Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
1.
J Immunol ; 210(12): 1913-1924, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37133343

RESUMO

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is an ultra-rare combined primary immunodeficiency disease caused by heterozygous gain-of-function mutations in the chemokine receptor CXCR4. WHIM patients typically present with recurrent acute infections associated with myelokathexis (severe neutropenia due to bone marrow retention of mature neutrophils). Severe lymphopenia is also common, but the only associated chronic opportunistic pathogen is human papillomavirus and mechanisms are not clearly defined. In this study, we show that WHIM mutations cause more severe CD8 than CD4 lymphopenia in WHIM patients and WHIM model mice. Mechanistic studies in mice revealed selective and WHIM allele dose-dependent accumulation of mature CD8 single-positive cells in thymus in a cell-intrinsic manner due to prolonged intrathymic residence, associated with increased CD8 single-positive thymocyte chemotactic responses in vitro toward the CXCR4 ligand CXCL12. In addition, mature WHIM CD8+ T cells preferentially home to and are retained in the bone marrow in mice in a cell-intrinsic manner. Administration of the specific CXCR4 antagonist AMD3100 (plerixafor) in mice rapidly and transiently corrected T cell lymphopenia and the CD4/CD8 ratio. After lymphocytic choriomeningitis virus infection, we found no difference in memory CD8+ T cell differentiation or viral load between wild-type and WHIM model mice. Thus, lymphopenia in WHIM syndrome may involve severe CXCR4-dependent CD8+ T cell deficiency resulting in part from sequestration in the primary lymphoid organs, thymus, and bone marrow.


Assuntos
Agamaglobulinemia , Compostos Heterocíclicos , Síndromes de Imunodeficiência , Linfopenia , Neutropenia , Humanos , Animais , Camundongos , Síndromes de Imunodeficiência/genética , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Agamaglobulinemia/complicações , Agamaglobulinemia/genética , Neutropenia/genética , Linfócitos T CD8-Positivos , Receptores CXCR4/genética
2.
Proc Natl Acad Sci U S A ; 119(26): e2116738119, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35749366

RESUMO

Tumor infiltration by T cells profoundly affects cancer progression and responses to immunotherapy. However, the tumor immunosuppressive microenvironment can impair the induction, trafficking, and local activity of antitumor T cells. Here, we investigated whether intratumoral injection of virus-derived peptide epitopes could activate preexisting antiviral T cell responses locally and promote antitumor responses or antigen spreading. We focused on a mouse model of cytomegalovirus (CMV), a highly prevalent human infection that induces vigorous and durable T cell responses. Mice persistently infected with murine CMV (MCMV) were challenged with lung (TC-1), colon (MC-38), or melanoma (B16-F10) tumor cells. Intratumoral injection of MCMV-derived T cell epitopes triggered in situ and systemic expansion of their cognate, MCMV-specific CD4+ or CD8+ T cells. The MCMV CD8+ T cell epitopes injected alone provoked arrest of tumor growth and some durable remissions. Intratumoral injection of MCMV CD4+ T cell epitopes with polyinosinic acid:polycytidylic acid (pI:C) preferentially elicited tumor antigen-specific CD8+ T cells, promoted tumor clearance, and conferred long-term protection against tumor rechallenge. Notably, secondary proliferation of MCMV-specific CD8+ T cells correlated with better tumor control. Importantly, intratumoral injection of MCMV-derived CD8+ T cell-peptide epitopes alone or CD4+ T cell-peptide epitopes with pI:C induced potent adaptive and innate immune activation of the tumor microenvironment. Thus, CMV-derived peptide epitopes, delivered intratumorally, act as cytotoxic and immunotherapeutic agents to promote immediate tumor control and long-term antitumor immunity that could be used as a stand-alone therapy. The tumor antigen-agnostic nature of this approach makes it applicable across a broad range of solid tumors regardless of their origin.


