Control of Immunoregulatory Molecules by miRNAs in T Cell Activation

MiRNA targeting of key immunoregulatory molecules fine-tunes the immune response. This mechanism boosts or dampens immune functions to preserve homeostasis while supporting the full development of effector functions. MiRNA expression changes during T cell activation, highlighting that their function is constrained by a specific spatiotemporal frame related to the signals that induce T cell-based effector functions. Here, we update the state of the art regarding the miRNAs that are differentially expressed during T cell stimulation. We also revisit the existing data on miRNA function in T cell activation, with a special focus on the modulation of the most relevant immunoregulatory molecules.We thank Dr M. Vicente-Manzanares for critical reading of the manuscript and for assistance with English editing. This study was supported by the following grants from the Spanish Ministry of Economy and Competitiveness, (grant SAF2017-82886-R to FSM), CIBER CARDIOVASCULAR and PIE 13.0004-BIOIMID from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III with co-funding from the Fondo Europeo de Desarrollo Regional; FEDER), Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to FS-M, and ERC-2011-AdG294340-GENTRIS to FS-M. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECOaward SEV-2015-0505). AR-G is supported by the FPU program (Spanish Ministry of Education). LF-M is funded by the CIBER CARDIOVASCULAR.S

Control of Immunoregulatory Molecules by miRNAs in T Cell Activation

MiRNA targeting of key immunoregulatory molecules fine-tunes the immune response. This mechanism boosts or dampens immune functions to preserve homeostasis while supporting the full development of effector functions. MiRNA expression changes during T cell activation, highlighting that their function is constrained by a specific spatiotemporal frame related to the signals that induce T cell-based effector functions. Here, we update the state of the art regarding the miRNAs that are differentially expressed during T cell stimulation. We also revisit the existing data on miRNA function in T cell activation, with a special focus on the modulation of the most relevant immunoregulatory molecules

MicroRNAs in T Cell-Immunotherapy.

MicroRNAs (miRNAs) act as master regulators of gene expression in homeostasis and disease. Despite the rapidly growing body of evidence on the theranostic potential of restoring miRNA levels in pre-clinical models, the translation into clinics remains limited. Here, we review the current knowledge of miRNAs as T-cell targeting immunotherapeutic tools, and we offer an overview of the recent advances in miRNA delivery strategies, clinical trials and future perspectives in RNA interference technologies.This manuscript was funded by grants AEI/10.13039/501100011033, PID-2020-120412RBI100 and PDC2021-121797-I00 (F.S.-M.) from the Spanish Ministry of Economy and Competitiveness; CAM (S2017/BMD-3671-INFLAMUNE-CM) from the Comunidad de Madrid (F.S.-M.), CIBERCV (CB16/11/00272) and BIOIMID PIE13/041 from the Instituto de Salud Carlos “la Caixa” Foundation under the project code HR17-00016. The current research is supported by AECC-Coordinated Grant 2022 (PRYCO223002PEIN). The CNIC is supported by the Ministerio de Ciencia, Innovacion y Universidades and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015- 0505). IMDEA Nanociencia acknowledges support from the ‘Severo Ochoa’ Programme for Centres of Excellence in R&D (MINECO, CEX2020-001039-S). S.G.D. is supported by a grant from the Spanish Ministry of Universities.S

Congenital and perinatally-acquired infections in resource-constrained settings

INTRODUCTION: Congenital and perinatal infections are a leading cause of neonatal and infant morbidity and mortality. Maternal screening, vaccines or treatment where available, constitute effective prevention strategies to reduce the burden of these diseases. Data on the burden of congenital and perinatal infections are very limited for low and middle-income regions. AREAS COVERED: This review aims to summarize the burden of congenital and perinatal infections and the main challenges for their control in resource-limited settings. Articles were identified through the main electronic databases and cover the period 1971- 2016. Expert commentary: Estimates from low and middle-income countries indicate that the burden of congenital infections may be higher in these regions than in industrialized countries. As preventive and curative strategies are available to tackle some of these infections, efforts at the international and national levels must be made to implement those and thus reduce their burden in resource-limited countries

Adjunctive therapy for severe malaria: a review and critical appraisal.

BACKGROUND: Despite recent efforts and successes in reducing the malaria burden globally, this infection still accounts for an estimated 212 million clinical cases, 2 million severe malaria cases, and approximately 429,000 deaths annually. Even with the routine use of effective anti-malarial drugs, the case fatality rate for severe malaria remains unacceptably high, with cerebral malaria being one of the most life-threatening complications. Up to one-third of cerebral malaria survivors are left with long-term cognitive and neurological deficits. From a population point of view, the decrease of malaria transmission may jeopardize the development of naturally acquired immunity against the infection, leading to fewer total cases, but potentially an increase in severe cases. The pathophysiology of severe and cerebral malaria is not completely understood, but both parasite and host determinants contribute to its onset and outcomes. Adjunctive therapy, based on modulating the host response to infection, could help to improve the outcomes achieved with specific anti-malarial therapy. RESULTS AND CONCLUSIONS: In the last decades, several interventions targeting different pathways have been tested. However, none of these strategies have demonstrated clear beneficial effects, and some have shown deleterious outcomes. This review aims to summarize evidence from clinical trials testing different adjunctive therapy for severe and cerebral malaria in humans. It also highlights some preclinical studies which have evaluated novel strategies and other candidate therapeutics that may be evaluated in future clinical trials

Continuous Glucose Monitoring in Resource-Constrained Settings for Hypoglycaemia Detection: Looking at the Problem from the Other Side of the Coin

