Functional diversification of innate and inflammatory immune responses mediated by antibody fragment crystallizable activities against SARS-CoV-2.

Monoclonal antibodies (mAb) targeting the SARS-CoV-2 Spike (S) glycoprotein have been exploited for the treatment of severe COVID-19. In this study, we evaluated the immune-regulatory features of two neutralizing anti-S mAbs (nAbs), named J08 and F05, with wild-type (WT) conformation or silenced Fc functions. In the presence of D614G SARS-CoV-2, WT nAbs enhance intracellular viral uptake in immune cells and amplify antiviral type I Interferon and inflammatory cytokine and chemokine production without viral replication, promoting the differentiation of CD16+ inflammatory monocytes and innate/adaptive PD-L1+ and PD-L1+CD80+ plasmacytoid Dendritic Cells. In spite of a reduced neutralizing property, WT J08 nAb still promotes the IL-6 production and differentiation of CD16+ monocytes once binding Omicron BA.1 variant. Fc-mediated regulation of antiviral and inflammatory responses, in the absence of viral replication, highlighted in this study, might positively tune immune response during SARS-CoV-2 infection and be exploited also in mAb-based therapeutic and prophylactic strategies against viral infections.

Neurological assessment tool for screening infants during the first year after birth: The Brief-Hammersmith Infant Neurological Examination.

AIM: To develop a short version of the original Hammersmith Infant Neurological Examination (HINE) to be used as a screening tool (Brief-HINE) and to establish if the short examination maintains good accuracy and predictive power for detecting infants with cerebral palsy (CP). METHOD: Eleven items were selected from the original HINE ('visual response'; 'trunk posture'; 'movement quantity'; 'movement quality'; 'scarf sign'; 'hip adductor angles'; 'popliteal angle'; 'pull to sit'; 'lateral tilting'; 'forward parachute reaction'; 'tendon reflexes') identifying those items previously found to be more predictive of CP in both low- and high-risk infants. In order to establish the sensitivity of the new module, the selected items were applied to existing data, previously obtained using the full HINE at 3, 6, 9, and 12 months, in 228 infants with typical development at 2 years and in 82 infants who developed CP. RESULTS: Brief-HINE scores showed good sensitivity and specificity, at each age of assessment, for detecting infants with CP. At 3 months, a score of less than 22 was associated with CP with a sensitivity of 0.88 and a specificity of 0.92; at 6, 9, and 12 months, the cut-off scores were less than 25 (sensitivity 0.93; specificity 0.87), less than 27 (sensitivity 0.95; specificity 0.81), and less than 27 (sensitivity 1; specificity 0.86) respectively. The presence of more than one warning sign, or items that are not optimal for the age of assessment, imply the need for a full examination reassessment. INTERPRETATION: These findings support the validity of the Brief-HINE as a routine screening method and the possibility of its use in clinical practice.

Increased activity of IRE1 improves the clinical presentation of EAE.

Activation of the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme-1α (IRE1α) contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo. On the contrary, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1α, we used a mouse model expressing a C148S variant of IRE1α with increased and sustained activation. Surprisingly, the mutation did not affect the differentiation of highly secretory antibody-producing cells but exhibited a beneficial effect in a mouse model of experimental autoimmune encephalomyelitis (EAE). Although mechanical allodynia was unaffected, significant improvement in motor function was found in IRE1C148S mice with EAE relative to wild type (WT) mice. Coincident with this improvement, there was reduced microgliosis in the spinal cord of IRE1C148S mice, with reduced expression of proinflammatory cytokine genes. This was accompanied by reduced axonal degeneration and enhanced 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) levels, suggesting improved myelin integrity. Interestingly, while the IRE1C148S mutation is expressed in all cells, the reduction in proinflammatory cytokines and in the microglial activation marker ionized calcium-binding adapter molecule (IBA1), along with preservation of phagocytic gene expression, all point to microglia as the cell type contributing to the clinical improvement in IRE1C148S animals. Our data suggest that sustained increase in IRE1α activity can be beneficial in vivo, and that this protection is cell type and context dependent. Considering the overwhelming but conflicting evidence for the role of ER stress in neurological diseases, a better understanding of the function of ER stress sensors in physiological contexts is clearly needed.