Assuntos
Linfócitos T CD8-Positivos , Infecções por Citomegalovirus , Citomegalovirus , Epitopos de Linfócito T , Neoplasias , Animais , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/imunologia , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/imunologia , Imunoterapia , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Poli I-C/administração & dosagem , Poli I-C/imunologia , Microambiente Tumoral
3.
PLoS Biol ; 19(5): e3001259, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34038417

RESUMO

Removal of apoptotic cells is essential for maintenance of tissue homeostasis. Chemotactic cues termed "find-me" signals attract phagocytes toward apoptotic cells, which selectively expose the anionic phospholipid phosphatidylserine (PS) and other "eat-me" signals to distinguish healthy from apoptotic cells for phagocytosis. Blebs released by apoptotic cells can deliver find-me signals; however, the mechanism is poorly understood. Here, we demonstrate that apoptotic blebs generated in vivo from mouse thymus attract phagocytes using endogenous chemokines bound to the bleb surface. We show that chemokine binding to apoptotic cells is mediated by PS and that high affinity binding of PS and other anionic phospholipids is a general property of many but not all chemokines. Chemokines are positively charged proteins that also bind to anionic glycosaminoglycans (GAGs) on cell surfaces for presentation to leukocyte G protein-coupled receptors (GPCRs). We found that apoptotic cells down-regulate GAGs as they up-regulate PS on the cell surface and that PS-bound chemokines, unlike GAG-bound chemokines, are able to directly activate chemokine receptors. Thus, we conclude that PS-bound chemokines may serve as find-me signals on apoptotic vesicles acting at cognate chemokine receptors on leukocytes.


Assuntos
Apoptose , Quimiocinas , Animais , Feminino , Humanos , Masculino , Camundongos , Apoptose/imunologia , Apoptose/fisiologia , Membrana Celular/metabolismo , Quimiocinas/metabolismo , Quimiocinas/fisiologia , Quimiotaxia , Células CHO , Cricetulus , Camundongos Endogâmicos C57BL , Fagócitos/metabolismo , Fagocitose/fisiologia , Fosfatidilserinas/metabolismo , Receptores de Quimiocinas/metabolismo , Transdução de Sinais/fisiologia
4.
Proc Natl Acad Sci U S A ; 117(43): 26885-26894, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33046647

RESUMO

Ectromelia virus (ECTV) causes mousepox, a surrogate mouse model for smallpox caused by variola virus in humans. Both orthopoxviruses encode tumor necrosis factor receptor (TNFR) homologs or viral TNFR (vTNFR). These homologs are termed cytokine response modifier (Crm) proteins, containing a TNF-binding domain and a chemokine-binding domain called smallpox virus-encoded chemokine receptor (SECRET) domain. ECTV encodes one vTNFR known as CrmD. Infection of ECTV-resistant C57BL/6 mice with a CrmD deletion mutant virus resulted in uniform mortality due to excessive TNF secretion and dysregulated inflammatory cytokine production. CrmD dampened pathology, leukocyte recruitment, and inflammatory cytokine production in lungs including TNF, IL-6, IL-10, and IFN-γ. Blockade of TNF, IL-6, or IL-10R function with monoclonal antibodies reduced lung pathology and provided 60 to 100% protection from otherwise lethal infection. IFN-γ caused lung pathology only when both the TNF-binding and SECRET domains were absent. Presence of the SECRET domain alone induced significantly higher levels of IL-1ß, IL-6, and IL-10, likely overcoming any protective effects that might have been afforded by anti-IFN-γ treatment. The use of TNF-deficient mice and those that express only membrane-associated but not secreted TNF revealed that CrmD is critically dependent on host TNF for its function. In vitro, recombinant Crm proteins from different orthopoxviruses bound to membrane-associated TNF and dampened inflammatory gene expression through reverse signaling. CrmD does not affect virus replication; however, it provides the host advantage by enabling survival. Host survival would facilitate virus spread, which would also provide an advantage to the virus.


