RESUMEN
HIV mainly targets CD4+ T cells, from which Th17 cells represent a major cell type, permissive, and are capable of supporting intracellular replication at mucosal sites. Th17 cells possess well-described dual roles, while being central to maintaining gut integrity, these may induce inflammation and contribute to autoimmune disorders; however, Th17 cells' antiviral function in HIV infection is not completely understood. Th17 cells are star players to HIV-1 pathogenesis and a potential target to prevent or decrease HIV transmission. HIV-1 can be spread among permissive cells via direct cell-to-cell and/or cell-free infection. The debate on which mode of transmission is more efficient is still ongoing without a concrete conclusion yet. Most assessments of virus transmission analyzing either cell-to-cell or cell-free modes use in vitro systems; however, the actual interactions and conditions in vivo are not fully understood. The fact that infected breast milk, semen, and vaginal secretions contain a mix of both cell-free viral particles and infected cells presents an argument for the probability of HIV taking advantage of both modes of transmission to spread. Here, we review important insights and recent findings about the role of Th17 cells during HIV pathogenesis in mucosal surfaces, and the mechanisms of HIV-1 infection spread among T cells in tissues.
Asunto(s)
Infecciones por VIH/transmisión , Infecciones por VIH/virología , VIH-1/patogenicidad , Células Th17/virología , Animales , Modelos Animales de Enfermedad , Infecciones por VIH/inmunología , VIH-1/genética , VIH-1/inmunología , Humanos , Membrana Mucosa/patología , Células Th17/inmunología , Replicación ViralRESUMEN
Treg/Th17 cell imbalance and inflammatory response may occur in neonatal asthma. IL-35 and BCG have inhibitory effects on inflammatory responses in diseases. However, studies on neonatal asthma after combination of the two have not been reported so far. A respiratory syncytial virus (RSV)-induced neonatal asthma model was first developed in newborn mice. Pathological sections of lung tissue of asthmatic mice were observed by HE staining. Masson staining was used to observe the lung tissue and to compare the deposition of collagen fibers under bronchial epithelium in model mice. The expression of cytokines in serum was detected by ELISA. Giemsa staining analyzed each cell in bronchoalveolar lavage fluid (BALF). Flow cytometry was used to detect the differentiation and development of Treg and Th17 subgroups in BALF. The expression levels of inflammation-related factors were detected by RT-qPCR. Western blot was used to detect the expression of JNK pathway-related proteins. Recombinant IL-35-BCG improved the pathological response of asthmatic mice; inhibited the expression of IgE in serum, neutrophils, macrophages, and eosinophils in BALF; and increased the expression of lymphocytes. In addition, recombinant IL-35-BCG significantly inhibited Th17 differentiation, promoted Treg cell differentiation, and inhibited the expression of inflammatory factors in lung tissue homogenates, thereby reducing allergic airway inflammation. This process might be achieved by inhibiting the JNK signaling pathway. Recombinant IL-35-BCG can regulate Treg/Th17 cell imbalance and inflammatory response in asthmatic newborn mice induced by RSV through JNK signaling pathway, suggesting a new path to neonatal asthma treatment.
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Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Vacuna BCG/farmacología , Interleucinas/farmacología , Pulmón/efectos de los fármacos , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Animales Recién Nacidos , Asma/inmunología , Asma/metabolismo , Asma/virología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Pulmón/inmunología , Pulmón/inervación , Pulmón/virología , Ratones Endogámicos BALB C , Proteínas Recombinantes/farmacología , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/metabolismo , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/patogenicidad , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/virología , Células Th17/inmunología , Células Th17/metabolismo , Células Th17/virologíaRESUMEN
Understanding the earliest events of human immunodeficiency virus (HIV) sexual transmission is critical to developing and optimizing HIV prevention strategies. To gain insights into the earliest steps of HIV rectal transmission, including cellular targets, rhesus macaques were intrarectally challenged with a single-round simian immunodeficiency virus (SIV)-based dual reporter that expresses luciferase and near-infrared fluorescent protein 670 (iRFP670) upon productive transduction. The vector was pseudotyped with the HIV-1 envelope JRFL. Regions of tissue containing foci of luminescent transduced cells were identified macroscopically using an in vivo imaging system, and individual transduced cells expressing fluorescent protein were identified and phenotyped microscopically. This system revealed that anal and rectal tissues are both susceptible to transduction 48 h after the rectal challenge. Detailed phenotypic analysis revealed that, on average, 62% of transduced cells are CCR6-positive (CCR6+) T cells-the vast majority of which express RORγT, a Th17 lineage-specific transcription factor. The second most common target cells were immature dendritic cells at 20%. These two cell types were transduced at rates that are four to five times higher than their relative abundances indicate. Our work demonstrates that Th17 T and immature dendritic cells are preferential initial targets of HIV/SIV rectal transmission. IMPORTANCE Men and women who participate in unprotected receptive anal intercourse are at high risk of acquiring HIV. While in vitro data have developed a framework for understanding HIV cell tropism, the initial target cells in the rectal mucosa have not been identified. In this study, we identify these early host cells by using an innovative rhesus macaque rectal challenge model and methodology, which we previously developed. Thus, by shedding light on these early HIV/SIV transmission events, this study provides a specific cellular target for future prevention strategies.
