infection and nonlethal Plasmodium chabaudi chabaudi AS (PcAS) infection as two distinct models of blood-stage malaria. We found that IRF7 was not essential for tissue accumulation of parasites, cerebral symptoms, or brain pathology. Using timed administration of anti-IFNAR1 mAb, we show that late IFNAR1 signaling promotes fatal disease via IRF7-independent mechanisms. Despite this, IRF7 significantly impaired early splenic Th1 responses and limited control of parasitemia during PbA infection.  Finally, IRF7 also suppressed antiparasitic immunity and Th1 responses during nonlethal PcAS infection. Together, our data support a model in which IRF7 suppresses antiparasitic immunity in the spleen, while IFNAR1-mediated, but IRF7-independent, signaling contributes to pathology in the brain during experimental blood-stage malaria.


Subject(s)
Brain/immunology , Interferon Regulatory Factor-7/immunology , Malaria, Cerebral/immunology , Receptor, Interferon alpha-beta/immunology , Spleen/immunology , Th1 Cells/immunology , Animals , Antibodies, Monoclonal/pharmacology , Brain/drug effects , Brain/parasitology , Disease Susceptibility , Erythrocytes/parasitology , Female , Gene Expression Regulation , Host-Parasite Interactions , Interferon Regulatory Factor-7/genetics , Malaria, Cerebral/parasitology , Mice , Mice, Inbred C57BL , Plasmodium berghei/immunology , Plasmodium chabaudi/immunology , Receptor, Interferon alpha-beta/antagonists & inhibitors , Receptor, Interferon alpha-beta/genetics , Signal Transduction , Spleen/drug effects , Spleen/parasitology , Th1 Cells/parasitology , Time Factors
14.
J Clin Invest ; 124(6): 2483-96, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24789914

ABSTRACT

Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cellular immune responses through activation of type I IFN signaling. Recent evidence suggests that immune suppression and susceptibility to the malaria parasite, Plasmodium, is mediated by type I IFN; however, it is unclear how type I IFN suppresses immunity to blood-stage Plasmodium parasites. During experimental severe malaria, CD4+ Th cell responses are suppressed, and conventional DC (cDC) function is curtailed through unknown mechanisms. Here, we tested the hypothesis that type I IFN signaling directly impairs cDC function during Plasmodium infection in mice. Using cDC-specific IFNAR1-deficient mice, and mixed BM chimeras, we found that type I IFN signaling directly affects cDC function, limiting the ability of cDCs to prime IFN-γ-producing Th1 cells. Although type I IFN signaling modulated all subsets of splenic cDCs, CD8- cDCs were especially susceptible, exhibiting reduced phagocytic and Th1-promoting properties in response to type I IFNs. Additionally, rapid and systemic IFN-α production in response to Plasmodium infection required type I IFN signaling in cDCs themselves, revealing their contribution to a feed-forward cytokine-signaling loop. Together, these data suggest abrogation of type I IFN signaling in CD8- splenic cDCs as an approach for enhancing Th1 responses against Plasmodium and other type I IFN-inducing pathogens.


Subject(s)
Dendritic Cells/immunology , Interferon Type I/metabolism , Malaria/immunology , Th1 Cells/immunology , Animals , CD8 Antigens/metabolism , Dendritic Cells/classification , Female , Immune Tolerance , Immunity, Cellular , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/immunology , Plasmodium berghei/immunology , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , Signal Transduction/immunology
15.
J Immunol ; 192(8): 3709-18, 2014 Apr 15.
Article in English | MEDLINE | ID: mdl-24634490

