RESUMO
Borrelia burgdorferi, the spirochetal agent of Lyme disease, utilizes a variety of strategies to evade and suppress the host immune response, which enables it to chronically persist in the host. The resulting immune response is characterized by unusually strong IgM production and a lack of long-term protective immunity. Previous studies in mice have shown that infection with B. burgdorferi also broadly suppresses host antibody responses against unrelated antigens. Here, we show that mice infected with B. burgdorferi and concomitantly immunized with recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein had an abrogated antibody response to the immunization. To further define how long this humoral immune suppression lasts, mice were immunized at 2, 4, and 6 weeks post-infection. Suppression of host antibody production against the SARS-CoV-2 spike protein peaked at 2 weeks post-infection but continued for all timepoints measured. Antibody responses against the SARS-CoV-2 spike protein were also assessed following antibiotic treatment to determine whether this immune suppression persists or resolves following clearance of B. burgdorferi. Host antibody production against the SARS-CoV-2 spike protein returned to baseline following antibiotic treatment; however, anti-SARS-CoV-2 IgM remained high, comparable to levels found in B. burgdorferi-infected but untreated mice. Thus, our data demonstrate restored IgG responses following antibiotic treatment but persistently elevated IgM levels, indicating lingering effects of B. burgdorferi infection on the immune system following treatment.
Assuntos
Borrelia burgdorferi , Doença de Lyme , Glicoproteína da Espícula de Coronavírus , Camundongos , Humanos , Animais , Imunidade Humoral , Imunoglobulina M , Antibacterianos , Anticorpos AntibacterianosRESUMO
Neutrophils have historically been characterized as first responder cells vital to host survival because of their ability to contain and eliminate bacterial and fungal pathogens. However, recent studies have shown that neutrophils participate in both protective and detrimental responses to a diverse array of inflammatory and infectious diseases. Although the contribution of neutrophils to extracellular infections has been investigated for decades, their specific role during intracellular bacterial infections has only recently been appreciated. During infection with the Gram-positive intracellular pathogen Listeria monocytogenes, neutrophils are recruited from the bone marrow to sites of infection where they use novel bacterial-sensing pathways leading to phagocytosis and production of bactericidal factors. This review summarizes the requirement of neutrophils during L. monocytogenes infection by examining both neutrophil trafficking and function during primary and secondary infection.
Assuntos
Citoplasma/microbiologia , Listeria monocytogenes/patogenicidade , Listeriose/imunologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Animais , Medula Óssea/imunologia , Coinfecção/imunologia , Coinfecção/microbiologia , Citocinas/biossíntese , Citoplasma/imunologia , Humanos , Listeria monocytogenes/fisiologia , Listeriose/microbiologia , Camundongos , Neutrófilos/fisiologia , Fagocitose , Transdução de SinaisRESUMO
Listeria monocytogenes is a Gram-positive intracellular pathogen that causes spontaneous abortion in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals. Although L. monocytogenes can usually be effectively treated with antibiotics, there is still around a 25% mortality rate with individuals who develop clinical listeriosis. Neutrophils are innate immune cells required for the clearance of pathogenic organisms, including L. monocytogenes The diverse roles of neutrophils during both infectious and noninfectious inflammation have recently gained much attention. However, the impact of reactive oxygen species, and the enzymes that control their production, on neutrophil recruitment and function is not well understood. Using congenic mice with varying levels of extracellular superoxide dismutase (ecSOD) activity, we have recently shown that the presence of ecSOD decreases clearance of L. monocytogenes while increasing the recruitment of neutrophils that are not protective in the liver. The data presented here show that ecSOD activity does not lead to a cell-intrinsic increase in neutrophil-homing potential or a decrease in protection against L. monocytogenes Instead, ecSOD activity enhances the production of neutrophil-attracting factors and protects hyaluronic acid (HA) from damage. Furthermore, neutrophils from the livers of ecSOD-expressing mice have decreased intracellular and surface-bound myeloperoxidase, are less capable of killing phagocytosed L. monocytogenes, and have decreased oxidative burst. Collectively, our data reveal that ecSOD activity modulates neutrophil recruitment and function in a cell-extrinsic fashion, highlighting the importance of the enzyme in protecting tissues from oxidative damage.