Acute and post-acute multidisciplinary outcomes of newborns born from mothers with SARS-CoV-2 infection during pregnancy or the perinatal period.

INTRODUCTION: We performed a single-center, prospective, observational study of newborns born from mothers with microbiologically confirmed SARS-CoV-2 infection in pregnancy or at time of delivery to evaluate acute and mid-term multidisciplinary outcomes. METHODS: Infants were offered a multidisciplinary follow-up consisting of nasopharyngeal Polymerase Chain Reaction test at birth and at 48-72 h of life, auxological and ophthalmological assessments, and serologic testing. RESULTS: 791 women and their 791 children (52.3% males) were included. Most placentas (94.9%) had abnormal inflammatory findings. 171 (27.3%) and 36 (13.7%) children respectively had pathological TEOAEs in at least one ear and bilaterally, while only four of the 85 children that underwent ABR had pathological findings (4.7%). 64 children underwent fluorescein angiography, which resulted pathological only in 1 case (1.6%). Anti-SARS-CoV-2 IgGs were found in up to 60% of children tested at six months of age. Our findings showed no association between the maternal vaccination status or the presence of maternal symptoms during pregnancy and neonatal outcomes. CONCLUSIONS: Our study shows that the large majority of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life have optimal outcomes. Our previous report of abnormal ophthalmologic findings was not confirmed on a larger cohort, while further studies are needed to better characterize audiological outcomes. Further prospective, case-controlled studies are still needed.

From Bacterial Toxin to Therapeutic Agent: The Unexpected Fate of Mycolactone.

"Recognizing a surprising fact is the first step towards discovery." This famous quote from Louis Pasteur is particularly appropriate to describe what led us to study mycolactone, a lipid toxin produced by the human pathogen Mycobacterium ulcerans. M. ulcerans is the causative agent of Buruli ulcer, a neglected tropical disease manifesting as chronic, necrotic skin lesions with a "surprising" lack of inflammation and pain. Decades after its first description, mycolactone has become much more than a mycobacterial toxin. This uniquely potent inhibitor of the mammalian translocon (Sec61) helped reveal the central importance of Sec61 activity for immune cell functions, the spread of viral particles and, unexpectedly, the viability of certain cancer cells. We report in this review the main discoveries that marked our research into mycolactone, and the medical perspectives they opened up. The story of mycolactone is not over and the applications of Sec61 inhibition may go well beyond immunomodulation, viral infections, and oncology.

Increased activity of IRE1 improves the clinical presentation of EAE.

Activation of the ER stress sensor IRE1α contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo. On the other hand, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1α, we used a mouse model expressing a C148S variant of IRE1α with increased and sustained activation. Surprisingly, the mutation did not affect the differentiation of highly secretory antibody-producing cells, but exhibited a strong protective effect in a mouse model of experimental autoimmune encephalomyelitis (EAE). Significant improvement in motor function was found in IRE1C148S mice with EAE relative to WT mice. Coincident with this improvement, there was reduced microgliosis in the spinal cord of IRE1C148S mice, with reduced expression of pro-inflammatory cytokine genes. This was accompanied by reduced axonal degeneration and enhanced CNPase levels, suggestiing improved myelin integrity. Interestingly, while the IRE1C148S mutation is expressed in all cells, the reduction in proinflammatory cytokines and in the activation of microglial activation marker IBA1, along with preservation of phagocytic gene expression, all point to microglia as the cell type contributing to the clinical improvement in IRE1C148S animals. Our data suggest that sustained increase in IRE1α activity can be protective in vivo, and that this protection is cell type and context dependent. Considering the overwhelming but conflicting evidence for the role of the ER stress in neurological diseases, a better understanding of the function of ER stress sensors in physiological contexts is clearly needed.