ABSTRACT

Organ-specific immunity is a feature of many infectious diseases, including visceral leishmaniasis caused by Leishmania donovani. Experimental visceral leishmaniasis in genetically susceptible mice is characterized by an acute, resolving infection in the liver and chronic infection in the spleen. CD4+ T cell responses are critical for the establishment and maintenance of hepatic immunity in this disease model, but their role in chronically infected spleens remains unclear. In this study, we show that dendritic cells are critical for CD4+ T cell activation and expansion in all tissue sites examined. We found that FTY720-mediated blockade of T cell trafficking early in infection prevented Ag-specific CD4+ T cells from appearing in lymph nodes, but not the spleen and liver, suggesting that early CD4+ T cell priming does not occur in liver-draining lymph nodes. Extended treatment with FTY720 over the first month of infection increased parasite burdens, although this associated with blockade of lymphocyte egress from secondary lymphoid tissue, as well as with more generalized splenic lymphopenia. Importantly, we demonstrate that CD4+ T cells are required for the establishment and maintenance of antiparasitic immunity in the liver, as well as for immune surveillance and suppression of parasite outgrowth in chronically infected spleens. Finally, although early CD4+ T cell priming appeared to occur most effectively in the spleen, we unexpectedly revealed that protective CD4+ T cell-mediated hepatic immunity could be generated in the complete absence of all secondary lymphoid tissues.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Immunologic Memory , Leishmania donovani/immunology , Leishmaniasis, Visceral/immunology , Animals , Antigens, Protozoan/immunology , CD4-Positive T-Lymphocytes/drug effects , Dendritic Cells/immunology , Epitopes, T-Lymphocyte/immunology , Female , Fingolimod Hydrochloride , Immunosuppressive Agents/pharmacology , Liver/drug effects , Liver/immunology , Liver/parasitology , Lymphocyte Activation/immunology , Lymphoid Tissue/drug effects , Lymphoid Tissue/immunology , Lymphoid Tissue/parasitology , Mice , Mice, Knockout , Propylene Glycols/pharmacology , Sphingosine/analogs & derivatives , Sphingosine/pharmacology , Spleen/drug effects , Spleen/immunology , Spleen/parasitology
16.
Infect Immun ; 82(1): 212-20, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24144725

ABSTRACT

Parasite biomass and microvasculature obstruction are strongly associated with disease severity and death in Plasmodium falciparum-infected humans. This is related to sequestration of mature, blood-stage parasites (schizonts) in peripheral tissue. The prevailing view is that schizont sequestration leads to an increase in pathogen biomass, yet direct experimental data to support this are lacking. Here, we first studied parasite population dynamics in inbred wild-type (WT) mice infected with the rodent species of malaria, Plasmodium berghei ANKA. As is commonly reported, these mice became moribund due to large numbers of parasites in multiple tissues. We then studied infection dynamics in a genetically targeted line of mice, which displayed minimal tissue accumulation of parasites. We constructed a mathematical model of parasite biomass dynamics, incorporating schizont-specific host clearance, both with and without schizont sequestration. Combined use of mathematical and in vivo modeling indicated, first, that the slowing of parasite growth in the genetically targeted mice can be attributed to specific clearance of schizonts from the circulation and, second, that persistent parasite growth in WT mice can be explained solely as a result of schizont sequestration. Our work provides evidence that schizont sequestration could be a major biological process driving rapid, early increases in parasite biomass during blood-stage Plasmodium infection.


Subject(s)
Biomass , Erythrocytes/parasitology , Malaria/parasitology , Models, Biological , Plasmodium berghei/growth & development , Animals , Cytokines/metabolism , Disease Models, Animal , Erythrocytes/metabolism , Female , Flow Cytometry , Luminescent Measurements , Malaria/blood , Mice , Mice, Inbred C57BL , Plasmodium berghei/pathogenicity , Schizonts/parasitology
17.
PLoS One ; 8(2): e55961, 2013.
Article in English | MEDLINE | ID: mdl-23441158

ABSTRACT

Traditional approaches to measuring the level of malaria infection involve counting the proportion of parasite-infected red blood cells (iRBC) in circulating blood, known as parasitaemia. However, iRBC can also accumulate within the microvasculature of tissues and organs, a process called sequestration. Thus measurements of parasitemia do not necessarily reflect the total parasite burden (TPB). Recent experimental advances have allowed TPB measurements to be made in humans and experimental models. TPB is particularly important because it is the best current predictor of malaria disease severity and death in humans. Understanding the relationship between freely circulating iRBC versus tissue-sequestered iRBC is an important question in infection dynamics. The recent ability to experimentally measure the dynamics of iRBC in blood and tissue during murine malaria provides an exciting potential window into sequestration, but new modeling approaches are clearly required to understand these interactions. We present a model of malaria dynamics during early infection that incorporates iRBC that both circulate in the blood and sequester in tissue microvasculature. We explore the effect that perturbations to the system have on the ratio of the number of iRBC between these compartments, and consider which changes are most consistent with experimental data from mice. Using this model we predict an increase in the clearance rate of sequestered iRBCs around the time when mild symptoms become apparent, but a more pronounced increase in the rate of sequestration of iRBCs associated with the onset of severe malaria symptoms.


