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1.
Rev Med Virol ; 31(1): 1-10, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32845042

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic is a rapidly evolving global emergency that continues to strain healthcare systems. Emerging research describes a plethora of patient factors-including demographic, clinical, immunologic, hematological, biochemical, and radiographic findings-that may be of utility to clinicians to predict COVID-19 severity and mortality. We present a synthesis of the current literature pertaining to factors predictive of COVID-19 clinical course and outcomes. Findings associated with increased disease severity and/or mortality include age > 55 years, multiple pre-existing comorbidities, hypoxia, specific computed tomography findings indicative of extensive lung involvement, diverse laboratory test abnormalities, and biomarkers of end-organ dysfunction. Hypothesis-driven research is critical to identify the key evidence-based prognostic factors that will inform the design of intervention studies to improve the outcomes of patients with COVID-19 and to appropriately allocate scarce resources.


Assuntos
COVID-19 , Índice de Gravidade de Doença , Adulto , Envelhecimento , Biomarcadores , COVID-19/mortalidade , COVID-19/patologia , COVID-19/transmissão , Criança , Comorbidade , Humanos , Hipóxia/patologia , Prognóstico , SARS-CoV-2/patogenicidade
3.
PLoS One ; 7(8): e42850, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22880122

RESUMO

Various cell types in both lymphoid and non-lymphoid tissues produce the anti-inflammatory cytokine interleukin (IL)-10 during murine cytomegalovirus (MCMV) infection. The functions of IL-10 in the liver during acute infection and the cells that generate this cytokine at this site have not been extensively investigated. In this study, we demonstrate that the production of IL-10 in the liver is elevated in C57BL/6 mice during late acute MCMV infection. Using IL-10 green fluorescence protein (GFP) reporter knock-in mice, designated IL-10-internal ribosomal entry site (IRES)-GFP-enhanced reporter (tiger), NK cells are identified as major IL-10 expressing cells in the liver after infection, along with T cells and other leukocytes. In the absence of IL-10, mice exhibit marked elevations in proinflammatory cytokines and in the numbers of mononuclear cells and lymphocytes infiltrating the liver during this infection. IL-10-deficiency also enhances liver injury without improving viral clearance from this site. Collectively, the results indicate that IL-10-producing cells in the liver provide protection from collateral injury by modulating the inflammatory response associated with MCMV infection.


Assuntos
Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Inflamação/patologia , Interleucina-10/metabolismo , Fígado/imunologia , Fígado/patologia , Muromegalovirus/fisiologia , Doença Aguda , Alanina Transaminase/sangue , Animais , Linfócitos T CD8-Positivos , Quimiocinas/biossíntese , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/virologia , Inflamação/sangue , Inflamação/complicações , Inflamação/microbiologia , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-10/biossíntese , Interleucina-10/deficiência , Leucócitos/metabolismo , Fígado/virologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral
4.
PLoS One ; 7(6): e39161, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22723955

RESUMO

Antiviral defense in the liver during acute infection with the hepatotropic virus murine cytomegalovirus (MCMV) involves complex cytokine and cellular interactions. However, the mechanism of viral sensing in the liver that promotes these cytokine and cellular responses has remained unclear. Studies here were undertaken to investigate the role of nucleic acid-sensing Toll-like receptors (TLRs) in initiating antiviral immunity in the liver during infection with MCMV. We examined the host response of UNC93B1 mutant mice, which do not signal properly through TLR3, TLR7 and TLR9, to acute MCMV infection to determine whether liver antiviral defense depends on signaling through these molecules. Infection of UNC93B1 mutant mice revealed reduced production of systemic and liver proinflammatory cytokines including IFN-α, IFN-γ, IL-12 and TNF-α when compared to wild-type. UNC93B1 deficiency also contributed to a transient hepatitis later in acute infection, evidenced by augmented liver pathology and elevated systemic alanine aminotransferase levels. Moreover, viral clearance was impaired in UNC93B1 mutant mice, despite intact virus-specific CD8+ T cell responses in the liver. Altogether, these results suggest a combined role for nucleic acid-sensing TLRs in promoting early liver antiviral defense during MCMV infection.