A specific anti-COVID-19 BNT162b2 vaccine-induced early innate immune signature positively correlates with the humoral protective response in healthy and multiple sclerosis vaccine recipients.

Objectives: The very rapidly approved mRNA-based vaccines against SARS-CoV-2 spike glycoprotein, including Pfizer-BioNTech BNT162b2, are effective in protecting from severe coronavirus disease 2019 (COVID-19) in immunocompetent population. However, establishing the duration and identifying correlates of vaccine-induced protection will be crucial to optimise future immunisation strategies. Here, we studied in healthy vaccine recipients and people with multiple sclerosis (pwMS), undergoing different therapies, the regulation of innate immune response by mRNA vaccination in order to correlate it with the magnitude of vaccine-induced protective humoral responses. Methods: Healthy subjects (n = 20) and matched pwMS (n = 22) were longitudinally sampled before and after mRNA vaccination. Peripheral blood mononuclear cell (PBMC)-associated type I and II interferon (IFN)-inducible gene expression, serum innate cytokine/chemokine profile as well as binding and neutralising anti-SARS-COV-2 antibodies (Abs) were measured. Results: We identified an early immune module composed of the IFN-inducible genes Mx1, OAS1 and IRF1, the serum cytokines IL-15, IL-6, TNF-α and IFN-γ and the chemokines IP-10, MCP-1 and MIG, induced 1 day post second and third BNT162b2 vaccine doses, strongly correlating with magnitude of humoral response to vaccination in healthy and MS vaccinees. Moreover, induction of the early immune module was dramatically affected in pwMS treated with fingolimod and ocrelizumab, both groups unable to induce a protective humoral response to COVID-19 vaccine. Conclusion: Overall, this study suggests that the vaccine-induced early regulation of innate immunity is mediated by IFN signalling, impacts on the magnitude of adaptive responses and it might be indicative of vaccine-induced humoral protection.

Visual Function in Children with GNAO1-Related Encephalopathy.

BACKGROUND: GNAO1-related encephalopathies include a broad spectrum of developmental disorders caused by de novo heterozygous mutations in the GNAO1 gene, encoding the G (o) subunit α of G-proteins. These conditions are characterized by epilepsy, movement disorders and developmental impairment, in combination or as isolated features. OBJECTIVE: This study aimed at describing the profile of neurovisual competences in children with GNAO1 deficiency to better characterize the phenotype of the disease spectrum. METHODS: Four male and three female patients with confirmed genetic diagnosis underwent neurological examination, visual function assessment, and neurovisual and ophthalmological evaluation. Present clinical history of epilepsy and movement disorders, and neuroimaging findings were also evaluated. RESULTS: The assessment revealed two trends in visual development. Some aspects of visual function, such as discrimination and perception of distance, depth and volume, appeared to be impaired at all ages, with no sign of improvement. Other aspects, reliant on temporal lobe competences (ventral stream) and more related to object-face exploration, recognition and environmental control, appeared to be preserved and improved with age. SIGNIFICANCE: Visual function is often impaired, with patterns of visual impairment affecting the ventral stream less.

Novel evidence of Thymosin α1 immunomodulatory properties in SARS-CoV-2 infection: Effect on innate inflammatory response in a peripheral blood mononuclear cell-based in vitro model.