Subject(s)
Erythrocytes/parasitology , Malaria/parasitology , Models, Biological , Algorithms , Animals , Disease Models, Animal , Female , Life Cycle Stages , Mice , Parasitemia/parasitology , Plasmodium berghei/growth & development , Time Factors
18.
Diabetes ; 61(5): 1281-90, 2012 May.
Article in English | MEDLINE | ID: mdl-22403299

ABSTRACT

Novel biomarkers of disease progression after type 1 diabetes onset are needed. We profiled peripheral blood (PB) monocyte gene expression in six healthy subjects and 16 children with type 1 diabetes diagnosed ∼3 months previously and analyzed clinical features from diagnosis to 1 year. Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy control subjects, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose-adjusted HbA(1c) levels during the first year, compared with patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g., induction of HIF1A, DDIT3, DDIT4, and GRP78). Quantitative PCR (qPCR) of a 9-gene panel correlated with glycemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. A PB gene expression signature correlates with glycemic control in the first year after diabetes diagnosis and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and postonset and systemic stresses as contributors to innate immune function in type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1/metabolism , Gene Expression Regulation/physiology , Monocytes/metabolism , Adolescent , Child , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/genetics , Endoplasmic Reticulum Chaperone BiP , Female , Gene Expression Profiling , Humans , Male
19.
Eur J Immunol ; 41(9): 2688-98, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21674481

ABSTRACT

During blood-stage Plasmodium infection, large-scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice, CD4(+) T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8(+) T cells. Expression analysis revealed that the transcriptional signature of CD4(+) T cells from PbA-infected mice was dominated by type I IFN (IFN-I) and IFN-γ-signalling pathway-related genes. A role for IFN-I during blood-stage Plasmodium infection had yet to be established. Here, we observed IFN-α protein production in the spleen of PbA-infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN-I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN-I substantially inhibited CD4(+) T-bet(+) T-cell-derived IFN-γ production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN-I signalled predominantly via radio-sensitive, haematopoietic cells, but did not suppress CD4(+) T cells via direct signalling to this cell type. Finally, we found that IFN-I suppressed IFN-γ production, and hampered efficient control of parasitaemia in mice infected with non-lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood-stage Plasmodium infection that suppresses CD4(+) T-cell-mediated parasite control.


Subject(s)
Interferon Type I/metabolism , Malaria/immunology , Plasmodium berghei/immunology , Plasmodium chabaudi/immunology , Th1 Cells/metabolism , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/parasitology , CD8-Positive T-Lymphocytes/pathology , Cells, Cultured , Immune Evasion , Immunosuppression Therapy , Interferon Type I/immunology , Interferon-gamma/metabolism , Life Cycle Stages , Mice , Mice, Inbred C57BL , Plasmodium berghei/pathogenicity , Plasmodium chabaudi/pathogenicity , Signal Transduction/immunology , T-Box Domain Proteins/metabolism , Th1 Cells/immunology , Th1 Cells/parasitology , Th1 Cells/pathology , Transplantation Chimera , Virulence
20.
J Immunol ; 186(11): 6148-56, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21525386

ABSTRACT

Parasite burden predicts disease severity in malaria and risk of death in cerebral malaria patients. In murine experimental cerebral malaria (ECM), parasite burden and CD8(+) T cells promote disease by mechanisms that are not fully understood. We found that the majority of brain-recruited CD8(+) T cells expressed granzyme B (GzmB). Furthermore, gzmB(-/-) mice harbored reduced parasite numbers in the brain as a consequence of enhanced antiparasitic CD4(+) T cell responses and were protected from ECM. We showed in these ECM-resistant mice that adoptively transferred, Ag-specific CD8(+) T cells migrated to the brain, but did not induce ECM until a critical Ag threshold was reached. ECM induction was exquisitely dependent on Ag-specific CD8(+) T cell-derived perforin and GzmB, but not IFN-γ. In wild-type mice, full activation of brain-recruited CD8(+) T cells also depended on a critical number of parasites in this tissue, which in turn, was sustained by these tissue-recruited cells. Thus, an interdependent relationship between parasite burden and CD8(+) T cells dictates the onset of perforin/GzmB-mediated ECM.


Subject(s)
Brain/immunology , CD8-Positive T-Lymphocytes/immunology , Granzymes/immunology , Malaria, Cerebral/immunology , Adoptive Transfer , Animals , Brain/metabolism , Brain/parasitology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/transplantation , Cell Movement/immunology , Female , Flow Cytometry , Granzymes/genetics , Host-Parasite Interactions/immunology , Interferon-gamma/immunology , Interferon-gamma/metabolism , Malaria, Cerebral/parasitology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Perforin/immunology , Perforin/metabolism , Plasmodium chabaudi/immunology , Plasmodium chabaudi/physiology , Plasmodium yoelii/immunology , Plasmodium yoelii/physiology
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