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1.
J Infect Dis ; 2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36482781

RESUMO

BACKGROUND: Monocyte activation is a driver of inflammation in the course of chronic HIV infection. Prostaglandin E2 (PGE2) is known to mediate anti-inflammatory effects, notably the inhibition of TNF-α production by monocytes. We aim to investigate the effects of PGE2 on the activation of monocytes in the course of chronic HIV infection and the mechanisms through which PGE2 modulates their inflammatory signature. METHODS: We recruited a group of people with HIV (PWH) and matched healthy uninfected persons. Then we compared plasma levels of PGE2, monocyte activation and sensitivity of monocytes to the inhibitory actions mediated by PGE2. RESULTS: We found increased plasma levels of PGE2 in PWH, and an activated phenotype in circulating monocytes, compared with uninfected individuals. Monocytes from PWH showed a significant resistance to the inhibitory actions mediated by PGE2. In fact, the concentration of PGE2 able to inhibit 50% of the production of TNF-α by LPS-stimulated monocytes was 10 times higher in PWH compared with uninfected controls. Furthermore, the expression of phosphodiesterase 4B, a negative regulator of PGE2 activity, was significantly increased in monocytes from PWH. CONCLUSION: Resistance to the inhibitory actions mediated by PGE2 could account, at least in part, to the inflammatory profile of circulating monocytes in PWH.

2.
Front Immunol ; 13: 992370, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36225925

RESUMO

The COVID-19 pandemic has particularly affected older adults residing in nursing homes, resulting in high rates of hospitalisation and death. Here, we evaluated the longitudinal humoral response and neutralising capacity in plasma samples of volunteers vaccinated with different platforms (Sputnik V, BBIBP-CorV, and AZD1222). A cohort of 851 participants, mean age 83 (60-103 years), from the province of Buenos Aires, Argentina were included. Sequential plasma samples were taken at different time points after vaccination. After completing the vaccination schedule, infection-naïve volunteers who received either Sputnik V or AZD1222 exhibited significantly higher specific anti-Spike IgG titers than those who received BBIBP-CorV. Strong correlation between anti-Spike IgG titers and neutralising activity levels was evidenced at all times studied (rho=0.7 a 0.9). Previous exposure to SARS-CoV-2 and age <80 years were both associated with higher specific antibody levels. No differences in neutralising capacity were observed for the infection-naïve participants in either gender or age group. Similar to anti-Spike IgG titers, neutralising capacity decreased 3 to 9-fold at 6 months after initial vaccination for all platforms. Neutralising capacity against Omicron was between 10-58 fold lower compared to ancestral B.1 for all vaccine platforms at 21 days post dose 2 and 180 days post dose 1. This work provides evidence about the humoral response and neutralising capacity elicited by vaccination of a vulnerable elderly population. This data could be useful for pandemic management in defining public health policies, highlighting the need to apply reinforcements after a complete vaccination schedule.


Assuntos
COVID-19 , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais , Argentina/epidemiologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , ChAdOx1 nCoV-19 , Humanos , Imunoglobulina G , Pandemias , SARS-CoV-2 , Vacinação
3.
Medicine (Baltimore) ; 101(36): e30500, 2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36086703

RESUMO

BACKGROUND: The choice of an appropriate probiotic for pediatric acute gastroenteritis (PAGE) can be confusing. Our aim was to compare the efficacy and safety of 2 probiotics (Saccharomyces boulardii CNCM I-745 vs a 4-strain mixture of Bacillus clausii O/C, SIN, N/R, T) for the treatment of PAGE. METHODS: A 2-arm parallel, randomized trial recruited children (6 months to 5 years old) with mild-moderate acute diarrhea, from 8 centers in Argentina. A total of 317 children were enrolled and blindly randomized to 5 days of either S boulardii CNCM I-745 (n = 159) or a 4-strain mixture of B clausii (n = 158), then followed for 7 days post-probiotic treatment. A stool sample was collected at inclusion for pathogen identification. The primary outcome was duration of diarrhea defined as the time from enrollment to the last loose stool followed by the first 24-hour period with stool consistency improvement. Secondary outcomes included frequency of loose stools/day, severity of diarrhea, number reporting no diarrhea at Day 6, time-to-first formed stool, recurrence of diarrhea by study end (Day 12) and safety outcomes. RESULTS: Three hundred twelve (98%) children completed the study. S boulardii CNCM I-745 showed a significant reduction (P = .04) in the mean duration of diarrhea (64.6 hours, 95% confidence interval [CI] 56.5-72.8) compared to those given B clausii (78.0 hours, 95% CI 69.9-86.1). Both probiotics showed improvement in secondary outcomes and were well-tolerated. CONCLUSION: In this study, S boulardii CNCM I-745 demonstrated better efficacy than B clausii mix for reducing the duration of pediatric acute diarrhea.