Assuntos
Fígado/enzimologia , Neutrófilos/fisiologia , Superóxido Dismutase/metabolismo , Animais , Quimiocinas/genética , Quimiocinas/metabolismo , Regulação Enzimológica da Expressão Gênica , Listeria monocytogenes , Camundongos , Superóxido Dismutase/genéticaRESUMO
Increasing evidence shows that psychological stress can have dramatic impacts on the immune system, particularly the cutaneous immune response in dermatological disorders. While there have been many studies examining the impact of acute psychological stress on contact hypersensitivity there are relatively few studies concerning the impact of chronic psychological stress. Furthermore, the local immunological mechanisms by which chronic psychological stress impacts contact hypersensitivity still remain to be explored. Here we show that restraint-induced chronic psychological stress stimulates activation of the hypothalamus-pituitary-adrenal axis and delays weight gain in female BALB/c mice. We observed that chronic psychological stress reduces the cutaneous immune response as evidence by reduced ear swelling. This correlated with a significant decrease in the inflammatory cell infiltrate. On the other hand, chronic psychological stress does not influence T cell proliferation, activation, or sensitivity to corticosterone but does increase CD4(+) and CD8(+) T cell percentages in draining lymph nodes during a contact hypersensitivity reaction. Chronic psychological stress induces a decrease in overall circulating white blood cells, lymphocytes, and monocytes during a contact hypersensitivity reaction suggesting extravasation from the circulation. Finally, we found markedly reduced local IFN-γ production in chronically stressed animals. Based on these findings we propose that chronic psychological stress reduces contact hypersensitivity due to dysregulated cell trafficking and reduced production of IFN-γ.
Assuntos
Dermatite de Contato/imunologia , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipófise-Suprarrenal/imunologia , Estresse Psicológico/imunologia , Animais , Peso Corporal , Movimento Celular , Doença Crônica , Corticosterona/sangue , Citocinas/metabolismo , Orelha/patologia , Orelha/fisiologia , Feminino , Interferon gama/biossíntese , Leucócitos/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Restrição Física , Linfócitos T/metabolismoRESUMO
Reactive oxygen species and reactive nitrogen species play important roles during immune responses to bacterial pathogens. Extracellular superoxide dismutase (ecSOD) regulates extracellular concentrations of reactive oxygen species and reactive nitrogen species and contributes to tissue protection during inflammatory insults. The participation of ecSOD in immune responses seems therefore intuitive, yet is poorly understood. In the current study, we used mice with varying levels of ecSOD activity to investigate the involvement of this enzyme in immune responses against Listeria monocytogenes. Surprisingly, our data demonstrate that despite enhanced neutrophil recruitment to the liver, ecSOD activity negatively affected host survival and bacterial clearance. Increased ecSOD activity was accompanied by decreased colocalization of neutrophils with bacteria, as well as increased neutrophil apoptosis, which reduced overall and neutrophil-specific TNF-α production. Liver leukocytes from mice lacking ecSOD produced equivalent NO· compared with liver leukocytes from mice expressing ecSOD. However, during infection, there were higher levels of peroxynitrite (NO(3)·(-)) in livers from mice lacking ecSOD compared with livers from mice expressing ecSOD. Neutrophil depletion studies revealed that high levels of ecSOD activity resulted in neutrophils with limited protective capacity, whereas neutrophils from mice lacking ecSOD provided superior protection compared with neutrophils from wild-type mice. Taken together, our data demonstrate that ecSOD activity reduces innate immune responses during bacterial infection and provides a potential target for therapeutic intervention.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Neutrófilos/imunologia , Espécies Reativas de Nitrogênio/metabolismo , Superóxido Dismutase/imunologia , Animais , Apoptose , Quimiotaxia de Leucócito , Suscetibilidade a Doenças , Indução Enzimática , Feminino , Listeria monocytogenes/isolamento & purificação , Listeriose/complicações , Fígado/química , Fígado/enzimologia , Fígado/microbiologia , Subpopulações de Linfócitos/imunologia , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutropenia/complicações , Neutropenia/imunologia , Óxido Nítrico/metabolismo , Ácido Peroxinitroso/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Baço/química , Baço/enzimologia , Baço/microbiologia , Superóxido Dismutase/deficiência , Superóxido Dismutase/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Resolution of acute of infection caused by capsular Streptococcus pneumoniae infection in the absence of effective antibiotic therapy requires tight regulation of immune and inflammatory responses. To provide new mechanistic insight of the requirements needed for innate host defenses against acute S. pneumoniae infection, we examined how IL-23 deficiency mediated acute pulmonary resistance. We found that IL-23 deficient mice were more susceptible to bacterial colonization in the lungs corresponding with greater bacterial dissemination. The lack of IL-23 was found to decrease IL-6 and IL-12p70 cytokine levels in bronchiolar lavage within the initial day after infection. Pulmonary leukocytes isolated from infected IL-23 deficient mice demonstrated a dramatic decrease in IL-17A and IFN-γ in response to heat-killed organisms. These findings corresponded with significant abrogation of neutrophilic infiltrate in the lungs compared to IL-23 competent mice. Whereas previous studies have shown opposing influences of IL-12/IL-23 regulation, our findings suggest a concordant dependency of IL-23 expression on Th1 and Th17-related responses.
