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There is emerging evidence that age-dependent differences in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlate with stronger innate immune response in the upper respiratory tract in children compared to adults. The efficient induction of interferon (IFN) alpha and beta (α and β) signaling, and interferon-stimulated genes (ISGs) is fundamental to the host antiviral response. In-silico transcriptomic analyses was conducted to determine the expression levels of IFN α/β pathway genes as well as 524 human ISGs in upper and lower airways of children and adults at baseline and post respiratory infections including coronavirus disease 2019 (COVID-19). To validate our in-silico analysis, we conducted qRT-PCR to measure ISGs levels in children and adult's nasal epithelial samples. At baseline, children had significantly higher levels of IFN α/β and ISGs genes compared to adults. More distinction was also seen in bronchial compared to nasal basal levels. Children nasal epithelial cells exhibited superior antiviral IFN α/β and associated ISGs response following ex-vivo poly (I:C) treatment model, and in clinical samples of SARS-CoV-2 infected patients. This was also confirmed in nasal epithelial samples using qRT-PCR validation. No gender-based difference in type I IFN levels across both age groups were observed. Understanding the biological basis for children resistance against severe COVID-19 is a challenge that has substantial clinical importance. More mechanistic studies are needed to carefully quantify how much of early IFN levels is needed to bypass the viral evasion mechanism and prevent its further replication and dissemination to lower airways and the rest of the body.

NK cells play an important role in the defense against viral infections. Activation of resting NK cells is tightly controlled by the balance of surface inhibitory and activating receptors and aided by cytokines released by accessory cells along the anti-viral response. On the other hand, NK cells express functional pattern recognition receptors (PRRs) whose function has been mostly addressed by the use of synthetic agonists. The present study was undertaken to investigate whether NK cells could directly recognize a complex pathogen such as Human Cytomegalovirus (HCMV). Exposure of primary human NK cells to HCMV (TB40/E strain) induced the expression of CD69, promoted IFNγ secretion, and increased their cytotoxic activity against HCMV-infected autologous monocyte-derived dendritic cells. The divergent response induced by infective and UV-inactivated virions indicated the involvement of different NK cell sensors in the recognition of HCMV. The fact that NK cell activation could be partially prevented by blocking mAb specific for IFNAR and TLR2, together with the induction of IFNβ mRNA, supported the involvement of IFNβ and TLR2 in the response to HCMV. Thus, our data indicate that simultaneous activation of several PRRs leads to the autonomous priming of NK cell effector functions and could be a previously unappreciated mechanism presumably contributing to the control of HCMV infection.