Assuntos
Bacillus clausii , Gastroenterite , Probióticos , Saccharomyces boulardii , Criança , Diarreia/terapia , Gastroenterite/terapia , Humanos , Probióticos/uso terapêutico
4.
EBioMedicine ; 83: 104230, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35988465

RESUMO

BACKGROUND: Despite that pediatric COVID-19 is usually asymptomatic or mild, SARS-CoV-2 infection typically results in the development of an antibody response. Contradictory observations have been reported when the antibody response of children and adults were compared in terms of strength, specificity and perdurability. METHODS: This observational study includes three cohorts infected with SARS-CoV-2 between March 2020-July 2021: unvaccinated infected children (n=115), unvaccinated infected adults (n=62), and vaccinated infected children (n=76). Plasma anti-spike IgG antibodies and neutralising activity against Wuhan, Delta and Omicron variants after 7-17 months post-infection were analysed. FINDINGS: More than 95% of unvaccinated infected children and adults remained seropositive when evaluated at 382-491 and 386-420 days after infection, respectively. Anti-spike IgG titers and plasma neutralising activity against Wuhan, Delta and Omicron variants were higher in children compared to adults. No differences were found when unvaccinated infected children were stratified by age, gender or presence/absence of symptoms in the acute phase of SARS-CoV-2 infection, but a slight decrease in the antibody response was observed in those with comorbidities. Vaccination of previously infected children with two doses of the inactivated BBIBP-CorV or the mRNA vaccines, BNT162b2 and/or mRNA-1273, further increased anti-spike IgG titers and neutralising activity against Wuhan, Delta and Omicron variants. INTERPRETATION: Unvaccinated infected children mount a more potent and sustained antibody response compared with adults, which is significantly increased after vaccination. Further studies including not only the analysis of the immune response but also the effectiveness to prevent reinfections by the different Omicron lineages are required to optimise vaccination strategy in children. FUNDING: National Agency for Scientific and Technological Promotion from Argentina (PICTO-COVID-SECUELAS-00007 and PMO-BID-PICT2018-2548).


Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais , Formação de Anticorpos , Vacina BNT162 , Criança , Estudos de Coortes , Humanos , Imunoglobulina G
6.
J Infect Dis ; 226(10): 1717-1720, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-35723970

RESUMO

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is usually asymptomatic or mild and appears to be poorly immunogenic at least in unvaccinated individuals. Here, we found that health care workers vaccinated with 2 doses of Sputnik V and a booster dose of ChAdOx1 mount a vigorous neutralizing-antibody response after Omicron breakthrough infection.


Assuntos
Formação de Anticorpos , COVID-19 , Humanos , SARS-CoV-2 , COVID-19/prevenção & controle , Vacinação , Anticorpos Neutralizantes , Anticorpos Antivirais
7.
J Infect Dis ; 226(3): 374-385, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-35668702

RESUMO

BACKGROUND: The true burden of lower respiratory tract infections (LRTIs) due to respiratory syncytial virus (RSV) remains unclear. This study aimed to provide more robust, multinational data on RSV-LRTI incidence and burden in the first 2 years of life. METHODS: This prospective, observational cohort study was conducted in Argentina, Bangladesh, Canada, Finland, Honduras, South Africa, Thailand, and United States. Children were followed for 24 months from birth. Suspected LRTIs were detected via active (through regular contacts) and passive surveillance. RSV and other viruses were detected from nasopharyngeal swabs using PCR-based methods. RESULTS: Of 2401 children, 206 (8.6%) had 227 episodes of RSV-LRTI. Incidence rates (IRs) of first episode of RSV-LRTI were 7.35 (95% confidence interval [CI], 5.88-9.08), 5.50 (95% CI, 4.21-7.07), and 2.87 (95% CI, 2.18-3.70) cases/100 person-years in children aged 0-5, 6-11, and 12-23 months. IRs for RSV-LRTI, severe RSV-LRTI, and RSV hospitalization tended to be higher among 0-5 month olds and in lower-income settings. RSV was detected for 40% of LRTIs in 0-2 month olds and for approximately 20% of LRTIs in older children. Other viruses were codetected in 29.2% of RSV-positive nasopharyngeal swabs. CONCLUSIONS: A substantial burden of RSV-LRTI was observed across diverse settings, impacting the youngest infants the most. Clinical Trials Registration. NCT01995175.


Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Infecções Respiratórias , Vírus , Criança , Hospitalização , Humanos , Incidência , Lactente , Estudos Prospectivos
9.
Br J Haematol ; 197(3): 283-292, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35076084

RESUMO

Severe COVID-19 is associated with a systemic inflammatory response and progressive CD4+ T-cell lymphopenia and dysfunction. We evaluated whether platelets might contribute to CD4+ T-cell dysfunction in COVID-19. We observed a high frequency of CD4+ T cell-platelet aggregates in COVID-19 inpatients that inversely correlated with lymphocyte counts. Platelets from COVID-19 inpatients but not from healthy donors (HD) inhibited the upregulation of CD25 expression and tumour necrosis factor (TNF)-α production by CD4+ T cells. In addition, interferon (IFN)-γ production was increased by platelets from HD but not from COVID-19 inpatients. A high expression of PD-L1 was found in platelets from COVID-19 patients to be inversely correlated with IFN-γ production by activated CD4+ T cells cocultured with platelets. We also found that a PD-L1-blocking antibody significantly restored platelets' ability to stimulate IFN-γ production by CD4+ T cells. Our study suggests that platelets might contribute to disease progression in COVID-19 not only by promoting thrombotic and inflammatory events, but also by affecting CD4+ T cells functionality.


Assuntos
Antígeno B7-H1 , COVID-19 , Antígeno B7-H1/metabolismo , Plaquetas/metabolismo , Linfócitos T CD4-Positivos , Humanos , Interferon gama
10.
mBio ; : e0344221, 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35073758

RESUMO

Recent studies have shown a temporal increase in the neutralizing antibody potency and breadth to SARS-CoV-2 variants in coronavirus disease 2019 (COVID-19) convalescent individuals. Here, we examined longitudinal antibody responses and viral neutralizing capacity to the B.1 lineage virus (Wuhan related), to variants of concern (VOC; Alpha, Beta, Gamma, and Delta), and to a local variant of interest (VOI; Lambda) in volunteers receiving the Sputnik V vaccine in Argentina. Longitudinal serum samples (N = 536) collected from 118 volunteers obtained between January and October 2021 were used. The analysis indicates that while anti-spike IgG levels significantly wane over time, the neutralizing capacity for the Wuhan-related lineages of SARS-CoV-2 and VOC is maintained within 6 months of vaccination. In addition, an improved antibody cross-neutralizing ability for circulating variants of concern (Beta and Gamma) was observed over time postvaccination. The viral variants that displayed higher escape to neutralizing antibodies with respect to the original virus (Beta and Gamma variants) were the ones showing the largest increase in susceptibility to neutralization over time after vaccination. Our observations indicate that serum neutralizing antibodies are maintained for at least 6 months and show a reduction of VOC escape to neutralizing antibodies over time after vaccination. IMPORTANCE Vaccines have been produced in record time for SARS-CoV-2, offering the possibility of halting the global pandemic. However, inequalities in vaccine accessibility in different regions of the world create a need to increase international cooperation. Sputnik V is a recombinant adenovirus-based vaccine that has been widely used in Argentina and other developing countries, but limited information is available about its elicited immune responses. Here, we examined longitudinal antibody levels and viral neutralizing capacity elicited by Sputnik V vaccination. Using a cohort of 118 volunteers, we found that while anti-spike antibodies wane over time, the neutralizing capacity to viral variants of concern and local variants of interest is maintained within 4 months of vaccination. In addition, we observed an increased cross-neutralization activity over time for the Beta and Gamma variants. This study provides valuable information about the immune response generated by a vaccine platform used in many parts of the world.

