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1.
Mem Inst Oswaldo Cruz ; 117: e210287, 2022.
Article in English | MEDLINE | ID: mdl-35730803

ABSTRACT

BACKGROUND: It has been demonstrated that proteins expressed by liver-stage Plasmodium parasites can inhibit the translocation of transcription factors to the nucleus of different cells. This process would hinder the expression of immune genes, such as the CCL20 chemokine. OBJECTIVE: Since CCR6 is the only cognate receptor for CCL20, we investigated the importance of this chemokine-receptor axis against rodent malaria. METHODS: CCR6-deficient (KO) and wild-type (WT) C57BL/6 mice were challenged with Plasmodium berghei (Pb) NK65 sporozoites or infected red blood cells (iRBCs). Liver parasitic cDNA, parasitemia and serum cytokine concentrations were respectively evaluated through reverse transcription-polymerase chain reaction (RT-PCR), staining thin-blood smears with Giemsa solution, and enzyme-linked immunosorbent assay (ELISA). FINDINGS: Although the sporozoite challenges yielded similar liver parasitic cDNA and parasitemia, KO mice presented a prolonged survival than WT mice. After iRBC challenges, KO mice kept displaying higher survival rates as well as a decreased IL-12 p70 concentration in the serum than WT mice. CONCLUSION: Our data suggest that malaria triggered by PbNK65 liver- or blood-stage forms elicit a pro-inflammatory environment that culminates with a decreased survival of infected C57BL/6 mice.


Subject(s)
Malaria , Plasmodium berghei , Animals , DNA, Complementary , Malaria/parasitology , Mice , Mice, Inbred C57BL , Parasitemia/parasitology , Receptors, CCR6
2.
Infect Immun ; 89(10): e0002421, 2021 09 16.
Article in English | MEDLINE | ID: mdl-34251290

ABSTRACT

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a severe complication of malaria that occurs despite effective antimalarial treatment. Currently, noninvasive imaging procedures such as chest X-rays are used to assess edema in established MA-ARDS, but earlier detection methods are needed to reduce morbidity and mortality. The early stages of MA-ARDS are characterized by the infiltration of leukocytes, in particular monocytes/macrophages; thus, monitoring of immune infiltrates may provide a useful indicator of early pathology. In this study, Plasmodium berghei ANKA-infected C57BL/6 mice, a rodent model of MA-ARDS, were longitudinally imaged using the 18-kDa translocator protein (TSPO) imaging agent [18F]FEPPA as a marker of macrophage accumulation during the development of pathology and in response to combined artesunate and chloroquine diphosphate (ART+CQ) therapy. [18F]FEPPA uptake was compared to blood parasitemia levels and to levels of pulmonary immune cell infiltrates by using flow cytometry. Infected animals showed rapid increases in lung retention of [18F]FEPPA, correlating well with increases in blood parasitemia and pulmonary accumulation of interstitial inflammatory macrophages and major histocompatibility complex class II (MHC-II)-positive alveolar macrophages. Treatment with ART+CQ abrogated this increase in parasitemia and significantly reduced both lung uptake of [18F]FEPPA and levels of macrophage infiltrates. We conclude that retention of [18F]FEPPA in the lungs is well correlated with changes in blood parasitemia and levels of lung-associated macrophages during disease progression and in response to ART+CQ therapy. With further development, TSPO biomarkers may have the potential to accurately assess the early onset of MA-ARDS.


Subject(s)
Biomarkers/metabolism , Lung/metabolism , Malaria/metabolism , Pneumonia/metabolism , Animals , Disease Models, Animal , Leukocytes/metabolism , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Monocytes/metabolism , Plasmodium berghei/pathogenicity , Positron-Emission Tomography/methods , Respiratory Distress Syndrome/metabolism
3.
Cell Microbiol ; 20(5): e12819, 2018 05.
Article in English | MEDLINE | ID: mdl-29281764