Asunto(s)
Células Dendríticas/virología , Infecciones por VIH/transmisión , Infecciones por VIH/virología , VIH-1/fisiología , Recto/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Células Th17/virología , Canal Anal/virología , Animales , Femenino , Mucosa Intestinal/virología , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Replicación ViralRESUMEN
Granuloma formation is the pathologic hallmark of tuberculosis (TB). Few studies have detailed the exact production of cytokines in human granulomatous inflammation and little is known about accessory molecule expressions in tuberculous granulomas. We aimed to identify some of the components of the immune response in granulomas in HIV-positive and -negative lymph nodes. We investigated the immunohistochemical profiles of CD4+, CD8+, CD68+, Th-17, Forkhead box P3 (FOXP3) cells, accessory molecule expression (human leukocyte antigen [HLA] classes I and II), and selected cytokines (interleukins 2, 4, and 6 and interferon-γ) of various cells, in granulomas within lymph nodes from 10 HIV-negative (-) and 10 HIV-positive (+) cases. CD4+ lymphocyte numbers were retained in HIV- granulomas, whereas CD4+:CD8 + cell were reversed in HIV+ TB granulomas. CD68 stained all histiocytes. Granulomas from the HIV+ group demonstrated a significant increase in FOXP3 cells. Interleukin-2 cytoplasmic expression was similar in both groups. Interferon-gamma (IFN-γ) expression was moderately increased, IL-6 was statistically increased and IL-4 expression was marginally lower in cells from HIV- than HIV+ TB granulomas. Greater numbers of cells expressed IFN-γ and IL-6 than IL-2 and IL-4 in HIV- TB granulomas. This study highlights the varied cytokine production in HIV-positive and -negative TB granulomas and indicates the need to identify localized tissue factors that play a role in mounting an adequate immune response required to halt infection. Although TB mono-infection causes variation in cell marker expression and cytokines in granulomas, alterations in TB and HIV coinfection are greater, pointing toward evolution of microorganism synergism.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Granuloma/inmunología , Infecciones por VIH/inmunología , Histiocitos/inmunología , Tuberculosis Latente/inmunología , Células Th17/inmunología , Tuberculosis Ganglionar/inmunología , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/inmunología , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/microbiología , Linfocitos T CD8-positivos/virología , Coinfección , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Expresión Génica , Granuloma/microbiología , Granuloma/patología , Granuloma/virología , VIH/inmunología , VIH/patogenicidad , Infecciones por VIH/microbiología , Infecciones por VIH/patología , Infecciones por VIH/virología , Histiocitos/microbiología , Histiocitos/virología , Humanos , Inmunohistoquímica , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Tuberculosis Latente/microbiología , Tuberculosis Latente/patología , Tuberculosis Latente/virología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/microbiología , Ganglios Linfáticos/virología , Recuento de Linfocitos , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Células Th17/microbiología , Células Th17/virología , Tuberculosis Ganglionar/microbiología , Tuberculosis Ganglionar/patología , Tuberculosis Ganglionar/virologíaRESUMEN
Although millions of patients have clinically recovered from COVID-19, little is known about the immune status of lymphocytes in these individuals. In this study, the peripheral blood mononuclear cells of a clinically recovered (CR) cohort were comparatively analyzed with those of an age- and sex-matched healthy donor cohort. We found that CD8+ T cells in the CR cohort had higher numbers of effector T cells and effector memory T cells but lower Tc1 (IFN-γ+), Tc2 (IL-4+), and Tc17 (IL-17A+) cell frequencies. The CD4+ T cells of the CR cohort were decreased in frequency, especially the central memory T cell subset. Moreover, CD4+ T cells in the CR cohort showed lower programmed cell death protein 1 (PD-1) expression and had lower frequencies of Th1 (IFN-γ+), Th2 (IL-4+), Th17 (IL-17A+), and circulating follicular helper T (CXCR5+PD-1+) cells. Accordingly, the proportion of isotype-switched memory B cells (IgM-CD20hi) among B cells in the CR cohort showed a significantly lower proportion, although the level of the activation marker CD71 was elevated. For CD3-HLA-DR- lymphocytes in the CR cohort, in addition to lower levels of IFN-γ, granzyme B and T-bet, the correlation between T-bet and IFN-γ was not observed. Additionally, by taking into account the number of days after discharge, all the phenotypes associated with reduced function did not show a tendency toward recovery within 4â11 weeks. The remarkable phenotypic alterations in lymphocytes in the CR cohort suggest that severe acute respiratory syndrome coronavirus 2 infection profoundly affects lymphocytes and potentially results in dysfunction even after clinical recovery.