11.
EBioMedicine ; 72: 103615, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34649078

RESUMO

BACKGROUND: Most children and youth develop mild or asymptomatic disease during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, a very small number of patients suffer severe Coronavirus induced disease 2019 (COVID-19). The reasons underlying these different outcomes remain unknown. METHODS: We analyzed three different cohorts: children with acute infection (n=550), convalescent children (n=138), and MIS-C (multisystem inflammatory syndrome in children, n=42). IgG and IgM antibodies to the spike protein of SARS-CoV-2, serum-neutralizing activity, plasma cytokine levels, and the frequency of circulating Follicular T helper cells (cTfh) and plasmablasts were analyzed by conventional methods. FINDINGS: Fifty-eight percent of the children in the acute phase of infection had no detectable antibodies at the time of sampling while a seronegative status was found in 25% and 12% of convalescent and MIS-C children, respectively. When children in the acute phase of the infection were stratified according disease severity, we found that contrasting with the response of children with asymptomatic, mild and moderate disease, children with severe COVID-19 did not develop any detectable response. A defective antibody response was also observed in the convalescent cohort for children with severe disease at the time of admission. This poor antibody response was associated to both, a low frequency of cTfh and a high plasma concentration of inflammatory cytokines. INTERPRETATION: A weak and delayed kinetic of antibody response to SARS-CoV-2 together with a systemic pro-inflammatory profile characterize pediatric severe COVID-19. Because comorbidities are highly prevalent in children with severe COVID-19, further studies are needed to clarify their contribution in the weak antibody response observed in severe disease. FUNDING: National Agency for Scientific and Technological Promotion from Argentina (IP-COVID-19-0277 and PMO-BID-PICT2018-2548).


Assuntos
Anticorpos Antivirais/sangue , Formação de Anticorpos , COVID-19/complicações , COVID-19/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Argentina , COVID-19/sangue , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Humanos , Lactente , Masculino , SARS-CoV-2/imunologia , Síndrome de Resposta Inflamatória Sistêmica/sangue
12.
Nat Commun ; 12(1): 5148, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446714

RESUMO

Coronavirus infection in humans is usually associated to respiratory tract illnesses, ranging in severity from mild to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists boost antiviral immunity, decrease viral titers and ameliorate Zika-induced pathology in vivo. Here we report that AHR is activated by infection with different coronaviruses, potentially impacting antiviral immunity and lung epithelial cells. Indeed, the analysis of single-cell RNA-seq from lung tissue detected increased expression of AHR and AHR transcriptional targets, suggesting AHR signaling activation in SARS-CoV-2-infected epithelial cells from COVID-19 patients. Moreover, we detected an association between AHR expression and viral load in SARS-CoV-2 infected patients. Finally, we found that the pharmacological inhibition of AHR suppressed the replication in vitro of one of the causative agents of the common cold, HCoV-229E, and the causative agent of the COVID-19 pandemic, SARS-CoV-2. Taken together, these findings suggest that AHR activation is a common strategy used by coronaviruses to evade antiviral immunity and promote viral replication, which may also contribute to lung pathology. Future studies should further evaluate the potential of AHR as a target for host-directed antiviral therapy.


Assuntos
Infecções por Coronavirus/metabolismo , Coronavirus/fisiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , COVID-19/genética , COVID-19/metabolismo , COVID-19/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Humanos , Masculino , Receptores de Hidrocarboneto Arílico/genética , SARS-CoV-2/fisiologia
13.
J Infect Dis ; 224(4): 575-585, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34398243

RESUMO

Severe coronavirus disease 2019 (COVID-19) is associated with an overactive inflammatory response mediated by macrophages. Here, we analyzed the phenotype and function of neutrophils in patients with COVID-19. We found that neutrophils from patients with severe COVID-19 express high levels of CD11b and CD66b, spontaneously produce CXCL8 and CCL2, and show a strong association with platelets. Production of CXCL8 correlated with plasma concentrations of lactate dehydrogenase and D-dimer. Whole blood assays revealed that neutrophils from patients with severe COVID-19 show a clear association with immunoglobulin G (IgG) immune complexes. Moreover, we found that sera from patients with severe disease contain high levels of immune complexes and activate neutrophils through a mechanism partially dependent on FcγRII (CD32). Interestingly, when integrated in immune complexes, anti-severe acute respiratory syndrome coronavirus 2 IgG antibodies from patients with severe COVID-19 displayed a higher proinflammatory profile compared with antibodies from patients with mild disease. Our study suggests that IgG immune complexes might promote the acquisition of an inflammatory signature by neutrophils, worsening the course of COVID-19.