Assuntos
Vírus da Ectromelia/fisiologia , Interações Hospedeiro-Patógeno , Receptores do Fator de Necrose Tumoral/metabolismo , Infecções Respiratórias/virologia , Proteínas Virais/metabolismo , Animais , Linhagem Celular , Chlorocebus aethiops , Feminino , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções Respiratórias/patologia , Carga Viral
5.
J Biol Chem ; 296: 100373, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33548230

RESUMO

Mouse Ccr1l1 (Ccr1-like 1) encodes an orphan G-protein-coupled receptor (GPCR) with the highest homology to the inflammatory and highly promiscuous chemokine receptors Ccr1 and Ccr3 (70 and 50% amino acid identity, respectively). Ccr1l1 was first cloned in 1995, yet current knowledge of this putative chemokine receptor is limited to its gene organization and chromosomal localization. Here we report that Ccr1l1 is a Rodentia-specific gene selectively expressed in eosinophils. However, eosinophil phenotypes, development, and responsiveness to chemokines were all normal in naïve Ccr1l1 knockout mice. We demonstrate for the first time that recombinant Ccr1l1 is expressed on the plasma membrane of transfected cells and contains an extracellular N terminus and an intracellular C terminus, consistent with GPCR topology. Using receptor internalization, ß-arrestin recruitment, calcium flux, and chemotaxis assays, we excluded all 37 available mouse chemokines, including Ccr1 ligands, and two viral chemokines as Ccr1l1 ligands, and demonstrated that mouse Ccr1, but not Ccr1l1, exhibits constitutive signaling activity. However, sequence analysis and structural modeling revealed that Ccr1l1 is well equipped to act as a classical signaling GPCR, with N-terminal sulfotyrosines as the only signaling and chemokine-binding determinant absent in Ccr1l1. Hereof, we show that a sulfatable N-terminal Ccr1 Y18 residue is essential for chemotaxis and calcium responses induced by Ccl3 and Ccl9/10, but substituting the corresponding Ccr1l1 F19 residue with tyrosine failed to confer responsiveness to Ccr1 ligands. Although Ccr1l1 remains an extreme outlier in the chemokine receptor family, our study supports that it might respond to unidentified mouse chemokine ligands in eosinophil-driven immune responses.


Assuntos
Receptores CCR1/metabolismo , Animais , Membrana Celular/metabolismo , Quimiocinas/metabolismo , Quimiocinas CC/metabolismo , Quimiotaxia de Leucócito , Eosinófilos/metabolismo , Feminino , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Receptores CCR1/fisiologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Roedores/genética , Transdução de Sinais , Relação Estrutura-Atividade
6.
J Biol Chem ; 294(13): 5214-5227, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30723161

RESUMO

Etanercept is a soluble form of the tumor necrosis factor receptor 2 (TNFR2) that inhibits pathological tumor necrosis factor (TNF) responses in rheumatoid arthritis and other inflammatory diseases. However, besides TNF, etanercept also blocks lymphotoxin-α (LTα), which has no clear therapeutic value and might aggravate some of the adverse effects associated with etanercept. Poxviruses encode soluble TNFR2 homologs, termed viral TNF decoy receptors (vTNFRs), that display unique specificity properties. For instance, cytokine response modifier D (CrmD) inhibits mouse and human TNF and mouse LTα, but it is inactive against human LTα. Here, we analyzed the molecular basis of these immunomodulatory activities in the ectromelia virus-encoded CrmD. We found that the overall molecular mechanism to bind TNF and LTα from mouse and human origin is fairly conserved in CrmD and dominated by a groove under its 50s loop. However, other ligand-specific binding determinants optimize CrmD for the inhibition of mouse ligands, especially mouse TNF. Moreover, we show that the inability of CrmD to inhibit human LTα is caused by a Glu-Phe-Glu motif in its 90s loop. Importantly, transfer of this motif to etanercept diminished its anti-LTα activity in >60-fold while weakening its TNF-inhibitory capacity in 3-fold. This new etanercept variant could potentially be used in the clinic as a safer alternative to conventional etanercept. This work is the most detailed study of the vTNFR-ligand interactions to date and illustrates that a better knowledge of vTNFRs can provide valuable information to improve current anti-TNF therapies.