Asunto(s)
Linfocitos T CD8-positivos/virología , COVID-19/sangre , Leucocitos Mononucleares/virología , SARS-CoV-2/patogenicidad , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , COVID-19/epidemiología , COVID-19/patología , COVID-19/virología , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Femenino , Regulación de la Expresión Génica/inmunología , Granzimas/genética , Humanos , Interferón gamma/genética , Leucocitos Mononucleares/patología , Masculino , Persona de Mediana Edad , Proteínas de Dominio T Box/genética , Células TH1/inmunología , Células TH1/virología , Células Th17/inmunología , Células Th17/virología , Células Th2/inmunología , Células Th2/virologíaRESUMEN
Virus-induced asthma is prevalent among children, but its underlying mechanisms are unclear. Accumulated evidence indicates that early-life respiratory virus infection increases susceptibility to allergic asthma. Nonetheless, the relationship between systemic virus infections, such as enterovirus infection, and the ensuing effects on allergic asthma development is unknown. Early-life enterovirus infection was correlated with higher risks of allergic diseases in children. Adult mice exhibited exacerbated mite allergen-induced airway inflammation following recovery from EV-A71 infection in the neonatal period. Bone marrow-derived macrophages (BMDMs) from recovered EV-A71-infected mice showed sustained innate immune memory (trained immunity) that could drive naïve T helper cells toward Th2 and Th17 cell differentiation when in contact with mites. Adoptive transfer of EV-A71-trained BMDMs induced augmented allergic inflammation in naïve recipient mice, which was inhibited by 2-deoxy-D-glucose (2-DG) pretreatment, suggesting that trained macrophages following enterovirus infection are crucial in the progression of allergic asthma later in life.
Asunto(s)
Alérgenos/efectos adversos , Asma/patología , Enterovirus Humano A/aislamiento & purificación , Infecciones por Enterovirus/complicaciones , Inmunidad Innata , Inflamación/patología , Macrófagos/inmunología , Animales , Animales Recién Nacidos , Asma/epidemiología , Asma/inmunología , Asma/virología , Diferenciación Celular , Niño , Preescolar , China/epidemiología , Infecciones por Enterovirus/virología , Humanos , Memoria Inmunológica , Inflamación/epidemiología , Inflamación/inmunología , Inflamación/virología , Macrófagos/virología , Ratones , Ratones Endogámicos BALB C , Pyroglyphidae , Células Th17/inmunología , Células Th17/virología , Células Th2/inmunología , Células Th2/virologíaRESUMEN
The present review provides an overview of recent advances regarding the function of Th17 cells and their produced cytokines in the progression of viral diseases. Viral infections alone do not lead to virus-induced malignancies, as both genetic and host safety factors are also involved in the occurrence of malignancies. Acquired immune responses, through the differentiation of Th17 cells, form the novel components of the Th17 cell pathway when reacting with viral infections all the way from the beginning to its final stages. As a result, instead of inducing the right immune responses, these events lead to the suppression of the immune system. In fact, the responses from Th17 cells during persistent viral infections causes chronic inflammation through the production of IL-17 and other cytokines which provide a favorable environment for tumor growth and its development. Additionally, during the past decade, these cells have been understood to be involved in tumor progression and metastasis. However, further research is required to understand Th17 cells' immune mechanisms in the vast variety of viral diseases. This review aims to determine the roles and effects of the immune system, especially Th17 cells, in the progression of viral diseases; which can be highly beneficial for the diagnosis and treatment of these infections.
Asunto(s)
Transformación Celular Viral , Neoplasias/virología , Células Th17/virología , Infecciones Tumorales por Virus/virología , Virus/patogenicidad , Animales , Interacciones Huésped-Patógeno , Humanos , Neoplasias/inmunología , Neoplasias/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Microambiente Tumoral , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/metabolismo , Virus/inmunologíaRESUMEN
Pseudomonas aeruginosa is a leading cause of chronic respiratory infections in people with cystic fibrosis (CF), bronchiectasis or chronic obstructive pulmonary disease (COPD), and acute infections in immunocompromised individuals. The adaptability of this opportunistic pathogen has hampered the development of antimicrobial therapies, and consequently, it remains a major threat to public health. Due to its antimicrobial resistance, vaccines represent an alternative strategy to tackle the pathogen, yet despite over 50 years of research on anti-Pseudomonas vaccines, no vaccine has been licensed. Nevertheless, there have been many advances in this field, including a better understanding of the host immune response and the biology of P. aeruginosa. Multiple antigens and adjuvants have been investigated with varying results. Although the most effective protective response remains to be established, it is clear that a polarised Th2 response is sub-optimal, and a mixed Th1/Th2 or Th1/Th17 response appears beneficial. This comprehensive review collates the current understanding of the complexities of P. aeruginosa-host interactions and its implication in vaccine design, with a view to understanding the current state of Pseudomonal vaccine development and the direction of future efforts. It highlights the importance of the incorporation of appropriate adjuvants to the protective antigen to yield optimal protection.