Assuntos
Subunidade p19 da Interleucina-23/deficiência , Infecções Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Células Cultivadas , Feminino , Imunidade Inata , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-17/metabolismo , Subunidade p19 da Interleucina-23/genética , Subunidade p19 da Interleucina-23/imunologia , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologiaRESUMO
Reconstituted high-density lipoprotein nanoparticles (rHDL NPs) have been utilized as delivery vehicles to a variety of targets, including cancer cells. However, the modification of rHDL NPs for the targeting of the pro-tumoral tumor-associated macrophages (TAMs) remains largely unexplored. The presence of mannose on nanoparticles can facilitate the targeting of TAMs which highly express the mannose receptor at their surface. Here, we optimized and characterized mannose-coated rHDL NPs loaded with 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an immunomodulatory drug. Lipids, recombinant apolipoprotein A-I, DMXAA, and different amounts of DSPE-PEG-mannose (DPM) were combined to assemble rHDL-DPM-DMXAA NPs. The introduction of DPM in the nanoparticle assembly altered the particle size, zeta potential, elution pattern, and DMXAA entrapment efficiency of the rHDL NPs. Collectively, the changes in physicochemical characteristics of rHDL NPs upon the addition of the mannose moiety DPM indicated that the rHDL-DPM-DMXAA NPs were successfully assembled. The rHDL-DPM-DMXAA NPs induced an immunostimulatory phenotype in macrophages pre-exposed to cancer cell-conditioned media. Furthermore, rHDL-DPM NPs delivered their payload more readily to macrophages than cancer cells. Considering the effects of the rHDL-DPM-DMXAA NPs on macrophages, the rHDL-DPM NPs have the potential to serve as a drug delivery platform for the selective targeting of TAMs.
RESUMO
Listeria monocytogenes is a gram-positive intracellular pathogen that causes meningitis and septicemia in immunocompromised individuals and spontaneous abortion in pregnant women. The innate immune response against L. monocytogenes is primarily mediated by neutrophils and monocytes. Interleukin-23 (IL-23) is an important proinflammatory cytokine well known for its role in neutrophil recruitment in various infectious and autoimmune diseases. We have previously shown that IL-23 is required for host resistance against L. monocytogenes and for neutrophil recruitment to the liver, but not the spleen, during infection. Despite efficient neutrophil recruitment to the spleen, IL-23p19 knockout (KO) mice have an increased bacterial burden in this organ, suggesting that IL-23 may regulate the recruitment/function of another cell type to the spleen. In this study, we show that specific depletion of neutrophils abrogated the differences in bacterial burdens in the livers but not the spleens of C57BL/6 (B6) and IL-23p19 KO mice. Interestingly, L. monocytogenes-infected IL-23p19 KO mice had fewer monocytes in the spleen than B6 mice, as well as a reduction in the monocyte-recruiting chemokines CCL2 and CCL7. Additionally, the overall concentrations of tumor necrosis factor alpha (TNF-α) and nitric oxide (NO(â¢)), as well as the percentages and total numbers of monocytes producing TNF-α and NO(â¢), were reduced in IL-23p19 KO mice compared to levels in B6 mice, leading to increased bacterial burdens in the spleens of L. monocytogenes-infected IL-23p19 KO mice. Collectively, our data establish that IL-23 is required for the optimal recruitment of TNF-α- and NO(â¢)-producing inflammatory monocytes, thus revealing a novel mechanism by which this proinflammatory cytokine provides protection against bacterial infection.