Assuntos
Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/metabolismo , Imunidade Inata , Inflamação/imunologia , Fígado/imunologia , Proteínas de Membrana Transportadoras/metabolismo , Muromegalovirus/imunologia , Animais , Citocinas/biossíntese , Citocinas/imunologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/virologia , Fígado/virologia , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Linfócitos T/imunologia , Receptores Toll-Like/metabolismo
5.
J Immunol ; 183(4): 2810-7, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19620305

RESUMO

Monocytes/macrophages are critical early innate immune responders during murine CMV (MCMV) infection. It has been established that inflammatory monocyte/macrophages are released from the bone marrow and into the peripheral blood before entry into infected tissue sites. We previously reported a role for IFN-alpha/beta in promotion of CCR2-mediated recruitment of monocyte/macrophages into the liver in response to MCMV infection. However, the mechanisms that support the migration of monocyte/macrophages from the bone marrow and into the peripheral blood under conditions of MCMV infection have not been elucidated. Herein, we demonstrate an accumulation of monocyte/macrophages in the bone marrow of MCMV-infected CCR2-deficient mice, whereas circulating monocyte/macrophages are profoundly diminished. The CCR2 ligands MCP-1, MCP-3, and MCP-5 are detected in bone marrow and in serum from MCMV-infected mice. Furthermore, bone marrow leukocytes from naive mice produce high levels of MCP-1 and MCP-5, and moderate levels of MCP-3, when stimulated with recombinant IFN-alpha in culture. We identify bone marrow F4/80(+) cells as major producers of MCP-1, MCP-3, and MCP-5. Moreover, induction of CCR2 ligands is dependent on IFN-alpha/beta-mediated signals and MCMV infection. Taken together, the results reveal a critical role for inflammatory cytokines in stimulating production of CCR2-binding chemokines from F4/80(+) cells in the bone marrow, and they suggest that local production of chemokines supports monocyte/macrophage egress from the bone marrow into the blood during a virus infection.


Assuntos
Células da Medula Óssea/imunologia , Infecções por Herpesviridae/imunologia , Mediadores da Inflamação/fisiologia , Interferon-alfa/fisiologia , Interferon beta/fisiologia , Muromegalovirus/imunologia , Receptores CCR2/biossíntese , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Células Cultivadas , Quimiocina CCL2/biossíntese , Quimiocina CCL2/metabolismo , Quimiotaxia de Leucócito/imunologia , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/patologia , Ligantes , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Receptores CCR2/deficiência , Receptores CCR2/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/imunologia
6.
J Immunol ; 179(9): 6176-83, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17947693

RESUMO

Chemokine responses critical for inflammation and promotion of effective innate control of murine CMV (MCMV) in liver have been shown to be dependent on immunoregulatory functions elicited by IFN-alphabeta. However, it remains to be determined whether upstream factors that promote viral sensing resulting in the rapid secretion of IFN-alphabeta in liver differ from those described in other tissues. Because plasmacytoid dendritic cells (pDCs) are known producers of high levels of systemic IFN-alpha in response to MCMV, this study examines the in vivo contribution of pDCs to IFN-alpha production in the liver, and whether production of the cytokine and ensuing inflammatory events are dependent on TLR9, MyD88, or both. We demonstrate that whereas MyD88 deficiency markedly impaired secretion of IFN-alpha, production of the cytokine was largely independent of TLR9 signaling, in the liver. MyD88 and TLR9 were needed for IFN-alpha production in the spleen. Moreover, hepatic but not splenic pDCs produced significant amounts of intracellular IFN-alpha in the absence of TLR9 function during infection. Furthermore, production of CCL2, CCL3, and IFN-gamma, as well as the accumulation of macrophages and NK cells, was not affected in the absence of functional TLR9 in the liver. In contrast, these responses were dramatically reduced in MyD88(-/-) mice. Additionally, MyD88(-/-) but not TLR9(-/-) mice exhibited increased sensitivity to virus infection in liver. Collectively, our results define contrasting compartmental functions for TLR9 and MyD88, and suggest that the infected tissue site uniquely contributes to the process of virus sensing and regulation of localized antiviral responses.