Asunto(s)
Anticuerpos Antibacterianos , Fibrosis Quística/microbiología , Infecciones por Pseudomonas/inmunología , Vacunas contra la Infección por Pseudomonas/inmunología , Infecciones del Sistema Respiratorio/microbiología , Adyuvantes Inmunológicos , Alginatos/química , Animales , Antígenos/metabolismo , Fibrosis Quística/inmunología , Exotoxinas/metabolismo , Flagelos/metabolismo , Humanos , Inmunidad Innata , Lipopolisacáridos , Estudios Longitudinales , Pulmón/inmunología , Pulmón/virología , Ratones , Pseudomonas aeruginosa , Infecciones del Sistema Respiratorio/inmunología , Células TH1/virología , Células Th17/virología , Células Th2/virología , Vacunas de ADN/metabolismoRESUMEN
Recurrent herpes labialis (RHL) is a common skin disease that is often caused by herpes simplex virus type I (HSV-1), but its immunology and pathogenesis remain unclear. The balance of Th17/Treg cells is crucial for maintaining immune homeostasis. This study aimed to investigate whether the balance of Th17/Treg cells and related cytokines may be a determinant occurrence in patients with RHL. This is a clinical experimental research based on clinical observation and analysis. We collected RHL patients from the outpatient clinic of the Department of Dermatology of Zhejiang Chinese Medical University (Hangzhou, China) in 2017, conducted questionnaire survey and signed informed consent. Peripheral blood was collected from 30 patients with RHL and 30 healthy volunteers. Flow cytometry was used to detect the percentages of Treg cells and Th17 cells. Protein microarrays coated with 20 cytokines related to T-cell subsets were performed. Enzyme-linked immunosorbent assay (ELISA) assay was conducted to further verify the expression levels of the cytokines that were screened by protein microarrays. Percentages of Th17/Treg cells in peripheral blood of RHL patients were significantly increased compared to those in healthy volunteers. The fold changes of GM-CSF, IL-4, TGF-ß, IL-12, IL-10, IL-17F, and TNF-α were significantly increased compared with healthy volunteers. In addition, the expression of IL-4, IL-10, and TGF-ß in the serum of RHL patients increased significantly. Our results indicated an imbalance of Th17/Treg cells in RHL, and this imbalance is probably an important factor in the occurrence, development, and recovery of RHL.
Asunto(s)
Herpes Labial/inmunología , Herpesvirus Humano 1/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adulto , Estudios de Casos y Controles , Diferenciación Celular , Citocinas/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Herpes Labial/sangre , Herpes Labial/diagnóstico , Herpes Labial/virología , Herpesvirus Humano 1/patogenicidad , Interacciones Huésped-Patógeno , Humanos , Inmunofenotipificación , Mediadores de Inflamación/sangre , Masculino , Persona de Mediana Edad , Análisis por Matrices de Proteínas , Recurrencia , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/virología , Células Th17/metabolismo , Células Th17/virología , Adulto JovenRESUMEN
BACKGROUND: Recent studies have shown that T cell-mediated cellular immune mechanisms play important roles in the progression of hepatitis B to liver cirrhosis, but the underlying mechanisms remain unclear. This present study was aimed to determine the relationship between Treg/Th17 and hepatitis B-associated liver cirrhosis. METHODS: The Treg and Th17 cell frequencies in the peripheral blood of all participants, including 93 patients with hepatitis B-associated liver cirrhosis and 40 healthy subjects, were measured by flow cytometer. Cox regression model and receiver operating characteristic(ROC) curves were applied to investigate the prognostic significance of Treg/Th17 ratio in decompensated liver cirrhosis. RESULTS: We observed the Treg/Th17 imbalance was present in patients with hepatitis B-associated liver cirrhosis, with reduced Treg cells in their peripheral blood, increased Th17 cells and decreased Treg/Th17 ratio. Treg and Th17 cells were negatively correlated. Treg/Th17 imbalance was closely related to the clinical stage of hepatitis B-associated liver cirrhosis. The Virus load, Treg frequencies and the Treg/Th17 ratio were independent factors predicting decompensated liver cirrhosis from a Cox regression model. The ROC analysis showed that the Treg/Th17 ratio was the best marker for predicting decompensated liver cirrhosis. CONCLUSIONS: Treg/Th17 imbalance is involved in the pathogenesis of hepatitis B-associated liver cirrhosis and the Treg/Th17 ratio can be used as a potential marker for predicting decompensated liver cirrhosis.