Assuntos
Anticorpos Antivirais/imunologia , Complexo Antígeno-Anticorpo/imunologia , COVID-19/imunologia , Imunoglobulina G/imunologia , Ativação de Neutrófilo/imunologia , Adulto , Idoso , Anticorpos Antivirais/sangue , Complexo Antígeno-Anticorpo/sangue , Antígenos CD/imunologia , Antígeno CD11b/imunologia , Moléculas de Adesão Celular/imunologia , Feminino , Proteínas Ligadas por GPI/imunologia , Humanos , Imunoglobulina G/sangue , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Receptores de IgG/imunologia , SARS-CoV-2/imunologia , Adulto Jovem
14.
Oncoimmunology ; 8(9): e1629257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428526

RESUMO

Clusterin is a glycoprotein able to mediate different physiological functions such as control of complement activation, promotion of unfolded protein clearance and modulation of cell survival. Clusterin is overexpressed in many types of cancers and a large body of evidence suggests that it promotes carcinogenesis and tumor progression. We have previously described a novel clusterin glycoform present in human semen, but not in serum, highly enriched in terminal fucose motifs. Here we show that human luminal breast cancer (LBC) clusterin also bears terminal fucosylated glycans, conferring clusterin the ability to interact with DC-SIGN, a C-type lectin receptor expressed by myeloid cells. This clusterin glycosylation pattern was absent or diminished in non-involved juxtatumoral tissue, suggesting that fucosylated clusterin might represent a cancer associated glycoform. We also found that DC-SIGN is expressed by luminal breast cancer intratumoral macrophages. Moreover, experiments performed in vitro using semen fucosylated clusterin and monocyte derived macrophages showed that the interaction of semen clusterin with DC-SIGN promoted a proangiogenic profile, characterized by a high production of VEGF, IL-8 and TNF-α. Our results reveal an unexpected complexity on the structure and function of secretory clusterin produced by tumors and suggest that fucosylated clusterin produced by luminal breast cancer cells might play a role in tumor progression by promoting the release of pro-angiogenic factors by intratumoral macrophages.

15.
J Virol ; 93(4)2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30518643

RESUMO

Histidine-rich glycoprotein (HRG) is an abundant plasma protein with a multidomain structure, allowing its interaction with many ligands, including phospholipids, plasminogen, fibrinogen, IgG antibodies, and heparan sulfate. HRG has been shown to regulate different biological responses, such as angiogenesis, coagulation, and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of Ghost cells, Jurkat cells, CD4+ T cells, and macrophages by HIV-1 at a low pH (range, 6.5 to 5.5) but not at a neutral pH. HRG was shown to interact with the heparan sulfate expressed by target cells, inhibiting an early postbinding step associated with HIV-1 infection. More importantly, by acting on the viral particle itself, HRG induced a deleterious effect, which reduces viral infectivity. Because cervicovaginal secretions in healthy women show low pH values, even after semen deposition, our observations suggest that HRG might represent a constitutive defense mechanism in the vaginal mucosa. Of note, low pH also enabled HRG to inhibit the infection of HEp-2 cells and Vero cells by respiratory syncytial virus (RSV) and herpes simplex virus 2 (HSV-2), respectively, suggesting that HRG might display broad antiviral activity under acidic conditions.IMPORTANCE Vaginal intercourse represents a high-risk route for HIV-1 transmission. The efficiency of male-to-female HIV-1 transmission has been estimated to be 1 in every 1,000 episodes of sexual intercourse, reflecting the high degree of protection conferred by the genital mucosa. However, the contribution of different host factors to the protection against HIV-1 at mucosal surfaces remains poorly defined. Here, we report for the first time that acidic values of pH enable the plasma protein histidine-rich glycoprotein (HRG) to strongly inhibit HIV-1 infection. Because cervicovaginal secretions usually show low pH values, our observations suggest that HRG might represent a constitutive antiviral mechanism in the vaginal mucosa. Interestingly, infection by other viruses, such as respiratory syncytial virus and herpes simplex virus 2, was also markedly inhibited by HRG at low pH values, suggesting that extracellular acidosis enables HRG to display broad antiviral activity.