Assuntos
Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Hepatopatias/metabolismo , Hepatopatias/virologia , Muromegalovirus/fisiologia , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , Infecções por Citomegalovirus/genética , Células Dendríticas/metabolismo , Inflamação/metabolismo , Interferon-alfa/biossíntese , Interferon beta/biossíntese , Hepatopatias/patologia , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Baço/metabolismo , Receptor Toll-Like 9/deficiência , Receptor Toll-Like 9/genética
7.
Am J Pathol ; 171(1): 87-96, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17591956

RESUMO

Although studies blocking the Fas pathway indicate it can decrease organ damage while improving septic (cecal ligation and puncture, CLP) mouse survival, little is known about how Fas-Fas ligand (FasL) interactions mediate this protection at the tissue level. Here, we report that although Fas expression on splenocytes and hepatocytes is up-regulated by CLP and is inhibited by in vivo short interfering RNA, FasL as well as the frequency of CD8(+) T cells are differentially altered by sepsis in the spleen (no change in FasL, decreased percentage of CD8(+) and CD4(+) T cells) versus the liver (increased FasL expression on CD8(+) T cells and increase in percentage/number). Adoptive transfer of CLP FasL(+/+) versus FasL(-/-) mouse liver CD8(+) T cells to severe combined immunodeficient or RAG1(-/-) recipient mice indicated that these cells could induce inflammation. The FasL-mediated cytotoxic capacity of these septic mouse liver CD8(+) T cells was shown by their ability to damage directly cultured hepatocytes. Finally, although CD8(-/-) mice exhibited a reduction in both CLP-induced liver active caspase-3 staining and blood interleukin-6 levels, only FasL(-/-) (but not CD8(-/-)) protected the septic mouse spleen from increasing apoptosis. Thus, although truncating Fas-FasL signaling ameliorates many untoward effects of sepsis, the pathological mode of action is distinct at the tissue level.


Assuntos
Apoptose , Linfócitos T CD8-Positivos/fisiologia , Proteína Ligante Fas/fisiologia , Hepatite/metabolismo , Sepse/imunologia , Receptor fas/fisiologia , Transferência Adotiva , Animais , Hepatite/imunologia , Inflamação/imunologia , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos SCID , Sepse/patologia , Transdução de Sinais , Baço/imunologia , Baço/metabolismo
8.
J Virol ; 81(3): 1241-50, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17108043

RESUMO

Innate inflammatory events promoting antiviral defense in the liver against murine cytomegalovirus (MCMV) infection have been characterized. However, the mechanisms that regulate the selective recruitment of inflammatory T lymphocytes to the liver during MCMV infection have not been defined. The studies presented here demonstrate the expression of monokine induced by gamma interferon (IFN-gamma; Mig/CXCL9) and IFN-gamma-inducible protein 10 (IP-10/CXCL10) in liver leukocytes and correlate their production with the infiltration of MCMV-specific CD8 T cells into the liver. Antibody-mediated neutralization of CXCL9 and CXCL10 and studies using mice deficient in CXCR3, the primary known receptor for these chemokines, revealed that CXCR3-dependent mechanisms promote the infiltration of virus-specific CD8 T cells into the liver during acute infection with MCMV. Furthermore, CXCR3 functions augmented the hepatic accumulation of CD8 T-cell IFN-gamma responses to MCMV. Evaluation of protective functions demonstrated enhanced pathology that overlapped with transient increases in virus titers in CXCR3-deficient mice. However, ultimate viral clearance and survival were not compromised. Thus, CXCR3-mediated signals support the accumulation of MCMV-specific CD8 T cells that contribute to, but are not exclusively required for, protective responses in a virus-infected tissue site.