Assuntos
Inflamação/imunologia , Interleucina-23/imunologia , Listeria monocytogenes/patogenicidade , Listeriose/imunologia , Monócitos/imunologia , Animais , Feminino , Humanos , Imunidade Inata , Inflamação/metabolismo , Interleucina-23/metabolismo , Subunidade p19 da Interleucina-23/genética , Subunidade p19 da Interleucina-23/imunologia , Subunidade p19 da Interleucina-23/metabolismo , Listeriose/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Previous studies have suggested that neutrophils are required for resistance during infection with multiple pathogenic microorganisms. However, the depleting antibody used in those studies binds to both Ly6G and Ly6C (anti-Gr-1; clone RB6-8C5). This antibody has been shown to deplete not only neutrophils but also monocytes and a subset of CD8(+) T cells. Recently, an antibody against Ly6G, which specifically depletes neutrophils, was characterized. In the present study, neutrophils are depleted using the antibody against Ly6G during infection with the intracellular bacterium Listeria monocytogenes (LM). Our data show that neutrophil-depleted mice are much less susceptible to infection than mice depleted with anti-Gr-1. Although neutrophils are required for clearance of LM, their importance is more pronounced in the liver and during a high-dose bacterial challenge. Furthermore, we demonstrate that the protection mediated by neutrophils is due to the production of TNF-α, but not IFN-γ. Additionally, neutrophils are not required for the recruitment of monocytes or the generation of adaptive T-cell responses during LM infection. This study highlights the importance of neutrophils during LM infection, and indicate that depletion of neutrophils is less detrimental to the host than depletion of all Gr-1-expressing cell populations.
Assuntos
Listeria monocytogenes/imunologia , Listeriose/imunologia , Monócitos/metabolismo , Neutrófilos/metabolismo , Linfócitos T/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Antígenos Ly/imunologia , Antígenos Ly/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Imunidade/efeitos dos fármacos , Procedimentos de Redução de Leucócitos , Listeria monocytogenes/patogenicidade , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Neutrófilos/patologia , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/microbiologia , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.
Assuntos
Proteínas de Caenorhabditis elegans , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Resposta de Saciedade , Caenorhabditis elegans/metabolismo , Mitocôndrias/metabolismo , Resposta a Proteínas não Dobradas , Mamíferos/metabolismoRESUMO
Most studies investigating the function of IL-23 have concluded that it promotes IL-17-secreting T cells. Although some reports have also characterized IL-23 as having redundant pro-inflammatory effects with IL-12, we have instead found that IL-23 antagonizes IL-12-induced secretion of IFN-γ. When splenocytes or purified populations of T cells were cultured with IL-23, IFN-γ secretion in response to IL-12 was dramatically reduced. The impact of IL-23 was most prominent in CD8(+) T cells, but was also observed in NK and CD4(+) T cells. Mechanistically, the IL-23 receptor was not required for this phenomenon, and IL-23 inhibited signaling through the IL-12 receptor by reducing IL-12-induced signal transducer and activator of transcription 4 (STAT4) phosphorylation. IL-23 was also able to reduce IFN-γ secretion by antagonizing endogenously produced IL-12 from Listeria monocytogenes (LM)-infected macrophages. In vivo, LM infection induced higher serum IFN-γ levels and a greater percentage of IFN-γ(+)CD8(+) T cells in IL-23p19-deficient mice as compared with WT mice. This increase in IFN-γ production coincided with increased LM clearance at days 2 and 3 post-infection. Our data suggest that IL-23 may be a key factor in determining the responsiveness of lymphocytes to IL-12 and their subsequent secretion of IFN-γ.
Assuntos
Interferon gama/biossíntese , Interleucina-12/antagonistas & inibidores , Interleucina-23/farmacologia , Listeriose/imunologia , Macrófagos/metabolismo , Linfócitos T/metabolismo , Animais , Carga Bacteriana/genética , Células Cultivadas , Regulação para Baixo , Imunomodulação , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/imunologia , Interleucina-12/metabolismo , Interleucina-23/genética , Listeriose/microbiologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-12/metabolismo , Fator de Transcrição STAT4/metabolismo , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Listeria monocytogenes (LM) is a Gram-positive, intracellular bacterium that can induce spontaneous abortion, septicemia, and meningitis. Although it is known that neutrophils are required for elimination of the bacteria and for survival of the host, the mechanisms governing the recruitment of neutrophils to LM-infected tissues are not fully understood. We demonstrate here that IL-23 and the IL-17 receptor A (IL-17RA), which mediates both IL-17A and IL-17F signaling, are necessary for resistance against systemic LM infection. LM-infected IL-23p19 knockout (KO) mice have decreased production of IL-17A and IL-17F, while IFN-gamma production is not altered by the lack of IL-23. LM induces the production of IL-17A from gammadelta T cells, but not CD4, CD8, or NK cells. Furthermore, a lack of efficient neutrophil recruitment to the liver is evident in both IL-23p19 KO and IL-17RA KO mice during LM infection. Immunocytochemical analysis of infected livers revealed that neutrophils were able to localize with LM in IL-23p19 KO and IL-17RA KO mice, indicating that IL-23 and IL-17RA do not regulate the precise localization of neutrophils with LM. The importance of IL-23-induced IL-17A was demonstrated by injecting IL-23p19 KO mice with recombinant IL-17A. These mice had reduced LM bacterial burdens compared with IL-23p19 KO mice that did not receive IL-17A. These results indicate that during LM infection, IL-23 regulates the production of IL-17A and IL-17F from gammadelta T cells, resulting in optimal liver neutrophil recruitment and enhanced bacterial clearance.
Assuntos
Interleucina-23/fisiologia , Listeriose/imunologia , Listeriose/prevenção & controle , Animais , Interleucina-17/deficiência , Interleucina-17/genética , Interleucina-17/fisiologia , Interleucina-23/genética , Subunidade p19 da Interleucina-23/deficiência , Subunidade p19 da Interleucina-23/genética , Subunidade p19 da Interleucina-23/fisiologia , Listeria monocytogenes/imunologia , Listeriose/microbiologia , Fígado/imunologia , Fígado/microbiologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/genética , Infiltração de Neutrófilos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/biossíntese , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Interferon (IFN)-gamma plays an important role in the innate immune response against intracellular bacterial pathogens. It is commonly thought that natural killer cells are the primary source of this cytokine that is involved in activating antibacterial effects in infected cells and polarizing CD4+ T cells toward the Th1 subset. However, here we show that both effector and memory CD8+ T cells have the potential to secrete IFN-gamma in response to interleukin (IL)-12 and IL-18 in the absence of cognate antigen. We demonstrate that memory CD8+ T cells specific for the ovalbumin protein secrete IFN-gamma rapidly after infection with wild-type Listeria monocytogenes (LM). Furthermore, small numbers of ovalbumin-specific, memory CD8+ T cells can reduce spleen and liver bacterial counts in IFN-gamma-deficient mice 3 d after LM infection. Up-regulation of the receptors for IL-12 and IL-18 provides a mechanism for the ability of memory CD8+ T cells to respond in this antigen nonspecific manner. Thus, CD8+ T cells play an important role in the innate immune response against intracellular pathogens by rapidly secreting IFN-gamma in response to IL-12 and IL-18.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Interferon gama/deficiência , Interleucina-12/farmacologia , Interleucina-18/farmacologia , Subunidade alfa de Receptor de Interleucina-18 , Camundongos , Receptores de Interleucina/imunologia , Receptores de Interleucina-12 , Receptores de Interleucina-18 , Regulação para Cima/imunologiaRESUMO
Immune responses to pathogens occur within the context of current and previous infections. Cross protection refers to the phenomena where infection with a particular pathogen provides enhanced resistance to a subsequent unrelated pathogen in an antigen-independent manner. Proposed mechanisms of antigen-independent cross protection have involved the secretion of IFN-gamma, which activates macrophages, thus providing enhanced innate immunity against the secondary viral or bacterial pathogen. Here we provide evidence that a primary infection with the chronic respiratory pathogen, Mycoplasma pulmonis, provides a novel form of cross protection against a secondary infection with Listeria monocytogenes that is not mediated by IFN-gamma, but instead relies upon IL-17 and mobilization of neutrophils. Mice infected with M. pulmonis have enhanced clearance of L. monocytogenes from the spleen and liver, which is associated with increased numbers of Gr-1(+)CD11b(+) cells and higher levels of IL-17. This enhanced clearance of L. monocytogenes was absent in mice depleted of Gr-1(+) cells or in mice deficient in the IL-17 receptor. Additionally, both the IL-17 receptor and neutrophils were essential for optimal clearance of M. pulmonis. Thus, a natural component of the immune response directed against M. pulmonis was able to enhance clearance of L. monocytogenes.
Assuntos
Interleucina-17/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Infecções por Mycoplasma/imunologia , Mycoplasma pulmonis/imunologia , Animais , Feminino , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/metabolismo , Listeriose/microbiologia , Fígado/imunologia , Fígado/microbiologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infecções por Mycoplasma/microbiologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-17/metabolismo , Baço/imunologia , Baço/microbiologiaRESUMO
The role of CD8 T cells in adaptive immune responses is well understood. These lymphocytes respond through their T cell receptors to diverse antigens presented by MHC class I molecules by proliferating, secreting cytokines and chemokines, and directly lysing infected cells. Recently, a role for CD8 T cells in the innate immune response has become apparent. Independent of T cell receptor ligation, CD8 T cells can mount a response against pathogens by secreting cytokines and can defend against tumors by directly killing transformed cells. This innate response has been shown to be beneficial in controlling several types of bacterial infections. However, a subset of CD8 T cells that have innate non-antigen-specific capabilities has been implicated in self-reactivity, which could lead to autoimmunity.
Assuntos
Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade Inata/imunologia , Animais , Autoimunidade/imunologia , Humanos , Modelos Imunológicos , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologiaRESUMO
Neutrophils and inflammatory monocytes are innate immune cells essential for protection during Listeria monocytogenes infection. Although certain functions have been generally assigned to each of the cells, similarities and differences in functions necessary for bacterial clearance have not previously been investigated. In the current study, phagocytosis, phagosomal containment, bacterial killing, and cytokine production by neutrophils and monocytes during L. monocytogenes infection were studied. Data obtained via in vitro studies show that neutrophils are more effective at L. monocytogenes uptake, phagosomal containment, and killing than monocytes. However, monocytes were found to be more effective at cytokine production during L. monocytogenes infection, in vivo. Additionally, the data demonstrated that neutrophils and monocytes are also capable of producing IL-1α, a cytokine that does not yet have a clearly defined role during infection with L. monocytogenes Furthermore, we were able to demonstrate a population of monocytes producing both TNF-α and IL-α, concurrently. This study highlights the multifunctional capabilities of neutrophils and monocytes, further adding to our knowledge of these innate immune cells during L. monocytogenes infection.
Assuntos
Listeria monocytogenes/imunologia , Listeriose/imunologia , Monócitos/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Fagossomos/imunologia , Animais , Imunidade Inata , Interleucina-1alfa/metabolismo , Listeriose/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismoRESUMO
CD94/NKG2 is a heterodimer expressed on natural killer (NK) and a small subset of T cells. This receptor varies in function as an inhibitor or activator depending on which isoform of NKG2 is expressed. The ligand for CD94/NKG2 is HLA-E in human and its homolog, Qa1 in mouse, which are both nonclassical class I molecules that bind leader peptides from other class I molecules. Although <5% of CD8 T cells express the receptor in a naïve mouse, its expression is upregulated upon specific recognition of antigen. Similar to NK cells, most CD8 T cells that express high levels of CD94 co-express NKG2A, the inhibitory isoform. The engagement of this receptor can lead to a blocking of cytotoxicity. However, these receptors have also been implicated in the cell survival of both NK and CD8 T cells. The level of CD94 expression is inversely correlated with the level of apoptosis in culture. Thus, CD94/NKG2 receptors may regulate effector functions and cell survival of NK cells and CD8 T cells, thereby playing a crucial role in the innate and adaptive immune response to a pathogen.
Assuntos
Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Naturais/imunologia , Lectinas Tipo C/imunologia , Receptores Imunológicos/imunologia , Animais , Apoptose/imunologia , Sobrevivência Celular/imunologia , Humanos , Imunidade Celular , Imunidade Inata , Subfamília C de Receptores Semelhantes a Lectina de Células NK , Subfamília D de Receptores Semelhantes a Lectina de Células NK , Receptores de Células Matadoras NaturaisRESUMO
Listeria monocytogenes (LM) is a gram-positive bacterium that is a common contaminant of processed meats and dairy products. In humans, ingestion of LM can result in intracellular infection of the spleen and liver, which can ultimately lead to septicemia, meningitis, and spontaneous abortion. Interleukin (IL)-23 is a cytokine that regulates innate and adaptive immune responses by inducing the production of IL-17A, IL-17F, and IL-22. We have recently demonstrated that the IL-23/IL-17 axis is required for optimal recruitment of neutrophils to the liver, but not the spleen, during LM infection. Furthermore, these cytokines are required for the clearance of LM during systemic infection. In other infectious models, IL-22 induces the secretion of anti-microbial peptides and protects tissues from damage by preventing apoptosis. However, the role of IL-22 has not been thoroughly investigated during LM infection. In the present study, we show that LM induces the production of IL-22 in vivo. Interestingly, IL-23 is required for the production of IL-22 during primary, but not secondary, LM infection. Our findings suggest that IL-22 is not required for clearance of LM during primary or secondary infection, using both systemic and mucosal models of infection. IL-22 is also not required for the protection of LM infected spleens and livers from organ damage. Collectively, these data indicate that IL-22 produced during LM infection must play a role other than clearance of LM or protection of tissues from pathogen- or immune-mediated damage.
Assuntos
Interleucina-23/metabolismo , Interleucinas/biossíntese , Listeria monocytogenes/patogenicidade , Listeriose/metabolismo , Animais , Coinfecção/imunologia , Coinfecção/metabolismo , Coinfecção/patologia , Feminino , Listeriose/imunologia , Listeriose/patologia , Masculino , Camundongos , Mucosa/imunologia , Mucosa/metabolismo , Mucosa/microbiologia , Análise de Sobrevida , Interleucina 22RESUMO
Imatinib mesylate (IM) is effective at inducing complete cytogenetic remission in patients with chronic myelogenous leukemia. Because its influence on CD8 T cell responsiveness in vivo is unknown, we investigated the effects of IM by analyzing the response of OT-1 CD8 T cells to Listeria monocytogenes (LM) that express the cognate epitope OVA(257-264) (LM-OVA). In vitro, IM had no effect on Ag-specific expansion, cell division, cell cycle progression, or IFN-gamma expression in naive or memory OT-1 T cells. However, IM induced apoptosis of naive and memory OT-1 T cells at doses of >5 microM. At 15 microM IM, OT-1 T cells did not survive in in vitro cultures. The primary response of OT-1 T cells in vivo to LM-OVA infection was unaltered. In contrast, continuous IM treatment resulted in a diminished memory OT-1 response. The expression of IL-7Ralpha, a receptor required for memory cell survival, was lower (on OT-1 cells) in animals receiving IM. These results indicate that IM treatment affects the ability of the CD8 memory pool to respond to Ag and has the potential to increase susceptibility to infection.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Animais , Antígenos de Bactérias/imunologia , Apoptose/imunologia , Benzamidas , Linfócitos T CD8-Positivos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Relação Dose-Resposta a Droga , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Mesilato de Imatinib , Interferon gama/biossíntese , Interferon gama/imunologia , Listeria monocytogenes/genética , Listeria monocytogenes/imunologia , Listeriose/genética , Listeriose/imunologia , Listeriose/metabolismo , Camundongos , Camundongos Transgênicos , Receptores de Interleucina-7/biossíntese , Receptores de Interleucina-7/imunologiaRESUMO
During the innate immune response to Listeria monocytogenes (LM), the secretion of IFN-gamma is crucial in controlling bacterial numbers. We have shown recently that CD8 T cells have the ability to rapidly secrete IFN-gamma independent of Ag, in response to IL-12 and IL-18, during a LM infection. In the current study, we compared the relative abilities of NK and CD8 T cells to provide innate immune protection. Upon transfer of either NK or memory OT-I T cells (specific for the OVA protein) into IFN-gamma-deficient hosts that were infected subsequently with wild-type LM, both cell types were found in the spleen and had the ability to secrete IFN-gamma. However, the OT-I T cells were more effective at providing innate immune protection as determined by spleen and liver LM burdens. We used immunocytochemistry to demonstrate that upon infection with LM, marginal zone macrophages were localized to the T cell area of the splenic follicle. Transferred memory OT-I T cells were also found in the T cell area of the spleen, co-localizing with the LM and macrophages. In sharp contrast, NK cells were found predominantly in the red pulp region of the spleen. In addition, memory OT-I T cells were also found to be associated with LM lesions in the liver. These results highlight the importance of CD8 T cells in innate immune responses to LM and suggest that their increased protective ability compared with NK cells is the result of their colocalization with LM and macrophages.