Assuntos
Vírus da Ectromelia/imunologia , Fatores Imunológicos/imunologia , Linfotoxina-alfa/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Receptores Chamariz do Fator de Necrose Tumoral/imunologia , Proteínas Virais/imunologia , Sequência de Aminoácidos , Animais , Vírus da Ectromelia/química , Ectromelia Infecciosa/virologia , Humanos , Fatores Imunológicos/química , Camundongos , Modelos Moleculares , Domínios Proteicos , Fator de Necrose Tumoral alfa/imunologia , Proteínas Virais/química
7.
J Biol Chem ; 292(23): 9613-9626, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28432120

RESUMO

Chemokines are essential for antimicrobial host defenses and tissue repair. Herpesviruses and poxviruses also encode chemokines, copied from their hosts and repurposed for multiple functions, including immune evasion. The CC chemokine MCK-2 encoded by mouse CMV (MCMV) has an atypical structure consisting of a classic chemokine domain N-terminal to a second unique domain, resulting from the splicing of MCMV ORFs m131 and m129 MCK-2 is essential for full MCMV infectivity in macrophages and for persistent infection in the salivary gland. However, information about its mechanism of action and specific biochemical roles for the two domains has been lacking. Here, using genetic, chemical, and enzymatic analyses of multiple mouse cell lines as well as primary mouse fibroblasts from salivary gland and lung, we demonstrate that MCK-2 binds glycosaminoglycans (GAGs) with affinities in the following order: heparin > heparan sulfate > chondroitin sulfate = dermatan sulfate. Both MCK-2 domains bound these GAGs independently, and computational analysis together with site-directed mutagenesis identified five basic residues distributed across the N terminus and the 30s and 50s loops of the chemokine domain that are important GAG binding determinants. Both domains were required for GAG-dependent oligomerization of full-length MCK-2. Thus, MCK-2 is an atypical viral chemokine consisting of a CC chemokine domain and a unique non-chemokine domain, both of which bind GAGs and are critical for GAG-dependent oligomerization of the full-length protein.


Assuntos
Quimiocinas CC/química , Quimiocinas CC/metabolismo , Muromegalovirus/química , Muromegalovirus/metabolismo , Multimerização Proteica/fisiologia , Proteínas Virais/química , Proteínas Virais/metabolismo , Animais , Quimiocinas CC/genética , Glicosaminoglicanos/química , Glicosaminoglicanos/genética , Glicosaminoglicanos/metabolismo , Células HEK293 , Humanos , Camundongos , Muromegalovirus/genética , Células NIH 3T3 , Fases de Leitura Aberta/fisiologia , Domínios Proteicos , Estrutura Secundária de Proteína , Proteínas Virais/genética
8.
J Biol Chem ; 290(26): 15973-84, 2015 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-25940088

RESUMO

The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin ß. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin ß. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs.


Assuntos
Vírus da Varíola Bovina/metabolismo , Poxviridae/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/química , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Receptores Chamariz do Fator de Necrose Tumoral/química , Receptores Chamariz do Fator de Necrose Tumoral/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo , Sequência de Aminoácidos , Animais , Vírus da Varíola Bovina/química , Vírus da Varíola Bovina/genética , Humanos , Linfotoxina-beta/metabolismo , Camundongos , Dados de Sequência Molecular , Poxviridae/química , Poxviridae/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Alinhamento de Sequência , Receptores Chamariz do Fator de Necrose Tumoral/genética , Fatores de Necrose Tumoral/metabolismo , Proteínas Virais/genética
9.
J Gen Virol ; 96(10): 3118-3123, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26242179

RESUMO

Poxviruses encode up to four different soluble TNF receptors, named cytokine response modifier B (CrmB), CrmC, CrmD and CrmE. These proteins mimic the extracellular domain of the cellular TNF receptors to bind and inhibit the activity of TNF and, in some cases, other TNF superfamily ligands. Most of these ligands are released after the enzymic cleavage of a membrane precursor. However, transmembrane TNF (tmTNF) is not only a precursor of soluble TNF but also exerts specific pro-inflammatory and immunological activities. Here, we report that viral TNF receptors bound and inhibited tmTNF and describe some interesting differences in their activity against the soluble cytokine. Thus, CrmE, which does not inhibit mouse soluble TNF, could block murine tmTNF-induced cytotoxicity. We propose that this anti-tmTNF effect should be taken into consideration when assessing the role of viral TNF decoy receptors in the pathogenesis of poxvirus.