Assuntos
Infecções por Citomegalovirus/imunologia , Ativação Linfocitária , Muromegalovirus/imunologia , Receptores de Quimiocinas/biossíntese , Linfócitos T/imunologia , Animais , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Muromegalovirus/efeitos dos fármacos , Muromegalovirus/crescimento & desenvolvimento , Receptores CXCR3 , Linfócitos T/metabolismo
9.
FASEB J ; 20(7): 896-905, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16675847

RESUMO

Leukocyte trafficking to the central nervous system (CNS), regulated in part by chemokines, determines severity of the demyelinating diseases multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). To examine chemokine receptor CX3CR1 in EAE, we studied CX3CR1(GFP/GFP) mice, in which CX3CR1 targeting by insertion of Green Fluorescent Protein (GFP) allowed tracking of CX3CR1+ cells in CX3CR1(+/GFP) animals and cells destined to express CX3CR1 in CX3CR1(GFP/GFP) knockouts. NK cells were markedly reduced in the inflamed CNS of CX3CR1-deficient mice with EAE, whereas recruitment of T cells, NKT cells and monocyte/macrophages to the CNS during EAE did not require CX3CR1. Impaired recruitment of NK cells in CX3CR1(GFP/GFP) mice was associated with increased EAE-related mortality, nonremitting spastic paraplegia and hemorrhagic inflammatory lesions. The absence of CD1d did not affect the severity of EAE in CX3CR1(GFP/GFP) mice, arguing against a role for NKT cells. Accumulation of NK cells in livers of wild-type (WT) and CX3CR1(GFP/GFP) mice with cytomegalovirus hepatitis was equivalent, indicating that CX3CL1 mediated chemoattraction of NK cells was relatively specific for the CNS. These results are the first to define a chemokine that governs NK cell migration to the CNS, and the findings suggest novel therapeutic manipulation of CX3CR1+ NK cells.


Assuntos
Sistema Nervoso Central/metabolismo , Quimiocinas CX3C/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Proteínas de Membrana/metabolismo , Animais , Antígenos CD1/metabolismo , Antígenos CD1d , Tronco Encefálico/patologia , Sistema Nervoso Central/patologia , Quimiocina CX3CL1 , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Hemorragia/patologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Paraparesia Espástica/fisiopatologia , Medula Espinal/patologia
10.
J Immunol ; 174(3): 1549-56, 2005 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-15661915

RESUMO

IFN-alpha/beta-mediated functions promote production of MIP-1alpha (or CCL3) by mediating the recruitment of MIP-1alpha-producing macrophages to the liver during early infection with murine CMV. These responses are essential for induction of NK cell inflammation and IFN-gamma delivery to support effective control of local infection. Nevertheless, it remains to be established if additional chemokine functions are regulated by IFN-alpha/beta and/or play intermediary roles in supporting macrophage trafficking. The chemokine MCP-1 (or CCL2) plays a distinctive role in the recruitment of macrophages by predominantly stimulating the CCR2 chemokine receptor. Here, we examine the roles of MCP-1 and CCR2 during murine CMV infection in liver. MCP-1 production preceded that of MIP-1alpha during infection and was dependent on IFN-alpha/beta effects for induction. Resident F4/80(+) liver leukocytes were identified as primary IFN-alpha/beta responders and major producers of MCP-1. Moreover, MCP-1 deficiency was associated with a dramatic reduction in the accumulation of macrophages and NK cells, as well as decreased production of MIP-1alpha and IFN-gamma in liver. These responses were also markedly impaired in mice with a targeted disruption of CCR2. Furthermore, MCP-1- and CCR2-deficient mice exhibited increased viral titers and elevated expression of the liver enzyme alanine aminotransferase in serum. These mice also had widespread virus-induced liver pathology and succumbed to infection. Collectively, these results establish MCP-1 and CCR2 interactions as factors promoting early liver inflammatory responses and define a mechanism for innate cytokines in regulation of chemokine functions critical for effective localized antiviral defenses.