Asunto(s)
Hepatitis B/patología , Cirrosis Hepática/virología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adulto , Biomarcadores/sangre , Progresión de la Enfermedad , Femenino , Hepatitis B/inmunología , Hepatitis B Crónica/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores/virología , Células Th17/virologíaRESUMEN
Respiratory syncytial virus (RSV) infection is the primary cause of respiratory disease in infants. The formalin-inactivated RSV (FI-RSV) vaccine resulted in an enhanced respiratory disease (ERD) in infants upon natural RSV infection, which is a major obstacle for development of safe and efficacious vaccines. Excessive and uncontrolled Th immune responses could be involved in the ERD. Agonists of TLRs are used as adjuvants to guide the type of immune response induced by vaccines. We evaluated the impact of lipopolysaccharide (LPS), the agonist of TLR4, on ERD as the adjuvant of FI-RSV. The results showed that LPS remarkably inhibited FI-RSV-enhanced lung inflammation, mucus production, airway inflammatory cell infiltration, and inflammatory cytokines following RSV challenge. Interestingly, LPS inhibited both Th2 and Th17 type cytokines in lungs of FI-RSV-immunized mice following RSV challenge, without an increase in the Th1 type cytokines, suggesting a controlled immune response. In contrast, Pam3Cys and Poly(I:C), the agonist of TLR1/2 or TLR3, partly inhibited FI-RSV-enhanced lung inflammation. Pam3Cys inhibited Th17 type cytokine IL-17, but promoted both Th1 and Th2 type cytokines. Poly(I:C) inhibited Th2 and Th17 type cytokines, but promoted Th1 type cytokines. In addition, LPS promoted IgG and IgG2a antibody production, which might provide protection from RSV challenge. These results suggest that LPS inhibits ERD without impairment in antibody production and protection, and the mechanism appears to be related with regulation of Th responses induced by FI-RSV.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Anticuerpos Antivirales/biosíntesis , Lipopolisacáridos/farmacología , Neumonía/prevención & control , Infecciones por Virus Sincitial Respiratorio/prevención & control , Vacunas contra Virus Sincitial Respiratorio/efectos adversos , Virus Sincitiales Respiratorios/efectos de los fármacos , Animales , Femenino , Formaldehído , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Lipoproteínas/farmacología , Ratones , Ratones Endogámicos C57BL , Neumonía/etiología , Neumonía/inmunología , Neumonía/patología , Poli I-C/farmacología , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/patología , Infecciones por Virus Sincitial Respiratorio/virología , Vacunas contra Virus Sincitial Respiratorio/administración & dosificación , Virus Sincitiales Respiratorios/inmunología , Virus Sincitiales Respiratorios/patogenicidad , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/virología , Balance Th1 - Th2/efectos de los fármacos , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/virología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/virología , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 3/agonistas , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/inmunología , Receptor Toll-Like 4/agonistas , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Vacunación , Vacunas de Productos InactivadosRESUMEN
Respiratory syncytial virus (RSV) is a leading cause of morbidity and mortality in human infants. Bovine RSV infection of neonatal calves is pathologically and immunologically similar to RSV infection in infants, and is therefore a useful preclinical model for testing novel therapeutics. Treatment of severe RSV bronchiolitis relies on supportive care and may include use of bronchodilators and inhaled or systemic corticosteroids. Interleukin-17A (IL-17) is an inflammatory cytokine that plays an important role in neutrophil recruitment and activation. IL-17 is increased in children and rodents with severe RSV infection; and in calves with severe BRSV infection. It is currently unclear if IL-17 and Th17 immunity is beneficial or detrimental to the host during RSV infection. Digoxin was recently identified to selectively inhibit IL-17 production by antagonizing its transcription factor, retinoid-related orphan receptor γ t (RORγt). Digoxin inhibits RORγt binding to IL-17 and Th17 associated genes, and suppresses IL-17 production in vitro in human and murine leukocytes and in vivo in rodent models of autoimmune disease. We demonstrate here that in vitro and in vivo digoxin treatment also inhibits IL-17 production by bovine leukocytes. To determine the role of IL-17 in primary RSV infection, calves were treated prophylactically with digoxin and infected with BRSV. Digoxin treated calves demonstrated reduced signs of clinical illness after BRSV infection, and reduced lung pathology compared to untreated control calves. Digoxin treatment did not adversely affect virus shedding or lung viral burden, but had a significant impact on pulmonary inflammatory cytokine expression on day 10 post infection. Together, our results suggest that exacerbated expression of IL-17 has a negative impact on RSV disease, and that development of specific therapies targeting Th17 immunity may be a promising strategy to improve disease outcome during severe RSV infection.