Assuntos
Evasão da Resposta Imune , Poxviridae/imunologia , Poxviridae/fisiologia , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Virais/metabolismo , Animais , Linhagem Celular , Fibroblastos/imunologia , Fibroblastos/virologia , Macrófagos/imunologia , Macrófagos/virologia , Camundongos
10.
bioRxiv ; 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39091850

RESUMO

Classically, chemokines coordinate leukocyte trafficking during immune responses; however, many chemokines have also been reported to possess direct antibacterial activity in vitro. Yet, the bacterial killing mechanism of chemokines and the biochemical properties that define which members of the chemokine superfamily are antimicrobial remain poorly understood. Here we report that the antimicrobial activity of chemokines is defined by their ability to bind phosphatidylglycerol and cardiolipin, two anionic phospholipids commonly found in the bacterial plasma membrane. We show that only chemokines able to bind these two phospholipids kill Escherichia coli and Staphylococcus aureus and that they exert rapid bacteriostatic and bactericidal effects against E. coli with a higher potency than the antimicrobial peptide beta-defensin 3. Furthermore, our data support that bacterial membrane cardiolipin facilitates the antimicrobial action of chemokines. Both biochemical and genetic interference with the chemokine-cardiolipin interaction impaired microbial growth arrest, bacterial killing, and membrane disruption by chemokines. Moreover, unlike conventional antibiotics, E. coli failed to develop resistance when placed under increasing antimicrobial chemokine pressure in vitro. Thus, we have identified cardiolipin and phosphatidylglycerol as novel binding partners for chemokines responsible for chemokine antimicrobial action. Our results provide proof of principle for developing chemokines as novel antibiotics resistant to bacterial antimicrobial resistance mechanisms.

11.
Virol J ; 10: 188, 2013 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-23758704

RESUMO

BACKGROUND: Lymphocystis disease virus (LCDV) is a large icosahedral dsDNA-containing virus of the Lymphocystivirus genus within the Iridoviridae family that can cause disease in more than 140 marine and freshwater fish species. While several isolates have been charcaterized and classified into distinct genotypes the complete genomic sequence is currently only available from two species, the LCDV-1, isolated from flounder (Platichtys flesus) in Europe and the LCDV-C, isolated from Japanese cultured flounder (Paralichthys olivaceus) in China. Analysis of the genome of LCDV-C showed it to encode a protein named LDVICp016 with similarities to the Tumour necrosis factor receptor (TNFR) superfamily with immunomodulatory potential. FINDINGS: We have expressed and purified the recombinant protein LDVICp016 and screened for potential interaction partners using surface plasmon resonance. Commercially available human and mouse members of the TNF superfamily (TNFSF), along with a representative set of fish-derived TNFSF were tested.We have found the LDVICp016 protein to be secreted and we have identified a second viral TNFR encoded by ORF 095 of the same virus. None of the 42 tested proteins were found to interact with LDVICp016. CONCLUSIONS: We show that LDVICp016 is a secreted protein belonging to the TNF receptor family that may be part of a larger gene family in Lymphocystiviruses. While the ligand of this protein remains unknown, possibly due to the species specific nature of this interaction, further investigations into the potential role of this protein in the blockade of immune responses in its fish host are required.


Assuntos
Iridoviridae/genética , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Animais , Peixes , Humanos , Camundongos , Ligação Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
12.
Front Immunol ; 14: 1021824, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37153622

RESUMO

Mucosal delivery of IL-27 has been shown to have a therapeutic benefit in murine models of inflammatory bowel disease (IBD). The IL-27 effect was associated with phosphorylated STAT1 (pSTAT1), a product of IL27 receptor signaling, in bowel tissue. To determine whether IL-27 acted directly on colonic epithelium, murine colonoids and primary intact colonic crypts were shown to be unresponsive to IL-27 in vitro and to lack detectable IL-27 receptors. On the other hand, macrophages, which are present in inflamed colon tissue, were responsive to IL-27 in vitro. IL-27 induced pSTAT1 in macrophages, the transcriptome indicated an IFN-like signature, and supernatants induced pSTAT1 in colonoids. IL-27 induced anti-viral activity in macrophages and MHC Class II induction. We conclude that the effects of mucosal delivery of IL-27 in murine IBD are in part based on the known effects of IL27 inducing immunosuppression of T cells mediated by IL-10. We also conclude that IL-27 has potent effects on macrophages in inflamed colon tissue, generating mediators that in turn act on colonic epithelium.