Assuntos
Quimiocina CCL2/fisiologia , Infecções por Citomegalovirus/imunologia , Interferon Tipo I/fisiologia , Fígado/imunologia , Fígado/patologia , Receptores de Quimiocinas/fisiologia , Animais , Movimento Celular/genética , Movimento Celular/imunologia , Quimiocina CCL2/biossíntese , Quimiocina CCL2/deficiência , Quimiocina CCL2/genética , Quimiocina CCL3 , Quimiocina CCL4 , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Imunidade Inata , Inflamação/imunologia , Inflamação/virologia , Interferon Tipo I/administração & dosagem , Interferon Tipo I/uso terapêutico , Cinética , Fígado/metabolismo , Fígado/virologia , Proteínas Inflamatórias de Macrófagos/biossíntese , Proteínas Inflamatórias de Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muromegalovirus/imunologia , Receptores CCR2 , Receptores de Quimiocinas/biossíntese , Receptores de Quimiocinas/deficiência , Receptores de Quimiocinas/genética , Proteínas Recombinantes , Carga Viral
11.
Viral Immunol ; 16(3): 291-306, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14583145

RESUMO

The recruitment of immune effector cells to localized sites of infection is crucial for the effective delivery of innate immune mechanisms. Under the conditions of infections with murine cytomegalovirus (MCMV), a herpesvirus with pathogenic potential, early immune functions are essential in the control of virus replication and virus-induced pathology. Our studies have demonstrated that the chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) is critical for natural killer (NK) cell inflammation and delivery of interferon (IFN)-gamma to mediate downstream protective responses against MCMV infection in liver. Moreover, IFN-alpha/beta-dependent mechanisms promote MIP-1alpha production and subsequently the accumulation of NK cells in liver. Taken together, the studies highlighted in this review define a unique in vivo pathway mediated by innate cytokines in regulating chemokine responses that are essential in the promotion of NK cell inflammation for localized antiviral defense. In addition, the downstream consequences of these events in enhancing endogenous adaptive immune responses will also be discussed. Overall, the innate cytokine/chemokine networks that are described emphasize the emerging importance of chemokine functions for protective immune responses during infection with viruses.


Assuntos
Quimiocinas/biossíntese , Citocinas/biossíntese , Inflamação/imunologia , Animais , Quimiocina CCL3 , Quimiocina CCL4 , Infecções por Herpesviridae/imunologia , Humanos , Imunidade Inata , Interferon Tipo I/biossíntese , Células Matadoras Naturais/imunologia , Fígado/imunologia , Proteínas Inflamatórias de Macrófagos/biossíntese , Proteínas Inflamatórias de Macrófagos/deficiência , Camundongos , Modelos Imunológicos , Muromegalovirus/imunologia , Muromegalovirus/patogenicidade
12.
Immunity ; 19(1): 59-70, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12871639

RESUMO

Dendritic cells (DCs) present microbial antigens to T cells and provide inflammatory signals that modulate T cell differentiation. While the role of DCs in adaptive immunity is well established, their involvement in innate immune defenses is less well defined. We have identified a TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice. The absence of Tip-DCs results in profound TNF and iNOS deficiencies and an inability to clear primary bacterial infection. CD8 and CD4 T cell responses to L. monocytogenes antigens are preserved in CCR2-deficient mice, indicating that Tip-DCs are not essential for T cell priming. Tip-DCs, as the predominant source of TNF and iNOS during L. monocytogenes infection, orchestrate and mediate innate immune defense against this intracellular bacterial pathogen.


Assuntos
Células Dendríticas/imunologia , Imunidade Inata , Listeriose/imunologia , Óxido Nítrico Sintase/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Animais , Antígenos de Diferenciação/análise , Antígeno CD11b/análise , Antígeno CD11c/análise , Listeria monocytogenes , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II , Receptores CCR2 , Receptores de Quimiocinas/fisiologia
13.
J Exp Med ; 197(7): 885-98, 2003 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-12682109

RESUMO

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-alpha/beta in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8alpha+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-alpha/beta regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8alpha+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-alpha/beta, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses.