Asunto(s)
Bronquiolitis/virología , Digoxina/administración & dosificación , Interleucina-17/metabolismo , Virus Sincitial Respiratorio Bovino/efectos de los fármacos , Animales , Animales Recién Nacidos , Bovinos , Digoxina/farmacología , Modelos Animales de Enfermedad , Regulación hacia Abajo , Femenino , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Leucocitos/virología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Profilaxis Posexposición , Virus Sincitial Respiratorio Bovino/inmunología , Células Th17/inmunología , Células Th17/virologíaRESUMEN
BACKGROUND: B cell-activating transcription factor (BATF) contributes to Th17 cell differentiation and pathological inflammatory responses. AIMS: This study explored BATF as a regulator of Th17 differentiation in normal and hepatitis B virus (HBV) transgenic mice. METHODS: Normal mice were divided into control, short hairpin RNA (shRNA) scramble, and shRNA BATF groups. HBV transgenic mice were divided into control, entecavir, shRNA scramble, entecavir + vector control, entecavir + shRNA scramble, shRNA BATF, and entecavir + shRNA BATF groups. Serum concentrations of AST, ALT, HBV-DNA, BATF, IL-17, and IL-22 and Th17 cell frequencies in the liver were compared among the groups. Correlations of serum HBV surface antigen (HBsAg), e-antigen (HBeAg), and core antigen (HBcAg) concentrations with BATF mRNA expression and the proportion of Th17 cells in the livers of HBV transgenic mice were also analyzed. RESULTS: Serum AST, ALT, BATF, IL-17, and IL-22 concentrations and Th17 cell proportions were higher in HBV transgenic mice relative to normal controls. Positive correlations of the HBcAg concentration with BATF mRNA and the proportion of Th17 cells were observed in HBV transgenic mice. BATF interference reduced the proportion of Th17 cells and serum IL-17 and IL-22 concentrations and led to obvious downregulation of AST, ALT, BATF, IL-17, and IL-22 expression and a reduced proportion of Th17 cells when combined with entecavir. CONCLUSION: HBV markedly upregulated BATF expression and promoted Th17 cell activation. By contrast, BATF interference significantly impeded the proliferation of Th17 cells and secretion of IL-17 and IL-22 while alleviating hepatic lesions.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Diferenciación Celular , Virus de la Hepatitis B/genética , Hepatitis B/metabolismo , Hígado/metabolismo , Activación de Linfocitos , Células Th17/metabolismo , Animales , Antivirales/farmacología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Guanina/análogos & derivados , Guanina/farmacología , Hepatitis B/inmunología , Hepatitis B/prevención & control , Hepatitis B/virología , Virus de la Hepatitis B/crecimiento & desarrollo , Interacciones Huésped-Patógeno , Interleucina-17/metabolismo , Interleucinas/metabolismo , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/virología , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Ratones Transgénicos , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/virología , Carga Viral , Interleucina-22RESUMEN
PURPOSE OF REVIEW: This review highlights current knowledge on the dichotomous role played by T helper 17 cells (Th17)-polarized CD4 T cells in maintaining mucosal immunity homeostasis versus fueling HIV/simian immunodeficiency virus (SIV) replication/persistence during antiretroviral therapy (ART), with a focus on molecular mechanisms underlying these processes. RECENT FINDING: Th17 cells bridge innate and adaptive immunity against pathogens at mucosal barrier surfaces. Th17 cells are located at portal sites of HIV/SIV entry, express a unique transcriptional/metabolic status compatible with viral replication, and represent the first targets of infection. The paucity of Th17 cells during HIV/SIV infection is caused by infection itself, but also by an altered Th17 differentiation, survival, and trafficking into mucosal sites. This causes major alterations of mucosal barrier integrity, microbial translocation, and disease progression. Unless initiated during the early acute infection phases, ART fails to restore the frequency/functionality of mucosal Th17 cells. A fraction of Th17 cells is long-lived and carry HIV reservoir during ART. Recent studies identified Th17-specific host factors controlling HIV transcription, a step untargeted by current ART. SUMMARY: The identification of molecular mechanisms contributing to HIV replication/persistence in mucosal Th17 cells paves the way toward the design of new Th17-specific therapeutic strategies aimed at improving mucosal immunity in HIV-infected individuals.
Asunto(s)
Infecciones por VIH/inmunología , VIH/fisiología , Células Th17/inmunología , Animales , Modelos Animales de Enfermedad , VIH/genética , Infecciones por VIH/virología , Humanos , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/fisiología , Células Th17/virología , Replicación ViralRESUMEN
BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold. AIMS: To establish a mouse model of virus infection-induced AE-IPF and investigate the mechanism underlying the AE-IPF. METHODS: Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild-type (WT) and IL-17A gene knockout (IL-17A-/- ) mice 21 days after intratracheal administration of bleomycin (BLM). RESULTS: HSV1 infection caused acute exacerbation in mice with BLM-induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)-related proteins in mice with BLM-induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL-17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE-IPF. Compared with WT mice with BLM+HSV1, IL-17A-/- mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response. CONCLUSIONS: HSV1 infection in addition to BLM-induced IPF can successfully establish AE-IPF in mice. IL-17A and ERS promote lung inflammation in AE-IPF development.