Assuntos
Infecções por HIV/metabolismo , Infecções por HIV/prevenção & controle , Proteínas/farmacologia , Animais , Antivirais , Proteínas Sanguíneas , Linhagem Celular , Muco do Colo Uterino/química , Muco do Colo Uterino/metabolismo , Chlorocebus aethiops , Feminino , Glicoproteínas/metabolismo , Glicoproteínas/farmacologia , HIV-1/metabolismo , Heparitina Sulfato/metabolismo , Herpesvirus Humano 2/metabolismo , Histidina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Proteínas/metabolismo , Vírus Sinciciais Respiratórios/metabolismo , Células Vero , Viroses/metabolismo , Viroses/prevenção & controle
16.
Front Immunol ; 9: 1441, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29988364

RESUMO

Inflammatory dendritic cells (DCs) are a distinct subset of DCs that derive from circulating monocytes infiltrating injured tissues. Monocytes can differentiate into DCs with different functional signatures, depending on the presence of environment stimuli. Among these stimuli, transforming growth factor-beta (TGF-ß) and prostaglandin E2 (PGE2) have been shown to modulate the differentiation of monocytes into DCs with different phenotypes and functional profiles. In fact, both mediators lead to contrasting outcomes regarding the production of inflammatory and anti-inflammatory cytokines. Previously, we have shown that human semen, which contains high concentrations of PGE2, promoted the differentiation of DCs into a tolerogenic profile through a mechanism dependent on signaling by E-prostanoid receptors 2 and 4. Notably, this effect was induced despite the huge concentration of TGF-ß present in semen, suggesting that PGE2 overrides the influence exerted by TGF-ß. No previous studies have analyzed the joint actions induced by PGE2 and TGF-ß on the function of monocytes or DCs. Here, we analyzed the phenotype and functional profile of monocyte-derived DCs differentiated in the presence of TGF-ß and PGE2. DC differentiation guided by TGF-ß alone enhanced the expression of CD1a and abrogated LPS-induced expression of IL-10, while differentiation in the presence of PGE2 impaired CD1a expression, preserved CD14 expression, abrogated IL-12 and IL-23 production, stimulated IL-10 production, and promoted the expansion of FoxP3+ regulatory T cells in a mixed lymphocyte reaction. Interestingly, DCs differentiated in the presence of TGF-ß and PGE2 showed a phenotype and functional profile closely resembling those induced by PGE2 alone. Finally, we found that PGE2 inhibited TGF-ß signaling through an action exerted by EP2 and EP4 receptors coupled to cyclic AMP increase and protein kinase A activity. These results indicate that PGE2 suppresses the influence exerted by TGF-ß during DC differentiation, imprinting a tolerogenic signature. High concentrations of TGF-ß and PGE2 are usually found in infectious, autoimmune, and neoplastic diseases. Our observations suggest that in these scenarios PGE2 might play a mandatory role in the acquisition of a regulatory profile by DCs.

17.
J Infect Dis ; 215(7): 1049-1058, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28199704

RESUMO

BACKGROUND: Although human airway epithelial cells are the main target of respiratory syncytial virus (RSV), it also infects immune cells, such as macrophages and B cells. Whether T cells are permissive to RSV infection is unknown. We sought to analyze the permissiveness of CD4+ T cells to RSV infection. METHODS: CD4+ and CD8+ T cells from cord blood, healthy young children, and adults were challenged by RSV or cocultured with infected HEp-2 cells. Infection, phenotype, and cytokine production by T cells were analyzed by flow cytometry or enzyme-linked immunosorbent assay. Expression of RSV antigens by circulating CD4+ T cells from infected children was analyzed by flow cytometry, and disease severity was defined by standard criteria. RESULTS: CD4+ and CD8+ T cells were productively infected by RSV. Infection decreased interleukin 2 and interferon γ production as well as the expression of CD25 and Ki-67 by activated CD4+ T cells. Respiratory syncytial virus antigens were detected in circulating CD4+ and CD8+ T cells during severe RSV infection of young children. Interestingly, the frequency of CD4+ RSV+ T cells positively correlated with disease severity. CONCLUSIONS: Respiratory syncytial virus infects CD4+ and CD8+ T cells and compromises T-cell function. The frequency of circulating CD4+ RSV+ T cells might represent a novel marker of severe infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Adulto , Biomarcadores/sangue , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Linhagem Celular , Feminino , Sangue Fetal/citologia , Citometria de Fluxo , Humanos , Lactente , Recém-Nascido , Interferon gama/imunologia , Interleucina-2/imunologia , Masculino , Vírus Sincicial Respiratório Humano
18.
Acta Trop ; 162: 180-187, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27394030