ABSTRACT

Host immune response has a key role in controlling the progression of malaria infection. In the well-established murine model of experimental cerebral malaria (ECM) with Plasmodium berghei ANKA infection, proinflammatory Th1 and CD8+ T cell response are essential for disease development. Interferon regulatory factor 1 (IRF1) is a transcription factor that promotes Th1 responses, and its absence was previously shown to protect from ECM death. Yet the exact mechanism of protection remains unknown. Here we demonstrated that IRF1-deficient mice (IRF1 knockout) were protected from ECM death despite displaying early neurological signs. Resistance to ECM death was a result of reduced parasite sequestration and pathogenic CD8+ T cells in the brain. Further analysis revealed that IRF1 deficiency suppress interferon-γ production and delayed CD8+ T cell proliferation. CXCR3 expression was found to be decreased in pathogenic CD8+ T cells, which limited their migration to the brain. In addition, reduced expression of adhesion molecules by brain endothelial cells hampered leucocyte retention in the brain. Taken together, these factors limited sequestration of pathogenic CD8+ T cells and consequently its ability to induce extensive damage to the blood-brain barrier.


Subject(s)
Interferon Regulatory Factor-1/genetics , Malaria, Cerebral/genetics , Plasmodium berghei/pathogenicity , Receptors, CXCR3/genetics , Animals , Brain/microbiology , Brain/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/microbiology , Cell Movement/genetics , Disease Models, Animal , Gene Expression Regulation , Humans , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Malaria, Cerebral/immunology , Malaria, Cerebral/microbiology , Mice , Mice, Knockout
4.
Cell Microbiol ; 19(11)2017 11.
Article in English | MEDLINE | ID: mdl-28664674

ABSTRACT

Artemisinin-based antimalarials, such as artesunate (ART), alone or in combination, are the mainstay of the therapy against malaria caused by Plasmodium falciparum. However, the emergence and spread of artemisinin resistance threatens the future success of its global malaria eradication. Although much of the reported artemisinin resistance can be attributed to mutations intrinsic to the parasite, a significant proportion of treatment failures are thought to be due to other factors such as the host's immune system. Exactly how the immune system participates in the clearance and elimination of malaria parasites during ART treatment is unknown. Here, we show that a developing primary immune response, involving both B and CD4+ T cells, is necessary for the complete elimination but not initial clearance, of Plasmodium yoelii YM parasites in mice treated with ART. Our study uncovers a dynamic interplay between ART and host adaptive immunity in Plasmodium sp. elimination.


Subject(s)
Antimalarials/therapeutic use , Artemisinins/therapeutic use , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Malaria/drug therapy , Plasmodium yoelii/drug effects , Plasmodium yoelii/immunology , Adaptive Immunity/immunology , Animals , Artesunate , Disease Models, Animal , Drug Resistance , Female , Malaria/immunology , Malaria/parasitology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Recurrence
5.
Infect Immun ; 85(6)2017 06.
Article in English | MEDLINE | ID: mdl-28396319

ABSTRACT

The resolution of malaria infection is dependent on a balance between proinflammatory and regulatory immune responses. While early effector T cell responses are required for limiting parasitemia, these responses need to be switched off by regulatory mechanisms in a timely manner to avoid immune-mediated tissue damage. Interleukin-10 receptor (IL-10R) signaling is considered to be a vital component of regulatory responses, although its role in host resistance to severe immune pathology during acute malaria infections is not fully understood. In this study, we have determined the contribution of IL-10R signaling to the regulation of immune responses during Plasmodium berghei ANKA-induced experimental cerebral malaria (ECM). We show that antibody-mediated blockade of the IL-10R during P. berghei ANKA infection in ECM-resistant BALB/c mice leads to amplified T cell activation, higher serum gamma interferon (IFN-γ) concentrations, enhanced intravascular accumulation of both parasitized red blood cells and CD8+ T cells to the brain, and an increased incidence of ECM. Importantly, the pathogenic effects of IL-10R blockade during P. berghei ANKA infection were reversible by depletion of T cells and neutralization of IFN-γ. Our findings underscore the importance of IL-10R signaling in preventing T-cell- and cytokine-mediated pathology during potentially lethal malaria infections.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Interferon-gamma/blood , Malaria, Cerebral/immunology , Plasmodium berghei/immunology , Receptors, Interleukin-10/immunology , Animals , Antibodies, Blocking/administration & dosage , Antibodies, Neutralizing/administration & dosage , Brain/pathology , CD8-Positive T-Lymphocytes/drug effects , Erythrocytes/drug effects , Erythrocytes/parasitology , Female , Liver/pathology , Lymphocyte Activation/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Parasitemia/immunology , Receptors, Interleukin-10/antagonists & inhibitors , Signal Transduction
6.
Blood ; 125(8): 1314-24, 2015 Feb 19.
Article in English | MEDLINE | ID: mdl-25414440

ABSTRACT

Plasmodium vivax merozoites only invade reticulocytes, a minor though heterogeneous population of red blood cell precursors that can be graded by levels of transferrin receptor (CD71) expression. The development of a protocol that allows sorting reticulocytes into defined developmental stages and a robust ex vivo P vivax invasion assay has made it possible for the first time to investigate the fine-scale invasion preference of P vivax merozoites. Surprisingly, it was the immature reticulocytes (CD71(+)) that are generally restricted to the bone marrow that were preferentially invaded, whereas older reticulocytes (CD71(-)), principally found in the peripheral blood, were rarely invaded. Invasion assays based on the CD71(+) reticulocyte fraction revealed substantial postinvasion modification. Thus, 3 to 6 hours after invasion, the initially biomechanically rigid CD71(+) reticulocytes convert into a highly deformable CD71(-) infected red blood cell devoid of host reticular matter, a process that normally spans 24 hours for uninfected reticulocytes. Concurrent with these changes, clathrin pits disappear by 3 hours postinvasion, replaced by distinctive caveolae nanostructures. These 2 hitherto unsuspected features of P vivax invasion, a narrow preference for immature reticulocytes and a rapid remodeling of the host cell, provide important insights pertinent to the pathobiology of the P vivax infection.


Subject(s)
Antigens, CD/metabolism , Plasmodium vivax/growth & development , Receptors, Transferrin/metabolism , Reticulocytes/physiology , Reticulocytes/parasitology , Tropism/physiology , Biomechanical Phenomena , Cells, Cultured , Erythrocyte Deformability , Humans , Malaria, Vivax/blood , Malaria, Vivax/parasitology , Reticulocytes/metabolism
7.
Antimicrob Agents Chemother ; 60(11): 6859-6866, 2016 11.
Article in English | MEDLINE | ID: mdl-27600050

ABSTRACT

Ex vivo assay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. For rodent malaria parasites, short-term in vitro culture and ex vivo antimalarial susceptibility assays are relatively cumbersome, relying on in vivo passage for synchronization, since ring-stage parasites are an essential starting material. Here, we describe a new approach based on the enrichment of ring-stage Plasmodium berghei, P. yoelii, and P. vinckei vinckei using a single-step Percoll gradient. Importantly, we demonstrate that the enriched ring-stage parasites develop synchronously regardless of the parasite strain or species used. Using a flow cytometry assay with Hoechst and ethidium or MitoTracker dye, we show that parasite development is easily and rapidly monitored. Finally, we demonstrate that this approach can be used to screen antimalarial drugs.


Subject(s)
Antimalarials/pharmacology , Drug Evaluation, Preclinical/methods , Malaria/parasitology , Plasmodium/drug effects , Plasmodium/physiology , Animals , Disease Models, Animal , Female , Flow Cytometry/methods , Malaria/drug therapy , Male , Mice, Inbred C57BL , Microbial Sensitivity Tests , Plasmodium/pathogenicity , Plasmodium berghei/drug effects , Plasmodium berghei/pathogenicity , Plasmodium berghei/physiology
8.
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
9.
Infect Immun ; 83(10): 3781-92, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26169268

ABSTRACT

Malaria remains a world-threatening disease largely because of the lack of a long-lasting and fully effective vaccine. MAEBL is a type 1 transmembrane molecule with a chimeric cysteine-rich ectodomain homologous to regions of the Duffy binding-like erythrocyte binding protein and apical membrane antigen 1 (AMA1) antigens. Although MAEBL does not appear to be essential for the survival of blood-stage forms, ectodomains M1 and M2, homologous to AMA1, seem to be involved in parasite attachment to erythrocytes, especially M2. MAEBL is necessary for sporozoite infection of mosquito salivary glands and is expressed in liver stages. Here, the Plasmodium yoelii MAEBL-M2 domain was expressed in a prokaryotic vector. C57BL/6J mice were immunized with doses of P. yoelii recombinant protein rPyM2-MAEBL. High levels of antibodies, with balanced IgG1 and IgG2c subclasses, were achieved. rPyM2-MAEBL antisera were capable of recognizing the native antigen. Anti-MAEBL antibodies recognized different MAEBL fragments expressed in CHO cells, showing stronger IgM and IgG responses to the M2 domain and repeat region, respectively. After a challenge with P. yoelii YM (lethal strain)-infected erythrocytes (IE), up to 90% of the immunized animals survived and a reduction of parasitemia was observed. Moreover, splenocytes harvested from immunized animals proliferated in a dose-dependent manner in the presence of rPyM2-MAEBL. Protection was highly dependent on CD4(+), but not CD8(+), T cells toward Th1. rPyM2-MAEBL antisera were also able to significantly inhibit parasite development, as observed in ex vivo P. yoelii erythrocyte invasion assays. Collectively, these findings support the use of MAEBL as a vaccine candidate and open perspectives to understand the mechanisms involved in protection.


Subject(s)
Malaria Vaccines/immunology , Malaria/prevention & control , Plasmodium yoelii/immunology , Protozoan Proteins/chemistry , Protozoan Proteins/immunology , Animals , Antibodies, Protozoan/immunology , Erythrocytes/parasitology , Female , Humans , Immunization , Malaria/immunology , Malaria/mortality , Malaria/parasitology , Malaria Vaccines/administration & dosage , Malaria Vaccines/chemistry , Malaria Vaccines/genetics , Male , Merozoites/chemistry , Merozoites/growth & development , Merozoites/immunology , Mice , Mice, Inbred C57BL , Plasmodium yoelii/chemistry , Plasmodium yoelii/genetics , Plasmodium yoelii/growth & development , Protein Structure, Tertiary , Protozoan Proteins/administration & dosage , Protozoan Proteins/genetics , Sporozoites/chemistry , Sporozoites/growth & development , Sporozoites/immunology
10.
Eur J Immunol ; 44(6): 1823-34, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24610714

ABSTRACT

Basophils, a rare leukocyte population in peripheral circulation, are conventionally identified as CD45(int) CD49b(+) FcεRI(+) cells. Here, we show that basophils from blood and several organs of naïve wild-type mice express CD41, the α subunit of α(IIb)ß3 integrin. CD41 expression on basophils is upregulated after in vivo IL-3 treatment and during infection with Nippostrongylus brasiliensis (Nb). Moreover, CD41 can be used as a reliable marker for basophils, circumventing technical difficulties associated with FcεRI for basophil identification in a Nb infection model. In vitro anti-IgE cross-linking and IL-3 basophil stimulation showed that CD41 upregulation positively correlates with augmented surface expression of CD200R and increased production of IL-4/IL-13, indicating that CD41 is a basophil activation marker. Furthermore, we found that infection with Plasmodium yoelii 17X (Py17x) induced a profound basophilia and using Mcpt8(DTR) reporter mice as a basophil-specific depletion model, we verified that CD41 can be used as a marker to track basophils in the steady state and during infection. During malarial infection, CD41 expression on basophils is negatively regulated by IFN-γ and positively correlates with increased basophil IL-4 production. In conclusion, we provide evidence that CD41 can be used as both an identification and activation marker for basophils during homeostasis and immune challenge.


Subject(s)
Basophils/immunology , Malaria/immunology , Nippostrongylus/immunology , Plasmodium yoelii/immunology , Platelet Membrane Glycoprotein IIb/immunology , Strongylida Infections/immunology , Animals , Antibodies, Helminth/immunology , Basophils/pathology , Female , Immunoglobulin E/immunology , Interleukin-3/immunology , Interleukin-4/immunology , Malaria/pathology , Membrane Glycoproteins/immunology , Mice , Mice, Inbred BALB C , Mice, Knockout , Strongylida Infections/pathology
11.
J Immunol ; 190(1): 259-69, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-23209328

ABSTRACT

Chikungunya virus (CHIKV) is an alphavirus that causes chronic and incapacitating arthralgia in humans. Injury to the joint is believed to occur because of viral and host immune-mediated effects. However, the exact involvement of the different immune mediators in CHIKV-induced pathogenesis is unknown. In this study, we assessed the roles of T cells in primary CHIKV infection, virus replication and dissemination, and virus persistence, as well as in the mediation of disease severity in adult RAG2(-/-), CD4(-/-), CD8(-/-), and wild-type CHIKV C57BL/6J mice and in wild-type mice depleted of CD4(+) or CD8(+) T cells after Ab treatment. CHIKV-specific T cells in the spleen and footpad were investigated using IFN-γ ELISPOT. Interestingly, our results indicated that CHIKV-specific CD4(+), but not CD8(+), T cells are essential for the development of joint swelling without any effect on virus replication and dissemination. Infection in IFN-γ(-/-) mice demonstrated that pathogenic CD4(+) T cells do not mediate inflammation via an IFN-γ-mediated pathway. Taken together, these observations strongly indicate that mechanisms of joint pathology induced by CHIKV in mice resemble those in humans and differ from infections caused by other arthritogenic viruses, such as Ross River virus.