The appearance, over a decade ago, of continuous glucose monitoring (CGM) devices has triggered a patient-centred revolution in the control and management of diabetes mellitus and other metabolic conditions, improving the patient’s glycaemic control and quality of life. Such devices, the use of which remains typically restricted to high-income countries on account of their elevated costs, at present show very limited implantation in resource-constrained settings, where many other urgent health priorities beyond diabetes prevention and management still need to be resolved. In this commentary, we argue that such devices could have an additional utility in low-income settings, whereby they could be selectively used among severely ill children admitted to hospital for closer monitoring of paediatric hypoglycaemia, a life-threatening condition often complicating severe cases of malaria, malnutrition, and other common paediatric conditions

Hypoxaemia in Mozambican children < 5 years of age admitted to hospital with clinical severe pneumonia: clinical features and performance of predictor models

OBJECTIVE: To determine the prevalence of hypoxaemia among under-five children admitted to hospital with clinical severe pneumonia, and to assess the performance to diagnose hypoxaemia of models based on clinical signs. METHODS: We conducted a hospital-based survey in a district hospital from Southern Mozambique. RESULTS: A total of 825 children were recruited after obtaining an informed consent. The prevalence of hypoxaemia on admission was 27.9%, and 19.8% of these children died (OR compared to non-hypoxaemic children 3.22, 95%CI 1.98 - 5.21, p<0.001). The model with larger area under the ROC curve (AUC-ROC) to predict hypoxaemia included cyanosis or thoracoabdominal breathing or respiratory rate >/= 70 breaths per minute. None of the models performed well when tested in different case scenarios of oxygen availability through mathematical modelling, with over 50% of hypoxaemic children not receiving oxygen even in favourable case scenarios. CONCLUSIONS: Clinical signs alone or in combination are not suitable to diagnose hypoxaemia. The use of pulse oximeters should be strongly encouraged. This article is protected by copyright. All rights reserved

Hypoglycemia and Risk Factors for Death in 13 Years of Pediatric Admissions in Mozambique

Hypoglycemia is a life-threatening complication of several diseases in childhood. We describe the prevalence and incidence of hypoglycemia among admitted Mozambican children, establishing its associated risk factors. We retrospectively reviewed clinical data of 13 years collected through an ongoing systematic morbidity surveillance in Manhica District Hospital in rural Mozambique. Logistic regression was used to identify risk factors for hypoglycemia and death. Minimum community-based incidence rates (MCBIRs) for hypoglycemia were calculated using data from the demographic surveillance system. Of 49,089 children < 15 years hospitalized in Manhica District Hospital, 45,573 (92.8%) had a glycemia assessment on admission. A total of 1,478 children (3.2%) presented hypoglycemia (< 3 mmol/L), of which about two-thirds (972) were with levels < 2.5 mmol/L. Independent risk factors for hypoglycemia on admission and death among hypoglycemic children included prostration, unconsciousness, edema, malnutrition, and bacteremia. Hypoglycemic children were significantly more likely to die (odds ratio [OR] = 7.11; P < 0.001), with an associated case fatality rate (CFR) of 19.3% (245/1,267). Overall MCBIR of hypoglycemia was 1.57 episodes/1,000 child years at risk (CYAR), significantly decreasing throughout the study period. Newborns showed the highest incidences (9.47 episodes/1,000 CYAR, P < 0.001). Hypoglycemia remains a hazardous condition for African children. Symptoms and signs associated to hypoglycemia should trigger the verification of glycemia and the implementation of life-saving corrective measures

Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria.

BACKGROUND: Despite the widespread use and availability of rapidly acting anti-malarials, the fatality rate of severe malaria in sub-Saharan Africa remains high. Adjunctive therapies that target the host response to malaria infection may further decrease mortality over that of anti-malarial agents alone. Peroxisome proliferator-activated receptor-gamma agonists (e.g. rosiglitazone) have been shown to act on several pathways implicated in the pathogenesis of severe malaria and may improve clinical outcome as an adjunctive intervention. METHODS: In this study, the safety and tolerability of adjunctive rosiglitazone in paediatric uncomplicated malaria infection was evaluated in Mozambique, as a prelude to its evaluation in a randomized controlled trial in paediatric severe malaria. The study was a prospective, randomized, double-blind, placebo-controlled, phase IIa trial of rosiglitazone (0.045 mg/kg/dose) twice daily for 4 days versus placebo as adjunctive treatment in addition to Mozambican standard of care (artemisinin combination therapy Coartem®) in children with uncomplicated malaria. The primary outcomes were tolerability and safety, including clinical, haematological, biochemical, and electrocardiographic evaluations. RESULTS: Thirty children were enrolled: 20 were assigned to rosiglitazone and 10 to placebo. Rosiglitazone treatment did not induce hypoglycaemia nor significantly alter clinical, biochemical, haematological, or electrocardiographic parameters. CONCLUSIONS: Adjunctive rosiglitazone was safe and well-tolerated in children with uncomplicated malaria, permitting the extension of its evaluation as adjunctive therapy for severe malaria. The trial is registered with Clinicaltrials.gov, NCT02694874

No differences of immune activation and microbial translocation among HIV-infected children receiving combined antiretroviral therapy or protease inhibitor monotherapy.

This is a cross-sectional study of 15 aviremic chronic HIV-infected children revealing no differences in immune activation (IA; HLA-DRCD38 CD4 and CD8 T cells, and sCD14) and microbial translocation (MT; lipopolysaccharides (LPS) and 16S rDNA) among HIV-infected patients under combined antiretroviral treatment (cART; n = 10) or ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv; n = 5). In both cases, IA and MT were lower in healthy control children (n = 32). This observational study suggests that ritonavir boosted protease inhibitor monotherapy (mtPI/rtv) is not associated with an increased state of IA or MT as compared with children receiving cART