RESUMO

Strongyloidiasis is widely distributed in the tropical and subtropical areas. Ivermectin is the drug of choice for the treatment. However, the concerns about relying treatment on a single drug make identification of new molecules a priority. Alkylphospholipid analogues, including edelfosine, are a group of synthetic compounds that have shown activity against some parasites. The objective was to assess the in vitro and in vivo activity of edelfosine, miltefosine, perifosine against Strongyloides venezuelensis. Moreover, apoptosis-like mechanism in larvae after treatment was studied. Edelfosine displayed the highest activity and the best selectivity index (LD50=49.6 ± 5.4µM, SI=1.1) compared to miltefosine or perifosine. Third stage larvae after culture with edelfosine were not able to develop an infection in mice. Treatment of mice with edelfosine showed reduction of 47% in parasitic females allocated in the gut. Moreover, DNA fragmentation was observed by TUNEL staining in larvae treated with edelfosine. These results suggest that edelfosine could be an effective drug against strongyloidiasis, probably through induction of apoptosis-like cell death.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Éteres Fosfolipídicos/farmacologia , Strongyloides/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Larva/efeitos dos fármacos , Camundongos , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Estrongiloidíase/parasitologia
19.
Parasit Vectors ; 9(1): 364, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27353595

RESUMO

BACKGROUND: Strongyloidiasis is a parasitic disease widely present in tropical and subtropical areas. Strongyloides stercoralis represents the main species that infects human beings. Ivermectin is the current drug of choice; however, issues related with treatment failure in patients with diabetes or infected with T-lymphotropic virus-1 make the identification of new molecules for alternative treatment a priority. In the present study, the activity of sphingosine-related aminoalcohol and diamine were evaluated against Strongyloides venezuelensis third-stage larva (L3) cultures and experimental infections in mice. METHODS: The efficacy of each compound against L3 was assessed using both XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay and microscopic observation with concentrations ranging from 1 to 350 µM. Cytotoxicity was evaluated using J774.2 macrophage cell line and XTT assay. Lethal concentration 50 (LC50), selectivity index (SI) and structure-activity relationships were established. The activity compounds 4 (2-(ethylamino) hexadecan-1-ol), 6 (2-(butylamino) hexadecan-1-ol), 17 (tert-butyl N-(1-aminododecan-2-yl) carbamate) and 18 (tert-butyl N-(1-aminohexadecan-2-yl) carbamate) were further assessed against experimental S. venezuelensis infections in CD1 mice measuring reductions in the numbers of parthenogenetic females and egg passed in faeces. Mice were infected with 3,000 L3 and treated with 20 mg/kg/day for five days. RESULTS: In the screening study of 15 aminoalcohols [lauryl (n = 9); palmityl (n = 13); stearyl (n = 15) and alcohol derivatives], the presence of a palmitol chain was associated with the highest efficacy against L3 (LC50 31.9-39.1 µM). Alkylation of the 2-amino group with medium size fragments as ethyl or n-butyl showed the best larvicidal activity. The dialkylation did not improve efficacy. Aminoalcohols 4 and 6 showed the highest SI (1.5 and 1.6, respectively). With respect to diamine derivative compounds, a chain size of sixteen carbon atoms (palmitoyl chain, n = 13), and the alkylation of the 2-amino group with medium-sized fragments, were associated with the highest lethal activities. The presence of carbamoyl group in diamines 17 and 18 yielded high SI (1.7 and 1.4, respectively). Infected mice treated with aminoalcohol 6 showed reduction in parthenogenetic females (59 %) and eggs in faeces (51 %). CONCLUSIONS: These results support the potentiality of aminoalcohol and diamine sphingosine-related compounds as suitable prototypes for developing new promising drugs against strongyloidiasis.


Assuntos
Amino Álcoois/farmacologia , Anti-Helmínticos/farmacologia , Diaminas/farmacologia , Strongyloides/efeitos dos fármacos , Estrongiloidíase/tratamento farmacológico , Amino Álcoois/química , Animais , Anti-Helmínticos/química , Diaminas/química , Masculino , Camundongos , Estrutura Molecular , Ratos , Estrongiloidíase/parasitologia , Relação Estrutura-Atividade
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