Assuntos
Células Dendríticas/imunologia , Infecções por Herpesviridae/imunologia , Interferon-alfa/fisiologia , Interferon beta/fisiologia , Muromegalovirus , Animais , Apresentação do Antígeno , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiocinas/biossíntese , Citocinas/biossíntese , Células Dendríticas/fisiologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL
14.
J Immunol ; 169(8): 4279-87, 2002 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-12370359

RESUMO

NK cell cytotoxicity, IFN-gamma expression, proliferation, and accumulation are rapidly induced after murine CMV infections. Under these conditions, the responses were shown to be elicited in overlapping populations. Nevertheless, there were distinct signaling molecule requirements for induction of functions within the subsets. IL-12/STAT4 was critical for NK cell IFN-gamma expression, whereas IFN-alphabeta/STAT1 were required for induction of cytotoxicity. The accumulation/survival of proliferating NK cells was STAT4-independent but required IFN-alphabeta/STAT1 induction of IL-15. Taken together, the results define the coordinated interactions between the cytokines IFN-alphabeta, IL-12, and IL-15 for activation of protective NK cell responses during viral infections, and emphasize these factors' nonredundant functions under in vivo physiological conditions.


Assuntos
Interferon-alfa/fisiologia , Interleucina-12/fisiologia , Interleucina-15/fisiologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/virologia , Animais , Citotoxicidade Imunológica/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Injeções Intraperitoneais , Interferon-alfa/administração & dosagem , Interferon-alfa/deficiência , Interferon-alfa/genética , Interferon beta/deficiência , Interferon beta/genética , Interferon beta/fisiologia , Interferon gama/biossíntese , Interleucina-12/administração & dosagem , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-15/biossíntese , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muromegalovirus/imunologia , Fator de Transcrição STAT1 , Fator de Transcrição STAT4 , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transativadores/deficiência , Transativadores/genética , Transativadores/fisiologia
15.
J Clin Invest ; 110(3): 321-30, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12163451

RESUMO

Macrophage inflammatory protein 1alpha (MIP-1alpha, CCL3) is critical for liver NK cell inflammation and delivery of IFN-gamma to mediate downstream protective responses against murine cytomegalovirus (MCMV) infections. This system was used to evaluate the upstream contribution of the type 1 IFNs, IFN-alpha/beta, in promotion of MIP-1alpha production. Mice deficient in IFN-alpha/beta functions, as a result of mutation in the receptor for these cytokines (IFN-alpha/betaR(-)), were profoundly deficient in MIP-1alpha expression and accumulation of NK cells and macrophages in the liver and had increased sensitivity to MCMV infection. The cytokines themselves were responsible for the immunoregulatory effects, since administration of recombinant IFN-alpha (rIFN-alpha) to immunocompetent mice also induced these changes. IFN-alpha/beta was required for NK cell accumulation during infection, and MIP-1alpha was required for NK cell accumulation in response to administered rIFN-alpha. In vivo trafficking assays demonstrated a requirement for IFN-alpha/betaR signaling for leukocyte localization in, and delivery of MIP-1alpha-producing macrophages to, the liver. These results extend characterization of the cytokine and chemokine cascade required for protection against viral infections in tissues by defining IFN-alpha/beta-dependent mechanisms promoting MIP-1alpha production and the resulting hepatic accumulation of NK cells.


Assuntos
Interferon-alfa/imunologia , Interferon beta/imunologia , Células Matadoras Naturais/imunologia , Fígado/imunologia , Proteínas Inflamatórias de Macrófagos/imunologia , Macrófagos/imunologia , Animais , Transporte Biológico , Movimento Celular , Quimiocina CCL3 , Quimiocina CCL4 , Feminino , Infecções por Herpesviridae/imunologia , Humanos , Interferon Tipo I/administração & dosagem , Interferon Tipo I/imunologia , Interferon-alfa/biossíntese , Interferon beta/biossíntese , Células Matadoras Naturais/citologia , Fígado/patologia , Proteínas Inflamatórias de Macrófagos/biossíntese , Proteínas Inflamatórias de Macrófagos/genética , Macrófagos/citologia , Masculino , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muromegalovirus/imunologia , Receptor de Interferon alfa e beta , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes
16.
J Virol ; 76(9): 4520-5, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11932417