Assuntos
Doenças Inflamatórias Intestinais , Interleucina-27 , Camundongos , Animais , Interleucina-27/uso terapêutico , Colo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Macrófagos , Epitélio
13.
Immunohorizons ; 6(7): 543-558, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35882421

RESUMO

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome immunodeficiency is caused by autosomal dominant gain-of-function CXCR4 mutations that promote severe panleukopenia caused by bone marrow retention of mature leukocytes. Consequently, WHIM patients develop recurrent bacterial infections; however, sepsis is uncommon. To study this clinical dichotomy, we challenged WHIM model mice with LPS. The LD50 was similar in WHIM and wild-type (WT) mice, and LPS induced acute lymphopenia in WT mice that was Cxcr4 independent. In contrast, in WHIM mice, LPS did not affect circulating T cell levels, but the B cell levels anomalously increased because of selective, cell-intrinsic, and Cxcr4 WHIM allele-dependent emergence of Cxcr4high late pre-B cells, a pattern that was phenocopied by Escherichia coli infection. In both WT and WHIM mice, the CXCR4 antagonist AMD3100 rapidly increased circulating lymphocyte levels that then rapidly contracted after subsequent LPS treatment. Thus, LPS-induced lymphopenia is CXCR4 independent, and a WHIM mutation does not increase clinical LPS sensitivity. Anomalous WT Cxcr4-independent, but Cxcr4 WHIM-dependent, promobilizing effects of LPS on late pre-B cell mobilization reveal a distinct signaling pathway for the variant receptor.


Assuntos
Agamaglobulinemia , Linfopenia , Neutropenia , Verrugas , Agamaglobulinemia/genética , Animais , Endotoxinas/uso terapêutico , Lipopolissacarídeos , Camundongos , Neutropenia/genética , Doenças da Imunodeficiência Primária , Verrugas/tratamento farmacológico , Verrugas/genética
14.
Science ; 373(6561): eabi8835, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34529475

RESUMO

Puel and Casanova and Kisand et al. challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathy­candidiasis­ectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases. However, our studies clearly document interferonopathy driving mucosal candidiasis with intact IL-17/IL-22 responses in Aire-deficient mice, with strong corroborative evidence in patients.


Assuntos
Imunidade nas Mucosas , Micoses , Humanos , Mucosa , Animais , Camundongos
15.
Science ; 371(6526)2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33446526

RESUMO

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.


Assuntos
Candida albicans/imunologia , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Imunidade nas Mucosas/imunologia , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Adolescente , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Humanos , Imunidade nas Mucosas/genética , Vigilância Imunológica/genética , Vigilância Imunológica/imunologia , Interferon gama/genética , Interleucinas/genética , Janus Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Receptores de Interleucina-17/genética , Fator de Transcrição STAT1/genética , Linfócitos T/imunologia , Adulto Jovem , Interleucina 22
16.
Viruses ; 12(1)2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31892128

RESUMO

Many viruses initiate interaction with target cells by binding to cell surface glycosaminoglycans (GAGs). Heparan sulfate (HS) appears to be particularly important in fibroblasts, epithelial cells and endothelial cells, where it represents the dominant GAG. How GAGs influence viral infectivity in HS-poor target cells such as macrophages has not been clearly defined. Here, we show that mouse cytomegalovirus (MCMV) targets HS in susceptible fibroblasts and cultured salivary gland acinar cells (SGACs), but not in macrophage cell lines and primary bone marrow-derived macrophages, where chondroitin sulfate was the dominant virus-binding GAG. MCK-2, an MCMV-encoded GAG-binding chemokine that promotes infection of macrophages as part of a gH/gL/MCK-2 entry complex, was dispensable for MCMV attachment to the cell surface and for direct infection of SGACs. Thus, MCMV tropism for target cells is markedly influenced by differential GAG expression, suggesting that the specificity of anti-GAG peptides now under development as HCMV therapeutics may need to be broadened for effective application as anti-viral agents.