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Lesión Pulmonar Aguda/virología , Estrés del Retículo Endoplásmico/inmunología , Herpes Simple/virología , Fibrosis Pulmonar Idiopática/virología , Interleucina-17/genética , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/mortalidad , Animales , Antiinflamatorios/farmacología , Antivirales/farmacología , Bleomicina , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/genética , Expresión Génica , Herpes Simple/inducido químicamente , Herpes Simple/tratamiento farmacológico , Herpes Simple/mortalidad , Herpesvirus Humano 1 , Humanos , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/mortalidad , Interleucina-17/deficiencia , Interleucina-17/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pruebas de Función Respiratoria , Análisis de Supervivencia , Ácido Tauroquenodesoxicólico/farmacología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/virologíaRESUMEN
BACKGROUND: Female gender and favorable IFNL3 genotypes are the primary independent predictors of spontaneous clearance of HCV infection. However, chronic hepatitis C infection occurs in numerous women carrying favorable IFNL3 genotypes, indicating that other host and/or virological factors contribute to the prognosis of infection. METHODS: A cohort of 137 anti-HCV-positive female Han Chinese cases, including 64 chronic HCV carriers and 73 HCV spontaneous resolvers, was recruited in the study. 111 SNPs in 23 genes encoding HCV co-receptors, transcription factors, Toll-like receptors, co-stimulating molecules, and cytokines were selected for SNP analysis. RESULTS: After comparison of genotypes and allelotype frequencies of 111 SNPs in 23 genes in the primary cohort, the SNPs rs9826 (P = 0.024 for CC/TT/CT; P = 0.015 for C allele/T allele) and rs1521177 (P = 0.017 for GG/TT/GT; P = 0.006 for G allele/T allele) in the RORC gene were significantly associated with spontaneous HCV clearance. In the sub-cohort carrying favorable IFNL3 genotypes (rs12979860CC, rs8099917 TT, rs12980275 AA), rs1521177 (genotype: P = 0.040; allelotype: P = 0.021) remained significantly associated with spontaneous HCV clearance. Importantly, the most common RORC haplotype rs9826-T/rs1521177-T was presented at significantly different frequencies in resolvers and carriers in both the primary cohort (P = 0.0027) and the IFNL3 favorable sub-cohort (P = 0.0117). CONCLUSIONS: This study indicates that genetic polymorphisms in human Th17-related RORC gene are associated with different natural prognosis of HCV infection. The RORC haplotype, rs9826-T/rs1521177-T, was favorable for spontaneous clearance of HCV infection.
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Hepatitis C Crónica/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Polimorfismo de Nucleótido Simple , Células Th17/fisiología , Alelos , Pueblo Asiatico/genética , Femenino , Genotipo , Haplotipos , Humanos , Interferones , Interleucinas/genética , Persona de Mediana Edad , Remisión Espontánea , Células Th17/virologíaRESUMEN
HIV and pathogenic SIV infection are characterized by mucosal dysfunction including epithelial barrier damage, loss of Th17 cells, neutrophil infiltration, and microbial translocation with accompanying inflammation. However, it is unclear how and when these contributing factors occur relative to one another. In order to determine whether any of these features initiates the cycle of damage, we longitudinally evaluated the kinetics of mucosal and systemic T-cell activation, microbial translocation, and Th17 cell and neutrophil frequencies following intrarectal SIV infection of rhesus macaques. We additionally assessed the colon proteome to elucidate molecular pathways altered early after infection. We demonstrate increased T-cell activation (HLA-DR+) beginning 3-14 days post-SIV challenge, reduced peripheral zonulin 3-14 days post-SIV, and evidence of microbial translocation 14 days post-SIV. The onset of mucosal dysfunction preceded peripheral and mucosal Th17 depletion, which occurred 14-28 days post-SIV, and gut neutrophil accumulation was not observed. Proteins involved in epithelial structure were downregulated 3 days post-SIV followed by an upregulation of immune proteins 14 days post-SIV. These data demonstrate that immune perturbations such as Th17 loss and neutrophil infiltration occur after alterations to epithelial structural protein pathways, suggesting that epithelial damage occurs prior to widespread immune dysfunction.
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Colon/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Mucosa Intestinal/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Colon/inmunología , Colon/virología , Regulación hacia Abajo/inmunología , Inflamación/inmunología , Inflamación/patología , Inflamación/virología , Estudios Longitudinales , Activación de Linfocitos/inmunología , Macaca mulatta , Masculino , Neutrófilos/inmunología , Neutrófilos/patología , Neutrófilos/virología , Células Th17/inmunología , Células Th17/virología , Regulación hacia Arriba/inmunologíaRESUMEN
Human cytomegalovirus (HCMV) donor positive (D+) serostatus with acute rejection is associated with renal allograft loss, but the impact of recipient positive (R+) serostatus is unclear. In an allogeneic renal transplant model, antiviral natural killer (NK) and CD8+ T cell memory responses in murine CMV (MCMV) D+/R+ transplants were compared to D-/R- and D+/R- transplants, with recipient infection varied by MCMV dose and strain. D+/R- transplants had high primary antiviral cytolytic (interferon-γ+) and cytotoxic (granzyme B+) NK responses, whereas NK memory responses were lower in D+/R+ recipients receiving a high primary MCMV dose. Despite MCMV immunity, D+/R+ recipients receiving a low MCMV dose showed primary-like high cytolytic and cytotoxic NK responses. D+/R+ transplants infected with different D/R strains had low cytolytic NK responses but high cytotoxic NK responses. NK memory also induced a novel TNF-α+ NK response among high-dose virus recipients. MCMV+ transplants had greater Th17 responses than MCMV-uninfected transplants and Th17 inhibition ameliorated graft injury. All MCMV+ recipients had similar CD8+ T cell responses. In sum, NK and Th17 responses, but not CD8+ T cells, varied according to conditions of primary recipient infection. This variability could contribute to variable graft outcomes in HCMV D+/R+ renal transplantation.