Subject(s)
Alphavirus Infections/immunology , Alphavirus Infections/pathology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , Chikungunya virus/immunology , Adaptive Immunity/genetics , Alphavirus Infections/genetics , Animals , Arthritis, Experimental/genetics , Arthritis, Experimental/immunology , Arthritis, Experimental/virology , CD4 Antigens/genetics , CD4-Positive T-Lymphocytes/pathology , Cell Movement/genetics , Cell Movement/immunology , Chikungunya Fever , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Female , Interferon-gamma/deficiency , Interferon-gamma/genetics , Lymphocyte Depletion , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction/genetics , Signal Transduction/immunology , Vero Cells
12.
PLoS Pathog ; 8(2): e1002504, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22319445

ABSTRACT

The balance between pro-inflammatory and regulatory immune responses in determining optimal T cell activation is vital for the successful resolution of microbial infections. This balance is maintained in part by the negative regulators of T cell activation, CTLA-4 and PD-1/PD-L, which dampen effector responses during chronic infections. However, their role in acute infections, such as malaria, remains less clear. In this study, we determined the contribution of CTLA-4 and PD-1/PD-L to the regulation of T cell responses during Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM) in susceptible (C57BL/6) and resistant (BALB/c) mice. We found that the expression of CTLA-4 and PD-1 on T cells correlates with the extent of pro-inflammatory responses induced during PbA infection, being higher in C57BL/6 than in BALB/c mice. Thus, ECM develops despite high levels of expression of these inhibitory receptors. However, antibody-mediated blockade of either the CTLA-4 or PD-1/PD-L1, but not the PD-1/PD-L2, pathways during PbA-infection in ECM-resistant BALB/c mice resulted in higher levels of T cell activation, enhanced IFN-γ production, increased intravascular arrest of both parasitised erythrocytes and CD8(+) T cells to the brain, and augmented incidence of ECM. Thus, in ECM-resistant BALB/c mice, CTLA-4 and PD-1/PD-L1 represent essential, independent and non-redundant pathways for maintaining T cell homeostasis during a virulent malaria infection. Moreover, neutralisation of IFN-γ or depletion of CD8(+) T cells during PbA infection was shown to reverse the pathologic effects of regulatory pathway blockade, highlighting that the aetiology of ECM in the BALB/c mice is similar to that in C57BL/6 mice. In summary, our results underscore the differential and complex regulation that governs immune responses to malaria parasites.


Subject(s)
Antigens, Differentiation/immunology , B7-H1 Antigen/immunology , CD8-Positive T-Lymphocytes/immunology , CTLA-4 Antigen/immunology , Plasmodium berghei/pathogenicity , Animals , Antigens, Differentiation/metabolism , B7-H1 Antigen/metabolism , CD8-Positive T-Lymphocytes/metabolism , CTLA-4 Antigen/metabolism , Erythrocytes/parasitology , Interferon-gamma/immunology , Lymphocyte Activation/immunology , Malaria, Cerebral/immunology , Malaria, Cerebral/microbiology , Malaria, Cerebral/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Plasmodium berghei/immunology , Programmed Cell Death 1 Receptor
13.
J Immunol ; 189(3): 1128-32, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22732587

ABSTRACT

Plasmodium infections trigger strong innate and acquired immune responses, which can lead to severe complications, including the most feared and often fatal cerebral malaria (CM). To begin to dissect the roles of different dendritic cell (DC) subsets in Plasmodium-induced pathology, we have generated a transgenic strain, Clec9A-diphtheria toxin receptor that allows us to ablate in vivo Clec9A(+) DCs. Specifically, we have analyzed the in vivo contribution of this DC subset in an experimental CM model using Plasmodium berghei, and we provide strong evidence that the absence of this DC subset resulted in complete resistance to experimental CM. This was accompanied with dramatic reduction of brain CD8(+) T cells, and those few cerebral CD8(+) T cells present had a less activated phenotype, unlike their wildtype counterparts that expressed IFN-γ and especially granzyme B. This almost complete absence of local cellular responses was also associated with reduced parasite load in the brain.


Subject(s)
Dendritic Cells/immunology , Dendritic Cells/metabolism , Lectins, C-Type/physiology , Malaria, Cerebral/immunology , Malaria, Cerebral/pathology , Receptors, Immunologic/physiology , Animals , CD11c Antigen/biosynthesis , Cell Death/immunology , Clone Cells , Dendritic Cells/parasitology , Diphtheria Toxin/administration & dosage , Diphtheria Toxin/toxicity , Disease Models, Animal , Disease Resistance/genetics , Disease Resistance/immunology , Female , Humans , Lectins, C-Type/biosynthesis , Malaria, Cerebral/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Plasmodium berghei/immunology , Receptors, Immunologic/biosynthesis
14.
Mediators Inflamm ; 2014: 243713, 2014.
Article in English | MEDLINE | ID: mdl-25157202

ABSTRACT

Malaria is one of the most serious infectious diseases in humans and responsible for approximately 500 million clinical cases and 500 thousand deaths annually. Acquired adaptive immune responses control parasite replication and infection-induced pathologies. Most infections are clinically silent which reflects on the ability of adaptive immune mechanisms to prevent the disease. However, a minority of these can become severe and life-threatening, manifesting a range of overlapping syndromes of complex origins which could be induced by uncontrolled immune responses. Major players of the innate and adaptive responses are interferons. Here, we review their roles and the signaling pathways involved in their production and protection against infection and induced immunopathologies.


Subject(s)
Interferon Regulatory Factors/metabolism , Interferons/metabolism , Malaria/metabolism , Animals , Humans
15.
Front Cell Infect Microbiol ; 14: 1421571, 2024.
Article in English | MEDLINE | ID: mdl-39211797

ABSTRACT

Arthritogenic alphaviruses pose a significant public health concern due to their ability to cause joint inflammation, with emerging evidence of potential neurological consequences. In this review, we examine the immunopathology and immune evasion strategies employed by these viruses, highlighting their complex mechanisms of pathogenesis and neurological implications. We delve into how these viruses manipulate host immune responses, modulate inflammatory pathways, and potentially establish persistent infections. Further, we explore their ability to breach the blood-brain barrier, triggering neurological complications, and how co-infections exacerbate neurological outcomes. This review synthesizes current research to provide a comprehensive overview of the immunopathological mechanisms driving arthritogenic alphavirus infections and their impact on neurological health. By highlighting knowledge gaps, it underscores the need for research to unravel the complexities of virus-host interactions. This deeper understanding is crucial for developing targeted therapies to address both joint and neurological manifestations of these infections.


Subject(s)
Alphavirus Infections , Alphavirus , Blood-Brain Barrier , Host-Pathogen Interactions , Immune Evasion , Humans , Alphavirus/pathogenicity , Alphavirus/immunology , Animals , Alphavirus Infections/immunology , Alphavirus Infections/virology , Host-Pathogen Interactions/immunology , Blood-Brain Barrier/immunology , Nervous System Diseases/immunology , Nervous System Diseases/virology
16.
Cell Death Differ ; 31(3): 280-291, 2024 03.
Article in English | MEDLINE | ID: mdl-38383887

ABSTRACT

Detection of cytosolic nucleic acids by pattern recognition receptors, including STING and RIG-I, leads to the activation of multiple signalling pathways that culminate in the production of type I interferons (IFNs) which are vital for host survival during virus infection. In addition to protective immune modulatory functions, type I IFNs are also associated with autoimmune diseases. Hence, it is important to elucidate the mechanisms that govern their expression. In this study, we identified a critical regulatory function of the DUSP4 phosphatase in innate immune signalling. We found that DUSP4 regulates the activation of TBK1 and ERK1/2 in a signalling complex containing DUSP4, TBK1, ERK1/2 and IRF3 to regulate the production of type I IFNs. Mice deficient in DUSP4 were more resistant to infections by both RNA and DNA viruses but more susceptible to malaria parasites. Therefore, our study establishes DUSP4 as a regulator of nucleic acid sensor signalling and sheds light on an important facet of the type I IFN regulatory system.


Subject(s)
Interferon Type I , Membrane Proteins , Protein Tyrosine Phosphatases , Receptors, Cell Surface , Roundabout Proteins , Virus Diseases , Animals , Mice , Immunity, Innate , Interferon Type I/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Virus Diseases/immunology , Virus Diseases/metabolism , Membrane Proteins/metabolism , Roundabout Proteins/metabolism , Protein Tyrosine Phosphatases/metabolism , Receptors, Cell Surface/metabolism
17.
Front Cell Infect Microbiol ; 12: 899581, 2022.
Article in English | MEDLINE | ID: mdl-35677654

ABSTRACT

Malaria-associated acute respiratory distress syndrome (MA-ARDS) is increasingly gaining recognition as a severe malaria complication because of poor prognostic outcomes, high lethality rate, and limited therapeutic interventions. Unfortunately, invasive clinical studies are challenging to conduct and yields insufficient mechanistic insights. These limitations have led to the development of suitable MA-ARDS experimental mouse models. In patients and mice, MA-ARDS is characterized by edematous lung, along with marked infiltration of inflammatory cells and damage of the alveolar-capillary barriers. Although, the pathogenic pathways have yet to be fully understood, the use of different experimental mouse models is fundamental in the identification of mediators of pulmonary vascular damage. In this review, we discuss the current knowledge on endothelial activation, leukocyte recruitment, leukocyte induced-endothelial dysfunction, and other important findings, to better understand the pathogenesis pathways leading to endothelial pulmonary barrier lesions and increased vascular permeability. We also discuss how the advances in imaging techniques can contribute to a better understanding of the lung lesions induced during MA-ARDS, and how it could aid to monitor MA-ARDS severity.


Subject(s)
Malaria , Respiratory Distress Syndrome , Animals , Disease Models, Animal , Humans , Lung/pathology , Malaria/pathology , Mice , Mice, Inbred C57BL , Plasmodium berghei/physiology , Respiratory Distress Syndrome/etiology
18.
Mem Inst Oswaldo Cruz ; 104 Suppl 1: 281-7, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19753486

ABSTRACT

Vaccines have had an unquestionable impact on public health during the last century. The most likely reason for the success of vaccines is the robust protective properties of specific antibodies. However, antibodies exert a strong selective pressure and many microorganisms, such as the obligatory intracellular parasite Trypanosoma cruzi, have been selected to survive in their presence. Although the host develops a strong immune response to T. cruzi, they do not clear the infection and instead progress to the chronic phase of the disease. Parasite persistence during the chronic phase of infection is now considered the main factor contributing to the chronic symptoms of the disease. Based on this finding, containment of parasite growth and survival may be one method to avoid the immunopathology of the chronic phase. In this context, vaccinologists have looked over the past 20 years for other immune effector mechanisms that could eliminate these antibody-resistant pathogens. We and others have tested the hypothesis that non-antibody-mediated cellular immune responses (CD4+ Th1 and CD8+ Tc1 cells) to specific parasite antigens/genes expressed by T. cruzi could indeed be used for the purpose of vaccination. This hypothesis was confirmed in different mouse models, indicating a possible path for vaccine development.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Chagas Disease/immunology , Protozoan Vaccines/immunology , Trypanosoma cruzi/immunology , Animals , Antigens, Protozoan/genetics , Antigens, Protozoan/immunology , Chagas Disease/prevention & control , Disease Models, Animal , Immunity, Cellular , Mice , Trypanosoma cruzi/genetics
20.
Nat Commun ; 10(1): 4241, 2019 09 18.
Article in English | MEDLINE | ID: mdl-31534124

ABSTRACT

Malaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8+T cells with anti-CD8ß antibodies in C57BL/6 mice infected with P. berghei ANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8+T cells into PbA-infected TCRß-/- mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8+T cells in an IFNγ-dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8+T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.


Subject(s)
Acute Lung Injury/pathology , CD8-Positive T-Lymphocytes/immunology , Cross-Priming/immunology , Interferon-gamma/immunology , Malaria/immunology , Respiratory Distress Syndrome/pathology , Acute Lung Injury/immunology , Acute Lung Injury/parasitology , Animals , Disease Models, Animal , Endothelial Cells/immunology , Female , Lung/parasitology , Lung/pathology , Malaria/drug therapy , Malaria/parasitology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Plasmodium berghei/immunology , Pulmonary Edema/parasitology , Pulmonary Edema/pathology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/parasitology
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