RESUMO

Viruses and viral components can be potent inducers of alpha/beta interferons (IFN-alpha/beta). In culture, IFN-alpha/beta prime for their own expression, in response to viruses, through interferon regulatory factor 7 (IRF-7) induction. The studies presented here evaluated the requirements for functional IFN receptors and the IFN signaling molecule STAT1 in IFN-alpha/beta induction during infections of mice with lymphocytic choriomeningitis virus (LCMV). At 24 h after infection, levels of induced IFN-alpha/beta in serum were reduced 90 to 95% in IFN-alpha/beta receptor-deficient (IFN-alpha/betaR(-/-)) and STAT1(-/-) mice compared to those in wild-type mice. However, at 48 h, these mice showed elevated expression in the serum whereas IFN-alpha/beta levels were still reduced >75% in IFN-alpha/betagammaR(-/-) mice even though the viral burden was heavy. Levels of IFN-beta, IFN-alpha4, and non-IFN-alpha4 subtype mRNA expression correlated with IFN-alpha/beta bioactivity, and all IFN-alpha/beta subtypes were coincidentally detectable. IRF-7 mRNA was induced under conditions of IFN-alpha/beta production, including late production in IFN-alpha/betaR(-/-) mice. These data demonstrate that the presence of the virus alone is not sufficient to induce IFN-alpha/beta during LCMV infection in vivo. Instead, autocrine amplification through the IFN-alpha/betaR is necessary for optimal induction. In the absence of a functional IFN-alpha/betaR, however, alternative mechanisms, independent of STAT1 but requiring a functional IFN-gammaR, take over.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Interferon-alfa/metabolismo , Interferon beta/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Receptores de Interferon/metabolismo , Transativadores/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Fator Regulador 7 de Interferon , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor de Interferon alfa e beta , Receptores de Interferon/genética , Fator de Transcrição STAT1 , Transativadores/genética
17.
J Exp Med ; 195(4): 517-28, 2002 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-11854364

RESUMO

Interferon (IFN)-alpha/beta and interleukin (IL)-12 are cytokines critical in defense against viruses, but their cellular sources and mechanisms of regulation for in vivo expression remain poorly characterized. The studies presented here identified a novel subset of dendritic cells (DCs) as major producers of the cytokines during murine cytomegalovirus (MCMV) but not lymphocytic choriomeningitis virus (LCMV) infections. These DCs differed from those activated by Toxoplasma antigen but were related to plasmacytoid cells, as assessed by their CD8alpha(+)Ly6G/C(+)CD11b(-) phenotype. Another DC subset (CD8alpha(2)Ly6G/C(-)CD11b(+)) also contributed to IL-12 production in MCMV-infected immunocompetent mice, modestly. However, it dramatically increased IL-12 expression in the absence of IFN-alpha/beta functions. Conversely, IFN-alpha/beta production was greatly reduced under these conditions. Thus, a cross-regulation of DC subset cytokine responses was defined, whereby secretion of type I IFNs by CD8alpha(+) DCs resulted in responses limiting IL-12 expression by CD11b(+) DCs but enhancing overall IFN-alpha/beta production. Taken together, these data indicate that CD8alpha(+)Ly6G/C(+)CD11b(-) DCs play important roles in limiting viral replication and regulating immune responses, through cytokine production, in some but not all viral infections. They also illustrate the plasticity of cellular sources for innate cytokines in vivo and provide new insights into the roles of IFNs in shaping immune responses to viruses.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação da Expressão Gênica , Interferon-alfa/imunologia , Interferon beta/imunologia , Interleucina-12/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Muromegalovirus/imunologia , Animais , Antígenos Virais/imunologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células Dendríticas/citologia , Citometria de Fluxo , Imuno-Histoquímica , Interferon-alfa/biossíntese , Interferon-alfa/genética , Interferon beta/biossíntese , Interferon beta/genética , Interleucina-12/biossíntese , Interleucina-12/genética , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Receptores de Interferon/metabolismo , Fator de Transcrição STAT1 , Transdução de Sinais , Baço/citologia , Baço/imunologia , Linfócitos T/imunologia , Transativadores/genética , Transativadores/metabolismo
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