Assuntos
Quimiocinas CC/imunologia , Sulfatos de Condroitina/metabolismo , Interações entre Hospedeiro e Microrganismos , Macrófagos/virologia , Muromegalovirus/fisiologia , Proteínas Virais/imunologia , Internalização do Vírus , Animais , Linhagem Celular , Quimiocinas CC/genética , Fibroblastos/virologia , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Proteínas Virais/genética , Proteínas Virais/metabolismo , Tropismo Viral
17.
J Innate Immun ; 10(5-6): 465-478, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30165356

RESUMO

Viruses use diverse molecular mechanisms to exploit and evade the immune response. Herpesviruses, in particular, encode functional chemokine and chemokine receptor homologs pirated from the host, as well as secreted chemokine-binding proteins with unique structures. Multiple functions have been described for herpesvirus chemokine components, including attraction of target cells, blockade of leukocyte migration, and modulation of gene expression and cell entry by the virus. Here we review current concepts about how human herpesvirus chemokines, chemokine receptors, and chemokine-binding proteins may be used to shape a proviral state in the host.


Assuntos
Infecções por Herpesviridae/imunologia , Herpesviridae/fisiologia , Leucócitos/imunologia , Animais , Movimento Celular , Quimiocinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Evasão da Resposta Imune , Leucócitos/virologia , Receptores de Quimiocinas/metabolismo
18.
Nat Commun ; 9(1): 1790, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29724993

RESUMO

The role of cytokines and chemokines in anti-viral defense has been demonstrated, but their relative contribution to protective anti-viral responses in vivo is not fully understood. Cytokine response modifier D (CrmD) is a secreted receptor for TNF and lymphotoxin containing the smallpox virus-encoded chemokine receptor (SECRET) domain and is expressed by ectromelia virus, the causative agent of the smallpox-like disease mousepox. Here we show that CrmD is an essential virulence factor that controls natural killer cell activation and allows progression of fatal mousepox, and demonstrate that both SECRET and TNF binding domains are required for full CrmD activity. Vaccination with recombinant CrmD protects animals from lethal mousepox. These results indicate that a specific set of chemokines enhance the inflammatory and protective anti-viral responses mediated by TNF and lymphotoxin, and illustrate how viruses optimize anti-TNF strategies with the addition of a chemokine binding domain as soluble decoy receptors.


Assuntos
Quimiocinas/fisiologia , Ectromelia Infecciosa/imunologia , Ectromelia Infecciosa/prevenção & controle , Inflamação/etiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Feminino , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Poxviridae/patogenicidade , Fatores de Virulência/fisiologia , Replicação Viral
19.
J Leukoc Biol ; 102(5): 1199-1217, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28848041

RESUMO

Viruses use diverse strategies to elude the immune system, including copying and repurposing host cytokine and cytokine receptor genes. For herpesviruses, the chemokine system of chemotactic cytokines and receptors is a common source of copied genes. Here, we review the current state of knowledge about herpesvirus-encoded chemokines and discuss their possible roles in viral pathogenesis, as well as their clinical potential as novel anti-inflammatory agents or targets for new antiviral strategies.


Assuntos
Quimiocinas/imunologia , Infecções por Herpesviridae/virologia , Herpesviridae/imunologia , Evasão da Resposta Imune , Receptores de Quimiocinas/imunologia , Animais , Quimiocinas/classificação , Quimiocinas/genética , Células Dendríticas/imunologia , Células Dendríticas/virologia , Regulação da Expressão Gênica , Herpesviridae/classificação , Herpesviridae/crescimento & desenvolvimento , Infecções por Herpesviridae/classificação , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Humanos , Monócitos/imunologia , Monócitos/virologia , Filogenia , Receptores de Quimiocinas/classificação , Receptores de Quimiocinas/genética , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/virologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA