RESUMEN
Silencing of interleukin-32 (IL-32) in a differentiated human promonocytic cell line impairs killing of Mycobacterium tuberculosis (MTB) but the role of IL-32 in vivo against MTB remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was generated in which the human IL-32γ gene is expressed using the surfactant protein C promoter (SPC-IL-32γTg). Wild-type and SPC-IL-32γTg mice were infected with a low-dose aerosol of a hypervirulent strain of MTB (W-Beijing HN878). At 30 and 60 d after infection, the transgenic mice had 66% and 85% fewer MTB in the lungs and 49% and 68% fewer MTB in the spleens, respectively; the transgenic mice also exhibited greater survival. Increased numbers of host-protective innate and adaptive immune cells were present in SPC-IL-32γTg mice, including tumor necrosis factor-alpha (TNFα) positive lung macrophages and dendritic cells, and IFN-gamma (IFNγ) and TNFα positive CD4(+) and CD8(+) T cells in the lungs and mediastinal lymph nodes. Alveolar macrophages from transgenic mice infected with MTB ex vivo had reduced bacterial burden and increased colocalization of green fluorescent protein-labeled MTB with lysosomes. Furthermore, mouse macrophages made to express IL-32γ but not the splice variant IL-32ß were better able to limit MTB growth than macrophages capable of producing both. The lungs of patients with tuberculosis showed increased IL-32 expression, particularly in macrophages of granulomas and airway epithelial cells but also B cells and T cells. We conclude that IL-32γ enhances host immunity to MTB.
Asunto(s)
Interleucinas/metabolismo , Mycobacterium tuberculosis/patogenicidad , Tuberculosis/inmunología , Tuberculosis/prevención & control , Inmunidad Adaptativa/inmunología , Animales , Antígenos Ly/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Humanos , Inmunidad Innata/inmunología , Interferón gamma , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Macrófagos Alveolares/inmunología , Ratones Transgénicos , Mutación/genética , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Proteína C Asociada a Surfactante Pulmonar/metabolismo , Sitios de Empalme de ARN/genética , Linfocitos T Reguladores/inmunología , Transfección , Transgenes , Tuberculosis/microbiología , Factor de Necrosis Tumoral alfa/metabolismo , Virulencia/inmunologíaRESUMEN
BACKGROUND: The lung is exposed to airborne fungal spores, and fungi that colonize the oral cavity such as Candida albicans, but does not develop disease to opportunistic fungal pathogens unless the immune system is compromised. The Group IVA cytosolic phospholipase A2 (cPLA2α) is activated in response to Candida albicans infection resulting in the release of arachidonic acid for eicosanoid production. Although eicosanoids such as prostaglandins and leukotrienes modulate inflammation and immune responses, the role of cPLA2α and eicosanoids in regulating C. albicans lung infection is not understood. METHODS: The responses of cPLA2α(+/+) and cPLA2α(-/-) Balb/c mice to intratracheal instillation of C. albicans were compared. After challenge, we evaluated weight loss, organ fungal burden, and the recruitment of cells and the levels of cytokines and eicosanoids in bronchoalveolar lavage fluid. The ability of macrophages and neutrophils from cPLA2α(+/+) and cPLA2α(-/-) mice to recognize and kill C. albicans was also compared. RESULTS: After C. albicans instillation, cPLA2α(+/+) mice recovered a modest weight loss by 48 h and completely cleared fungi from the lung by 12 h with no dissemination to the kidneys. In cPLA2α(-/-) mice, weight loss continued for 72 h, C. albicans was not completely cleared from the lung and disseminated to the kidneys. cPLA2α(-/-) mice exhibited greater signs of inflammation including higher neutrophil influx, and elevated levels of albumin and pro-inflammatory cytokines/chemokines (IL1α, IL1ß, TNFα, IL6, CSF2, CXCL1, CCL20) in bronchoalveolar lavage fluid. The amounts of cysteinyl leukotrienes, thromboxane B2 and prostaglandin E2 were significantly lower in bronchoalveolar lavage fluid from C. albicans-infected cPLA2α(-/-) mice compared to cPLA2α(+/+) mice. Alveolar macrophages and neutrophils from uninfected cPLA2α(-/-) mice exhibited less killing of C. albicans in vitro than cells from cPLA2α(+/+) mice. In addition alveolar macrophages from cPLA2α(-/-) mice isolated 6 h after instillation of GFP-C. albicans contained fewer internalized fungi than cPLA2α(+/+) macrophages. CONCLUSIONS: The results demonstrate that cPLA2α contributes to immune surveillance and host defense in the lung to prevent infection by the commensal fungus C. albicans and to dampen inflammation.
Asunto(s)
Candida albicans/inmunología , Candidiasis/inmunología , Enfermedades Pulmonares Fúngicas/inmunología , Pulmón/inmunología , Macrófagos Alveolares/fisiología , Neutrófilos/fisiología , Fosfolipasas A2/metabolismo , Animales , Ácido Araquidónico/metabolismo , Movimiento Celular , Células Cultivadas , Citocinas/metabolismo , Eicosanoides/metabolismo , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Pulmón/microbiología , Macrófagos Alveolares/microbiología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neutrófilos/microbiología , Fosfolipasas A2/genética , Fosfolipasas A2/inmunologíaRESUMEN
Glucocorticoid-induced TNFR family-related protein (GITR)-mediated activation of JNK was shown to regulate the suppressive activity of CD4(+)CD25(+) naturally occurring T regulatory cells (nTregs) in wild-type (WT) hosts. In this study, CD4(+)CD25(+) T cells were shown to be capable of becoming pathogenic effector cells in sensitized and challenged CD8(-/-) recipient mice. Only GITR-expressing CD4(+)CD25(+) T cells, but neither GITR knocked-in CD4(+)CD25(-) T cells nor GITR-silenced CD4(+)CD25(+) T cells, enhanced development of lung allergic responses. Inhibition of JNK in WT nTregs or nTregs from GITR(-/-)and JNK2(-/-) mice failed to enhance lung allergic responses in sensitized and challenged CD8(-/-) recipient mice. The failure to enhance responses was associated with increased bronchoalveolar lavage fluid levels of IL-10 and TGF-ß and decreased levels of IL-5, IL-6, and IL-13. In contrast, nTregs from JNK1(-/-) mice, similar to WT nTregs, were fully effective in enhancing responses. Thus, GITR stimulation of nTregs and signaling through JNK2, but not JNK1, triggered the loss of regulatory function while concomitantly gaining pathogenic CD4(+) T effector cell function responsible for exacerbating asthma-like immunopathology.
Asunto(s)
Asma/inmunología , Pulmón/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Proteína Quinasa 9 Activada por Mitógenos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Asma/genética , Asma/patología , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Pulmón/patología , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , Proteína Quinasa 8 Activada por Mitógenos/genética , Proteína Quinasa 8 Activada por Mitógenos/inmunología , Proteína Quinasa 9 Activada por Mitógenos/genética , Linfocitos T Reguladores/patología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
BACKGROUND: Ozone pollution has adverse effects on respiratory health in children and adults. This study was carried out in the mouse model to investigate the influence of age and to define the role of toll-like receptor four (TLR4) in the lung response to ozone exposure during postnatal development. METHODS: Female mice (1 to 6 weeks of age) were exposed for 3 h to ozone (1 part per million) or filtered air. Analyses were carried out at six and 24 h after completion of exposure, to assess the effects on lung permeability, airway neutrophilia, expression of antioxidants and chemokines, and mucus production. The role of TLR4 was defined by examining TLR4 expression in the lung during development, and by investigating the response to ozone in tlr4-deficient mice. RESULTS: Metallothionein-1, calcitonin gene-related product, and chemokine C-X-C ligand (CXCL) five were consistent markers induced by ozone throughout development. Compared with adults, neonates expressed lower levels of pulmonary TLR4 and responded with increased mucus production, and developed an attenuated response to ozone characterized by reduced albumin leakage and neutrophil influx into the airways, and lower expression of CXCL1 and CXCL2 chemokines. Examination of the responses in tlr4-deficient mice indicated that ozone-mediated airway neutrophilia, but not albumin leakage or mucus production were dependent on TLR4. CONCLUSIONS: Collectively, the data demonstrate that the response to ozone is determined by age and is partially dependent on TLR4 signaling. The reduced responsiveness of the neonatal lung to ozone may be due at least in part to insufficient pulmonary TLR4 expression.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Pulmón/efectos de los fármacos , Ozono/toxicidad , Receptor Toll-Like 4/efectos de los fármacos , Factores de Edad , Animales , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Quimiocinas/metabolismo , Femenino , Exposición por Inhalación , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Ratones Endogámicos BALB C , Ratones Noqueados , Moco/metabolismo , Neuropéptidos/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Albúmina Sérica/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illnesses in infants worldwide. Both RSV-G and RSV-F glycoproteins play pathogenic roles during infection with RSV. The objective of this study was to compare the effects of anti-RSV-G and anti-RSV-F monoclonal antibodies (mAbs) on airway hyperresponsiveness (AHR) and inflammation after primary or secondary RSV infection in mice. In the primary infection model, mice were infected with RSV at 6 weeks of age. Anti-RSV-G or anti-RSV-F mAbs were administered 24 hours before infection or Day +2 postinfection. In a secondary infection model, mice were infected (primary) with RSV at 1 week (neonate) and reinfected (secondary) 5 weeks later. Anti-RSV-G and anti-RSV-F mAbs were administered 24 hours before the primary infection. Both mAbs had comparable effects in preventing airway responses after primary RSV infection. When given 2 days after infection, anti-RSV-G-treated mice showed significantly decreased AHR and airway inflammation, which persisted in anti-RSV-F-treated mice. In the reinfection model, anti-RSV-G but not anti-RSV-F administered during primary RSV infection in neonates resulted in decreased AHR, eosinophilia, and IL-13 but increased levels of IFN-γ in bronchoalveolar lavage on reinfection. These results support the use of anti-RSV-G in the prevention and treatment of RSV-induced disease.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Bronquiolitis Viral/prevención & control , Inflamación/prevención & control , Hipersensibilidad Respiratoria/prevención & control , Infecciones por Virus Sincitial Respiratorio/prevención & control , Proteínas Virales de Fusión/inmunología , Animales , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéutico , Bronquiolitis Viral/etiología , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Inflamación/etiología , Ratones , Ratones Endogámicos BALB C , Hipersensibilidad Respiratoria/etiología , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/inmunología , Virus Sincitiales Respiratorios/patogenicidadRESUMEN
BACKGROUND: Numbers of CD8(+) T cells expressing the leukotriene B4 (LTB4) receptor, BLT1, have been correlated with asthma severity. OBJECTIVE: To examine the activation and numbers of BLT1-expressing peripheral blood CD4(+) and CD8(+) T cells from patients with steroid-sensitive (SS) and steroid-resistant (SR) asthma. METHODS: CD4(+) and CD8(+) T cells isolated from peripheral blood of healthy human subjects and patients with SS and SR asthma were stimulated in culture with anti-CD3/anti-CD28 followed by analysis of BLT1 surface expression and cytokine production. Activation of CD8(+) T cells after ligation of BLT1 by LTB4 was monitored by changes in intracellular Ca(2+) concentrations. RESULTS: The number of BLT1-expressing cells was larger in patients with asthma than in controls and larger on activated CD8(+) than on CD4(+) T cells. Addition of LTB4 to activated CD8(+) T cells resulted in increases in intracellular Ca(2+) concentrations. Expansion of activated CD4(+) T cells, unlike CD8(+) T cells, was significantly decreased in the presence of corticosteroid. In patients with SS asthma, numbers of BLT1-expressing CD8(+) T cells were lower in the presence of corticosteroid, unlike in those with SR asthma in whom cell expansion was maintained. Levels of interleukin-13 were highest in cultured CD8(+) T cells, whereas interleukin-10 levels were higher in CD4(+) T cells from controls and patients with SS asthma. Interferon-γ levels were lowest in patients with SR asthma. CONCLUSION: Differences in BLT1 expression, steroid sensitivity, and cytokine production were demonstrated in T lymphocytes from patients with SS and SR asthma. The LTB4-BLT1 pathway in CD8(+) cells may play an important role in asthma and serve as an important target in the treatment of patients with SR asthma.
Asunto(s)
Asma/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Dexametasona/farmacología , Receptores de Leucotrieno B4/metabolismo , Corticoesteroides/farmacología , Adulto , Anticuerpos Monoclonales/inmunología , Antígenos CD28/inmunología , Complejo CD3/inmunología , Calcio/metabolismo , Células Cultivadas , Medios de Cultivo Condicionados/química , Femenino , Humanos , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-13/metabolismo , Activación de Linfocitos/inmunología , MasculinoRESUMEN
Naturally occurring Foxp3(+)CD4(+)CD25(+) T regulatory cell (nTreg)-mediated suppression of lung allergic responses is abrogated following ligation of glucocorticoid-induced tumor necrosis receptor (GITR) family-related protein. In vitro stimulation of nTregs with GITR ligand increased phosphorylation of c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated protein kinase (ERK) or p38 MAPK. SP600125, a known JNK inhibitor, prevented GITR-mediated phosphorylation of JNK. Activation of JNK was associated with increases in the upstream mitogen-activated protein kinase kinase 7 (MKK7) and the downstream transcription factor NF-κß. Phosphorylated c-Jun (p-c-Jun), indicative of the activation of JNK, was detected in the immunoprecipitates of nTregs from wild-type but not JNK- or GITR-deficient mice. Treatment with an inhibitor of JNK phosphorylation resulted in complete reversal of all GITR-induced changes in nTreg phenotype and function, with full restoration of suppression of in vivo lung allergic responses and in vitro proliferation of activated CD4(+)CD25(-) T cells. Thus, regulation of JNK phosphorylation plays a central role in T regulatory cell function with therapeutic implications for the treatment of asthma and autoimmune diseases.
Asunto(s)
Proteína Relacionada con TNFR Inducida por Glucocorticoide/metabolismo , Tolerancia Inmunológica/fisiología , MAP Quinasa Quinasa 4/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Linfocitos T Reguladores/metabolismo , Animales , Antracenos/farmacología , Asma/genética , Asma/inmunología , Asma/metabolismo , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Activación Enzimática/genética , Activación Enzimática/inmunología , Femenino , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/inmunología , MAP Quinasa Quinasa 7/genética , MAP Quinasa Quinasa 7/inmunología , MAP Quinasa Quinasa 7/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Noqueados , FN-kappa B/genética , FN-kappa B/inmunología , FN-kappa B/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/genética , Fosforilación/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Linfocitos T Reguladores/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Naturally occurring CD4(+)CD25(+)Foxp3(+) T regulatory cells (nTregs) regulate lung allergic responses through production of IL-10 and TGF-ß. nTregs from CD8(-/-) mice failed to suppress lung allergic responses and were characterized by reduced levels of Foxp3, IL-10, and TGF-ß, and high levels of IL-6. Administration of anti-IL-6 or anti-IL-6R to wild-type recipients prior to transfer of CD8(-/-) nTregs restored suppression. nTregs from IL-6(-/-) mice were suppressive, but lost this capability if incubated with IL-6 prior to transfer. The importance of CD8 in regulating the production of IL-6 in nTregs was demonstrated by the loss of suppression and increases in IL-6 following transfer of nTregs from wild-type donors depleted of CD8(+) cells. Transfer of nTregs from CD8(-/-) donors reconstituted with CD8(+) T cells was suppressive, and accordingly, IL-6 levels were reduced. These data identify the critical role of CD8-T regulatory cell interactions in regulating the suppressive phenotype of nTregs through control of IL-6 production.
Asunto(s)
Antígenos CD8/fisiología , Inmunofenotipificación , Terapia de Inmunosupresión , Interleucina-6/biosíntesis , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Antígenos CD8/genética , Células Cultivadas , Femenino , Factores de Transcripción Forkhead/deficiencia , Factores de Transcripción Forkhead/genética , Interleucina-10/antagonistas & inhibidores , Interleucina-6/deficiencia , Interleucina-6/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/fisiología , Hipersensibilidad Respiratoria/genética , Factor de Crecimiento Transformador beta/antagonistas & inhibidoresRESUMEN
Respiratory syncytial virus (RSV) is the most common cause of hospitalization for respiratory tract infection in young children. It is also a significant cause of morbidity and mortality in elderly individuals and in persons with asthma and chronic obstructive pulmonary disease. Currently, no reliable vaccine or simple RSV antiviral therapy is available. Recently, we determined that the minor pulmonary surfactant phospholipid, palmitoyl-oleoyl-phosphatidylglycerol (POPG), could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4) interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. The phospholipid bound RSV with high affinity and inhibited viral attachment to HEp2 cells. POPG blocked viral plaque formation in vitro by 4 log units, and markedly suppressed the expansion of plaques from cells preinfected with the virus. Administration of POPG to mice, concomitant with viral infection, almost completely eliminated the recovery of virus from the lungs at 3 and 5 days after infection, and abrogated IFN-gamma (IFN-gamma) production and the enhanced expression of surfactant protein D (SP-D). These findings demonstrate an important approach to prevention and treatment of RSV infections using exogenous administration of a specific surfactant phospholipid.
Asunto(s)
Inflamación/inmunología , Fosfatidilgliceroles/farmacología , Surfactantes Pulmonares/farmacología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/inmunología , Animales , Muerte Celular/fisiología , Células Cultivadas , Niño , Citocinas/inmunología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inflamación/virología , Receptores de Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos BALB C , Fosfatidilgliceroles/uso terapéutico , Surfactantes Pulmonares/uso terapéutico , Mucosa Respiratoria/citología , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Virus Sincitiales Respiratorios/efectos de los fármacos , Receptor Toll-Like 4/inmunologíaRESUMEN
BACKGROUND: Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in T(H)2 priming and polarization. OBJECTIVES: We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection. METHODS: Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12. RESULTS: OX40L was expressed mainly on CD11c(+)MHC class II (MHCII)(+)CD11b(+) DCs but not CD103(+) DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection. CONCLUSIONS: In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and T(H)2 polarization, accounting for the enhanced response on reinfection.
Asunto(s)
Hiperreactividad Bronquial/inmunología , Citocinas/metabolismo , Células Dendríticas/inmunología , Ligando OX40/metabolismo , Eosinofilia Pulmonar/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/inmunología , Animales , Animales Recién Nacidos , Anticuerpos Bloqueadores/administración & dosificación , Hiperreactividad Bronquial/etiología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Células Dendríticas/efectos de los fármacos , Humanos , Inmunidad/efectos de los fármacos , Interleucina-12/metabolismo , Ratones , Ratones Endogámicos BALB C , Moco/metabolismo , Ligando OX40/genética , Ligando OX40/inmunología , Eosinofilia Pulmonar/etiología , Infecciones por Virus Sincitial Respiratorio/complicaciones , Linfopoyetina del Estroma TímicoRESUMEN
Invariant NKT cells (iNKT cells) play a pivotal role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation. However, it is unclear what role they play in the initiation (sensitization) phase as opposed to the effector (challenge) phase. The role of iNKT cells during sensitization was examined by determining the response of mice to intratracheal transfer of OVA-pulsed or OVA-alpha-galactosylceramide (OVA/alphaGalCer)-pulsed bone marrow-derived dendritic cells (BMDCs) prior to allergen challenge. Wild-type (WT) recipients of OVA-BMDCs developed AHR, increased airway eosinophilia, and increased levels of Th2 cytokines in bronchoalveolar lavage fluid, whereas recipients of OVA/alphaGalCer BMDCs failed to do so. In contrast, transfer of these same OVA/alphaGalCer BMDCs into IFN-gamma-deficient (IFN-gamma(-/-)) mice enhanced the development of these lung allergic responses, which was reversed by exogenous IFN-gamma treatment following OVA-BMDC transfer. Further, Jalpha18-deficient recipients, which lack iNKT cells, developed the full spectrum of lung allergic responses following reconstitution with highly purified WT liver or spleen iNKT cells and transfer of OVA-BMDCs, whereas reconstituted recipients of OVA/alphaGalCer BMDCs failed to do so. Transfer of iNKT cells from IFN-gamma(-/-) mice restored the development of these responses in Jalpha18-deficient recipients following OVA-BMDC transfer; the responses were enhanced following OVA/alphaGalCer BMDC transfer. iNKT cells from these IFN-gamma(-/-) mice produced higher levels of IL-13 in vitro compared with WT iNKT cells. These data identify IFN-gamma as playing a critical role in dictating the consequences of iNKT cell activation in the initiation phase of the development of AHR and airway inflammation.
Asunto(s)
Alérgenos/administración & dosificación , Interferón gamma/biosíntesis , Células T Asesinas Naturales/inmunología , Ovalbúmina/inmunología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/prevención & control , Traslado Adoptivo , Alérgenos/inmunología , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Hiperreactividad Bronquial/prevención & control , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/trasplante , Femenino , Galactosilceramidas/administración & dosificación , Galactosilceramidas/inmunología , Galactosilceramidas/metabolismo , Mediadores de Inflamación/administración & dosificación , Mediadores de Inflamación/metabolismo , Interferón gamma/deficiencia , Interferón gamma/fisiología , Intubación Intratraqueal , Ligandos , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/patología , Ovalbúmina/administración & dosificación , Hipersensibilidad Respiratoria/patologíaRESUMEN
Naturally occurring Foxp3(+)CD4(+)CD25(+) T cells isolated from lungs of naive mice regulate lung allergic airway hyperresponsiveness, inflammation, levels of Th2 cytokines, and mucus production. OVA-specific (alphabetaTCR(+)) CD4(+)CD25(+) T cells suppressed ragweed-induced airway hyperresponsiveness and inflammation as did anti-TCR-treated OVA-specific CD4(+)CD25(+) T cells, suggesting that Ag-specificity was not required for expression of regulatory activities. Suppression was associated with increased levels of IL-10 and TGF-beta; decreased levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid; and reduced recruitment and activation of CD8(+) T cells in the airways. Following intratracheal administration, OVA-specific CD4(+)CD25(+) T cells were identified in both the airway lumens and lung parenchyma, and in some instances in close proximity to host CD8(+) T cells. These results demonstrate that the regulatory activities of naturally occurring Foxp3(+)CD4(+)CD25(+) T cells on lung allergic responses are Ag-nonspecific and thus, independent of Ag-specific recognition.
Asunto(s)
Epítopos/inmunología , Hipersensibilidad/inmunología , Enfermedades Pulmonares/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Ambrosia/inmunología , Animales , Linfocitos T CD8-positivos , Citocinas/análisis , Inflamación , Ratones , Ratones Endogámicos , Ovalbúmina/inmunologíaRESUMEN
Suppressing the abnormalities associated with asthma has been difficult to accomplish using immunotherapy or vaccination once the disease is established. The effector cells necessary for effective immunization/vaccination and immunotherapy of asthma are also not well understood. Therefore, we vaccinated allergen (OVA)-sensitized mice to determine whether therapeutic immunization could suppress airway hyperresponsiveness (AHR) and inflammation and to identify key immune effector cells and cytokines. Mice were immunized with a vaccine comprised of Ag and cationic liposome-DNA complexes (CLDC), a vaccine which has previously been shown to elicit strong CD4(+) and CD8(+) T cell responses and activation of Th1 immunity. We showed that immunization with the OVA-CLDC vaccine significantly suppressed AHR, eosinophilia, goblet cell metaplasia, and Th2 cytokine production. In contrast, immunization with CLDC alone suppressed eosinophilia and Th2 cytokine production, but failed to suppress AHR and goblet cell changes. Using adoptive transfer experiments, we found that suppression of AHR was mediated by Ag-specific CD8(+) T cells and was dependent on IFN-gamma production by the transferred T cells. Thus, we conclude that generation of strong, allergen-specific CD8(+) T cell responses by immunization may be capable of suppressing AHR and allergic airway inflammation, even in previously sensitized and challenged mice.
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Hiperreactividad Bronquial/patología , Hiperreactividad Bronquial/prevención & control , Linfocitos T CD8-positivos/inmunología , Inmunosupresores/administración & dosificación , Mediadores de Inflamación/administración & dosificación , Mediadores de Inflamación/inmunología , Vacunas de ADN/inmunología , Traslado Adoptivo , Animales , Asma/inmunología , Asma/patología , Asma/prevención & control , Hiperreactividad Bronquial/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/trasplante , Cationes/administración & dosificación , Cationes/metabolismo , Citocinas/fisiología , Epítopos de Linfocito T/administración & dosificación , Epítopos de Linfocito T/inmunología , Femenino , Antígenos H-2/administración & dosificación , Antígenos H-2/genética , Antígenos H-2/inmunología , Humanos , Inmunosupresores/inmunología , Liposomas , Cloruro de Metacolina/administración & dosificación , Cloruro de Metacolina/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genéticaRESUMEN
Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyper-responsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8(+) T cells. Previously, two distinct populations of antigen-experienced CD8(+) T cells, termed effector (T(EFF)) and central memory (T(CM)) cells, have been described. After adoptive transfer into CD8-deficient mice, T(EFF), but not T(CM), cells restored AHR, eosinophilic inflammation and IL-13 levels. T(EFF), but not T(CM), cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred T(EFF) cells were a source of IL-13. These data suggest an important role for effector CD8(+) T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.
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Alérgenos/inmunología , Hiperreactividad Bronquial/inmunología , Bronquitis/inmunología , Linfocitos T CD8-positivos/inmunología , Subgrupos de Linfocitos T/inmunología , Traslado Adoptivo , Compuestos de Alumbre , Análisis de Varianza , Animales , Hiperreactividad Bronquial/patología , Bronquitis/fisiopatología , Líquido del Lavado Bronquioalveolar/inmunología , Antígenos CD8/inmunología , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Interleucina-13/inmunología , Pulmón/inmunología , Pulmón/patología , Cloruro de Metacolina , Ratones , Ratones Mutantes , OvalbúminaRESUMEN
RATIONALE: Respiratory syncytial virus (RSV) bronchiolitis in infants may be followed by the development of asthma-like symptoms. Age at first infection dictates consequences upon reinfection. Reinfection of mice initially exposed as neonates to RSV enhanced development of airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus hyperproduction. RSV lower respiratory tract disease is associated with activation of the leukotriene pathway. OBJECTIVES: To determine the effects of montelukast (MK), a cysteinyl leukotriene (cysLT) receptor antagonist, in primary and secondary RSV-infected newborn and adult mice. METHODS: BALB/c mice were infected with RSV at 1 week (neonate) or 6 to 8 weeks (adult) of age and reinfected 5 weeks later. MK was administered 1 day before the initial infection and through Day 6 after infection. Seven days after primary or secondary infection, airway function was assessed by lung resistance to increasing doses of inhaled methacholine; lung inflammation, goblet cell metaplasia, and cytokine levels in bronchoalveolar lavage fluid were monitored. MEASUREMENTS AND MAIN RESULTS: RSV infection induced cysLT release in bronchoalveolar lavage fluid. MK decreased RSV-induced AHR, airway inflammation, and increased IFN-gamma production in primary infected adult and neonatal mice. MK, administered during initial infection of neonates but not during secondary infection, prevented subsequent enhancement of AHR, airway eosinophilia, and mucus hyperproduction upon reinfection. CONCLUSIONS: MK attenuated the initial responses to primary RSV infection in both age groups and altered the consequences of RSV reinfection in mice initially infected as neonates. These data support an important role for cysLT in RSV-induced AHR and inflammation.
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Acetatos/farmacología , Antiasmáticos/farmacología , Inflamación/prevención & control , Quinolinas/farmacología , Hipersensibilidad Respiratoria/prevención & control , Infecciones por Virus Sincitial Respiratorio/complicaciones , Virus Sincitiales Respiratorios/efectos de los fármacos , Animales , Animales Recién Nacidos , Bronquiolitis Viral/complicaciones , Bronquiolitis Viral/prevención & control , Bronquiolitis Viral/virología , Líquido del Lavado Bronquioalveolar/virología , Ciclopropanos , Cisteína/antagonistas & inhibidores , Modelos Animales de Enfermedad , Inflamación/complicaciones , Interferón gamma/efectos de los fármacos , Antagonistas de Leucotrieno/farmacología , Leucotrienos , Ratones , Ratones Endogámicos BALB C , Recurrencia , Hipersensibilidad Respiratoria/etiología , SulfurosRESUMEN
BACKGROUND: Although implicated in the disease, the specific contributions of FcepsilonRI and IL-13 to the pathogenesis of peanut-induced intestinal allergy are not well defined. OBJECTIVES: We sought to determine the contributions of FcepsilonRI, IL-13, and mast cells to the development of intestinal mucosal responses in a murine model of peanut-induced intestinal allergy. METHODS: Sensitized wild-type (WT), FcepsilonRI-deficient (FcepsilonRI(-/-)), and mast cell-deficient (Kit(W-sh/W-sh)) mice received peanut orally every day for 1 week. Bone marrow-derived mast cells (BMMCs) from WT, FcepsilonRI(-/-), IL-4(-/-), IL-13(-/-), and IL-4/IL-13(-/-) mice were differentiated and transferred into WT, FcepsilonRI(-/-), and Kit(W-sh/W-sh) recipients. BMMCs from WT and UBI-GFP/BL6 mice were differentiated and transferred into WT and Kit(W-sh/W-sh) mice. Blockade of IL-13 was achieved by using IL-13 receptor alpha2 (IL-13Ralpha2)-IgG fusion protein. RESULTS: FcepsilonRI(-/-) mice showed decreased intestinal inflammation (mast cell and eosinophil numbers) and goblet cell metaplasia and reduced levels of IL4, IL6, IL13, and IL17A mRNA expression in the jejunum. Transfer of WT BMMCs to FcepsilonRI(-/-) recipients restored their ability to develop intestinal allergic responses unlike transfer of FcepsilonRI(-/-), IL-13(-/-), or IL-4/IL-13(-/-) BMMCs. FcepsilonRI(-/-) mice exhibited lower IL-13 levels and treatment of WT mice with IL-13 receptor alpha2 prevented peanut-induced intestinal allergy and inflammation. CONCLUSIONS: These data indicate that the development of peanut-induced intestinal allergy is mediated through a mast cell-dependent IgE-FcepsilonRI-IL-13 pathway. Targeting IL-13 might be a potential treatment for IgE-mediated peanut-induced allergic responses in the intestine.
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Arachis/efectos adversos , Inmunoglobulina E/inmunología , Interleucina-13/inmunología , Mastocitos/inmunología , Hipersensibilidad al Cacahuete/inmunología , Receptores de IgE/inmunología , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Inmunidad Mucosa/genética , Inmunidad Mucosa/inmunología , Inmunoglobulina E/genética , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/farmacología , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-13/antagonistas & inhibidores , Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/genética , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Intestinos/inmunología , Intestinos/patología , Mastocitos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Hipersensibilidad al Cacahuete/tratamiento farmacológico , Hipersensibilidad al Cacahuete/genética , Hipersensibilidad al Cacahuete/patología , Receptores de IgE/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/farmacologíaRESUMEN
Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B(4) (LTB(4)), interacting with its high-affinity receptor, LTB(4) receptor 1 (BLT1), is known to attract and activate leukocytes during inflammation. We have previously shown that BLT1 expression on Ag-primed T cells is required for the development of airway hyperresponsiveness (AHR; Miyahara et al. 2005. Am. J. Respir. Crit. Care Med. 172: 161-167). However, the role for the LTB(4)-BLT1 pathway in DC function in allergen-induced airway responses has not been defined. Bone marrow-derived DCs (BMDC) were generated. Naive BALB/c mice received OVA-pulsed BLT1-deficient (BLT1(-/-)) BMDCs or wild-type BMDCs intratracheally and were then challenged with OVA for 3 days. Airway responses were monitored 48 h after the last allergen challenge. BLT1(-/-) BMDCs showed normal maturation judged from surface expression of CD markers. Compared with recipients of wild-type BMDCs, mice that received BLT1(-/-) BMDCs developed significantly lower AHR to inhaled methacholine, lower goblet cell metaplasia, and eosinophilic infiltration in the airways and decreased levels of Th2 type cytokines in the bronchoalveolar lavage fluid. Migration of BLT1(-/-) BMDCs into peribronchial lymph nodes was significantly impaired compared with BLT1(+/+) BMDCs after intratracheal instillation. These data suggest that BLT1 expression on DCs is required for migration of DCs to regional lymph nodes as well as in the development of AHR and airway inflammation.
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Hiperreactividad Bronquial/inmunología , Células Dendríticas/inmunología , Pulmón/inmunología , Receptores de Leucotrieno B4/metabolismo , Células Th2/inmunología , Alérgenos/inmunología , Animales , Hiperreactividad Bronquial/metabolismo , Líquido del Lavado Bronquioalveolar/inmunología , Broncoconstrictores/administración & dosificación , Citocinas/análisis , Citocinas/inmunología , Células Dendríticas/metabolismo , Femenino , Leucotrieno A4/inmunología , Leucotrieno A4/metabolismo , Ganglios Linfáticos/inmunología , Cloruro de Metacolina/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ovalbúmina/inmunología , Receptores de Leucotrieno B4/inmunología , Células Th2/metabolismoRESUMEN
BACKGROUND: Ligation of the leukotriene B(4) (LTB(4)) receptor 1 on effector memory CD8(+) T cells by LTB(4) is important for the recruitment of CD8(+) T cells into the airways, which appears central to the induction of airway hyperresponsiveness (AHR) and allergic inflammation. Phosphorylation of extracellular signal-regulated kinase (ERK) is important in activation and cytokine production from many cell types. OBJECTIVE: The roles of ERKs in effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR were determined. METHODS: Effector CD8(+) T cells were generated from OVA(257-264) (SIINFEKL) peptide-primed mononuclear cells from OT-1 mice. The effects of U0126, an ERK inhibitor, on effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR and allergic inflammation were examined. RESULTS: Pretreatment of effector CD8(+) T cells with U0126 suppressed anti-CD3/anti-CD28-induced ERK1/2 phosphorylation and cytokine production, but did not affect LTB(4)-induced Ca(2+) mobilization or chemotaxis. Adoptive transfer of U0126-treated CD8(+) T cells into sensitized mice before secondary allergen challenge resulted in significant decreases in AHR, eosinophilic inflammation, goblet cell metaplasia, and IL-5 and IL-13 levels in bronchoalveolar lavage fluid of recipient mice. The number of transferred CD8(+) T cells accumulating in bronchoalveolar lavage fluid or lungs was unaffected by treatment. CONCLUSION: ERK1/2-dependent pathways are essential for the effector functions of CD8(+) T cells, including T(H)2 cytokine production, allergic inflammation, and development of AHR. Inhibition of ERK1/2 signaling has potential therapeutic benefit in preventing CD8(+) T cell-mediated AHR.
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Linfocitos T CD8-positivos/inmunología , Quimiotaxis/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Proteína Quinasa 1 Activada por Mitógenos/inmunología , Proteína Quinasa 3 Activada por Mitógenos/inmunología , Hipersensibilidad Respiratoria/inmunología , Traslado Adoptivo , Alérgenos/inmunología , Alérgenos/farmacología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Butadienos/farmacología , Linfocitos T CD8-positivos/enzimología , Linfocitos T CD8-positivos/patología , Calcio/inmunología , Calcio/metabolismo , Quimiotaxis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Eosinófilos/enzimología , Eosinófilos/inmunología , Eosinófilos/patología , Células Caliciformes/enzimología , Células Caliciformes/inmunología , Células Caliciformes/patología , Memoria Inmunológica/efectos de los fármacos , Memoria Inmunológica/inmunología , Inflamación/enzimología , Inflamación/inmunología , Inflamación/patología , Leucotrieno B4/inmunología , Leucotrieno B4/metabolismo , Leucotrieno B4/farmacología , Pulmón/enzimología , Pulmón/inmunología , Pulmón/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metaplasia/enzimología , Metaplasia/inmunología , Metaplasia/patología , Ratones , Ratones Transgénicos , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Nitrilos/farmacología , Receptores de Leucotrieno B4/inmunología , Receptores de Leucotrieno B4/metabolismo , Hipersensibilidad Respiratoria/enzimología , Hipersensibilidad Respiratoria/patología , Células Th2/enzimología , Células Th2/inmunología , Células Th2/patologíaRESUMEN
BACKGROUND: Respiratory syncytial virus (RSV)-specific IgE is a component of the host response to RSV infection, but its role in the subsequent enhancement of altered airway responsiveness is unknown. OBJECTIVE: To define the role of RSV-specific IgE in the enhancement of airway responsiveness on reinfection of newborn mice. METHODS: Mice were infected as newborns with RSV and were reinfected 5 weeks later. The role of IgE was determined by documenting RSV-specific IgE response after neonatal infection, and by assessing airway responsiveness on reinfection. RESULTS: After neonatal infection, wild-type (WT) mice developed an RSV-specific IgE response. On reinfection, these mice developed enhanced airway hyperresponsiveness (AHR), airway eosinophilia, and mucus hyperproduction, and their T-cell cytokine response was skewed toward a T(H)2 phenotype. None of these altered responses developed on reinfection of IL-4(-/-)/IL-13(-/-) mice, and no RSV-specific IgE could be detected after neonatal infection of these mice. Fc epsilon RI(-/-) mice did not develop the enhanced AHR on reinfection, and airway eosinophilia and mucus production were significantly attenuated. These responses could be restored in deficient mice reconstituted with WT mast cells. In RSV-infected newborn WT mice, administration of anti-IgE prevented the enhancement of AHR and attenuated eosinophilia and mucus hyperproduction on reinfection, an effect that was associated with diminished T(H)2 cytokine production and increased IFN-gamma production. CONCLUSION: Respiratory syncytial virus-specific IgE enhances the development of T(H)2-biased airway responsiveness on reinfection of mice initially infected as newborns.
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Anticuerpos Antivirales/inmunología , Inmunoglobulina E/inmunología , Hipersensibilidad Respiratoria/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/inmunología , Células Th2/inmunología , Animales , Animales Recién Nacidos , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores de IgE/genética , Receptores de IgE/inmunología , Hipersensibilidad Respiratoria/genética , Hipersensibilidad Respiratoria/virología , Infecciones por Virus Sincitial Respiratorio/genéticaRESUMEN
The negative immune regulator Tollip inhibits the proinflammatory response to rhinovirus (RV) infection, a contributor to airway neutrophilic inflammation and asthma exacerbations, but the underlying molecular mechanisms are poorly understood. Tollip may inhibit IRAK1, a signaling molecule downstream of ST2, the receptor of IL-33. This study was carried out to determine whether Tollip downregulates ST2 signaling via inhibition of IRAK1, but promotes soluble ST2 (sST2) production, thereby limiting excessive IL-8 production in human airway epithelial cells during RV infection in a type 2 cytokine milieu (e.g., IL-13 and IL-33 stimulation). Tollip- and IRAK1-deficient primary human tracheobronchial epithelial (HTBE) cells and Tollip knockout (KO) HTBE cells were generated using the shRNA knockdown and CRISPR/Cas9 approaches, respectively. Cells were stimulated with IL-13, IL-33, and/or RV16. sST2, activated IRAK1, and IL-8 were measured. A Tollip KO mouse model was utilized to test if Tollip regulates the airway inflammatory response to RV infection in vivo under IL-13 and IL-33 treatment. Following IL-13, IL-33, and RV treatment, Tollip-deficient (vs. -sufficient) HTBE cells produced excessive IL-8, accompanied by decreased sST2 production but increased IRAK1 activation. IL-8 production following IL-13/IL-33/RV exposure was markedly attenuated in IRAK1-deficient HTBE cells, as well as in Tollip KO HTBE cells treated with an IRAK1 inhibitor or a recombinant sST2 protein. Tollip KO (vs. wild-type) mice developed exaggerated airway neutrophilic responses to RV in the context of IL-13 and IL-33 treatment. Collectively, these data demonstrate that Tollip restricts excessive IL-8 production in type 2 cytokine-exposed human airways during RV infection by promoting sST2 production and inhibiting IRAK1 activation. sST2 and IRAK1 may be therapeutic targets for attenuating excessive neutrophilic airway inflammation in asthma, especially during RV infection.