There is emerging evidence that age-dependent differences in susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) correlate with stronger innate immune response in the upper respiratory tract in children compared to adults. The efficient induction of interferon (IFN) alpha and beta (α and β) signaling, and interferon-stimulated genes (ISGs) is fundamental to the host antiviral response. In-silico transcriptomic analyses was conducted to determine the expression levels of IFN α/β pathway genes as well as 524 human ISGs in upper and lower airways of children and adults at baseline and post respiratory infections including coronavirus disease 2019 (COVID-19). To validate our in-silico analysis, we conducted qRT-PCR to measure ISGs levels in children and adult's nasal epithelial samples. At baseline, children had significantly higher levels of IFN α/β and ISGs genes compared to adults. More distinction was also seen in bronchial compared to nasal basal levels. Children nasal epithelial cells exhibited superior antiviral IFN α/β and associated ISGs response following ex-vivo poly (I:C) treatment model, and in clinical samples of SARS-CoV-2 infected patients. This was also confirmed in nasal epithelial samples using qRT-PCR validation. No gender-based difference in type I IFN levels across both age groups were observed. Understanding the biological basis for children resistance against severe COVID-19 is a challenge that has substantial clinical importance. More mechanistic studies are needed to carefully quantify how much of early IFN levels is needed to bypass the viral evasion mechanism and prevent its further replication and dissemination to lower airways and the rest of the body., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Cerebral malaria (CM) is a life-threatening form of Plasmodium falciparum infection caused by brain inflammation. Brain endothelium dysfunction is a hallmark of CM pathology, which is also associated with the activation of the type I interferon (IFN) inflammatory pathway. The molecular triggers and sensors eliciting brain type I IFN cellular responses during CM remain largely unknown. We herein identified the stimulator of interferon response cGAMP interactor 1 (STING1) as the key innate immune sensor that induces Ifnβ1 transcription in the brain of mice infected with Plasmodium berghei ANKA ( Pba ). This STING1/IFNβ-mediated response increases brain CXCL10 governing the extent of brain leukocyte infiltration and blood-brain barrier (BBB) breakdown, and determining CM lethality. The critical role of brain endothelial cells (BECs) in fueling type I IFN-driven brain inflammation was demonstrated in brain endothelial-specific IFNβ-reporter and STING1-deficient Pba -infected mice, which were significantly protected from CM lethality. Moreover, extracellular particles (EPs) released from Pba -infected erythrocytes activated the STING1-dependent type I IFN response in BECs, a response requiring intracellular acidification. Fractionation of the EPs enabled us to identify a defined fraction carrying hemoglobin degradation remnants that activates STING1/IFNβ in the brain endothelium, a process correlated with heme content. Notably, stimulation of STING1-deficient BECs with heme, docking experiments, and in vitro binding assays unveiled that heme is a putative STING1 ligand. This work shows that heme resultant from the parasite heterotrophic activity operates as an alarmin, triggering brain endothelial inflammatory responses via the STING1/IFNβ/CXCL10 axis crucial to CM pathogenesis and lethality.

Abstract Background Achieving good adherence to self-injected treatments for multiple sclerosis can be difficult. Injection devices may help to overcome some of the injection-related barriers to adherence that can be experienced by patients. We sought to assess short-term adherence to, and tolerability of, interferon (IFN) β-1a administered via electronic autoinjection device in patients with relapsing-remitting multiple sclerosis (RRMS). Methods BRIDGE (RebiSmart to self-inject Rebif serum-free formulation in a multidose cartridge) was a 12-week, multicentre, open-label, single-arm, observational, Phase IV study in which patients self-administered IFN β-1a (titrated to 44 μg), subcutaneously (sc), three times weekly, via electronic autoinjection device. Patients were assessed at baseline and 4-weekly intervals to Week 12 or early termination (ET) for: physical examinations; diary card completion (baseline, Weeks 4, 8 only); neurological examinations (baseline, Week 12/ET only); MS Treatment Concern Questionnaire (MSTCQ; Weeks 4, 8, 12 only); Convenience Questionnaire (Week 12 only); Hospital Anxiety and Depression Scale (HADS); and Paced Auditory Serial Addition Task (PASAT; baseline only). Adherence was defined as administration of ≥ 80% of scheduled injections, recorded by the autoinjection device. Results Overall, 88.2% (105/119; intent-to-treat population) of patients were adherent; 67.2% (80/119) administered all scheduled injections. Medical reasons accounted for 35.6% (31/87) of missed injections, forgetfulness for 20.6% (18/87). Adherence did not correlate with baseline Expanded Disability Status Scale (P = 0.821) or PASAT (P = 0.952) scores, or pre-study therapy (P = 0.303). No significant changes (baseline-Week 12) in mean HADS depression (P = 0.482) or anxiety (P = 0.156) scores were observed. 'Overall convenience' was the most important reported benefit of the autoinjection device. Device features associated with handling and ease of use were highly rated. Mean MSTCQ scores for 'flu-like' symptoms (P = 0.022) and global side effects (P = 0.002) significantly improved from Week 4-12. Mean MSTCQ scores for pain at injection site and injection pain increased from Week 4-12 (P < 0.001). Adverse events were mild/moderate. No new safety signals were identified. Conclusion Convenience and ease of use of the autoinjection device may improve adherence and, therefore, outcomes, in patients with RRMS receiving sc IFN β-1a. Trial registration EU Clinical Trials Register (EU-CTR; http://www.clinicaltrialsregister.eu): 2009-013333-24