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Infecciones por Citomegalovirus/inmunología , Rechazo de Injerto/etiología , Trasplante de Riñón/efectos adversos , Células Asesinas Naturales/inmunología , Muromegalovirus/clasificación , Células Th17/inmunología , Carga Viral/inmunología , Aloinjertos , Animales , Infecciones por Citomegalovirus/virología , Rechazo de Injerto/patología , Células Asesinas Naturales/patología , Células Asesinas Naturales/virología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Muromegalovirus/inmunología , Células Th17/patología , Células Th17/virologíaRESUMEN
Measles is characterized by a transient immune suppression, leading to an increased risk of opportunistic infections. Measles virus (MV) infection of immune cells is mediated by the cellular receptor CD150, expressed by subsets of lymphocytes, dendritic cells, macrophages, and thymocytes. Previous studies showed that human and nonhuman primate memory T cells express higher levels of CD150 than naive cells and are more susceptible to MV infection. However, limited information is available about the CD150 expression and relative susceptibility to MV infection of B-cell subsets. In this study, we assessed the susceptibility and permissiveness of naive and memory T- and B-cell subsets from human peripheral blood or tonsils to in vitro MV infection. Our study demonstrates that naive and memory B cells express CD150, but at lower frequencies than memory T cells. Nevertheless, both naive and memory B cells proved to be highly permissive to MV infection. Furthermore, we assessed the susceptibility and permissiveness of various functionally distinct T and B cells, such as helper T (TH) cell subsets and IgG- and IgA-positive memory B cells, in peripheral blood and tonsils. We demonstrated that TH1TH17 cells and plasma and germinal center B cells were the subsets most susceptible and permissive to MV infection. Our study suggests that both naive and memory B cells, along with several other antigen-experienced lymphocytes, are important target cells of MV infection. Depletion of these cells potentially contributes to the pathogenesis of measles immune suppression.IMPORTANCE Measles is associated with immune suppression and is often complicated by bacterial pneumonia, otitis media, or gastroenteritis. Measles virus infects antigen-presenting cells and T and B cells, and depletion of these cells may contribute to lymphopenia and immune suppression. Measles has been associated with follicular exhaustion in lymphoid tissues in humans and nonhuman primates, emphasizing the importance of MV infection of B cells in vivo However, information on the relative susceptibility of B-cell subsets is scarce. Here, we compared the susceptibility and permissiveness to in vitro MV infection of human naive and memory T- and B-cell subsets isolated from peripheral blood or tonsils. Our results demonstrate that both naive and memory B cells are more permissive to MV infection than T cells. The highest infection levels were detected in plasma cells and germinal center B cells, suggesting that infection and depletion of these populations contribute to reduced host resistance.
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Linfocitos B/inmunología , Memoria Inmunológica , Virus del Sarampión/inmunología , Sarampión/inmunología , Células TH1/inmunología , Células Th17/inmunología , Adulto , Linfocitos B/patología , Linfocitos B/virología , Niño , Femenino , Humanos , Masculino , Sarampión/patología , Células TH1/patología , Células TH1/virología , Células Th17/patología , Células Th17/virologíaRESUMEN
The cluster of differentiation protein complex, CD80/CD86, regulates Th1/Th2 differentiation in autoimmune disease. In order to establish the effects of CD80/CD86 on Th17 cell differentiation in acute viral myocarditis (VMC), we infected C57BL/6 mice with Coxsackie virus B3 (CVB3) and examined the effects of the treatment with anti-CD80/CD86 monoclonal antibodies (mAbs) on Th17 cell differentiation in vivo. The effects of anti-CD80/CD86 mAbs on Th17 cell differentiation were further evaluated in vitro. The treatment with anti-CD80 mAb induced marked suppression of Th17 cell differentiation and ROR-γt mRNA expression, whereas anti-CD86 mAb alone had no effect, both in vivo and in vitro. Our finding that CD80 regulates Th17 differentiation supports the potential utility of anti-CD80 mAb as an effective new immunotherapeutic target in acute VMC.