The peculiar property of Thymosin alpha 1 (Tα1) to act as master regulator of immune homeostasis has been successfully defined in different physiological and pathological contexts ranging from cancer to infection. Interestingly, recent papers also demonstrated its mitigating effect on the "cytokine storm" as well as on the T-cell exhaustion/activation in SARS-CoV-2 infected individuals. Nevertheless, in spite of the increasing knowledge on Tα1-induced effects on T cell response confirming the distinctive features of this multifaceted peptide, little is known on its effects on innate immunity during SARS-CoV-2 infection. Here, we interrogated peripheral blood mononuclear cell (PBMC) cultures stimulated with SARS-CoV-2 to disclose Tα1 properties on the main cell players of early response to infection, namely monocytes and myeloid dendritic cells (mDC). Moving from ex vivo data showing an enhancement in the frequency of inflammatory monocytes and activated mDC in COVID-19 patients, a PBMC-based experimental setting reproduced in vitro a similar profile with an increased percentage of CD16+ inflammatory monocytes and mDC expressing CD86 and HLA-DR activation markers in response to SARS-CoV-2 stimulation. Interestingly, the treatment of SARS-CoV-2-stimulated PBMC with Tα1 dampened the inflammatory/activation status of both monocytes and mDC by reducing the release of pro-inflammatory mediators, including TNF-α, IL-6 and IL-8, while promoting the production of the anti-inflammatory cytokine IL-10. This study further clarifies the working hypothesis on Tα1 mitigating action on COVID-19 inflammatory condition. Moreover, these evidence shed light on inflammatory pathways and cell types involved in acute SARS-CoV-2 infection and likely targetable by newly immune-regulating therapeutic approaches.

Sec61 blockade therapy overrides resistance to proteasome inhibitors and immunomodulatory drugs in multiple myeloma.

Multiple Myeloma (MM) is an incurable neoplasm of mature B cells and the second most prevalent hematological malignancy worldwide. While combinations of proteasome inhibitors like bortezomib (Bz) and immunomodulators (IMiDs) like lenalinomide (Len) are generally effective in newly diagnosed patients, some do not respond to this first-line therapy, and all others will eventually become drug resistant. We previously reported that inhibiting the Sec61 translocon with mycolactone synergizes with Bz to induce terminal unfolded protein response in MM cells, irrespective of their resistance to proteasome inhibition. Here, we examined how Sec61 blockade interferes with IMiD action and whether it overrides resistance to Len. With this aim, we knocked out the IMiD target CRBN in the MM1S cell line and a Bz-resistant subclone to generate Len- and Len/Bz-resistant daughters, respectively. Both the Len- and Len/Bz-resistant clones were susceptible to mycolactone toxicity, especially the doubly resistant one. Notably, the synergy between mycolactone and Bz was maintained in these two clones, and mycolactone also synergized with Len in the two Len-susceptible ones. Further, mycolactone enhanced the therapeutic efficacy of the Bz/Len combination in both mice engrafted with parental or double drug resistant MM1S. Together, these data consolidate the interest of Sec61 blockers as new anti-MM agents and reveal their potential for treatment of refractory or relapsed MM.

Maternal Ureaplasma/Mycoplasma colonization during pregnancy and neurodevelopmental outcomes for preterm infants.

Introduction: Ureaplasma (U.) and Mycoplasma (M.) species have been related to pregnancy complications (including preterm birth) and worse neonatal outcomes. The aim of our work is to evaluate neurodevelopmental outcomes in preterm infants born to mothers with Ureaplasma/Mycoplasma colonization during pregnancy. Methods: Preterm infants with gestational age (GA) of ≤ 30 weeks were included in a retrospective follow-up study. To evaluate the effects of maternal vaginal colonization, we divided preterm infants into two groups: exposed and unexposed infants. All infants were assessed at 24 ± 3 months of age using Griffith's Mental Developmental Scales (GMDS). Results: Among 254 preterm infants, only 32 infants (12.6%) were exposed to U. /M. colonization during pregnancy. Exposed infants and unexposed ones had a similar Griffith's Developmental Quotient (106 ± 27.2 vs. 108.9 ± 19.5, respectively), without significant differences (p = 0.46). However, exposed infants had a significantly poorer outcome than their unexposed peers in terms of locomotor abilities (100.7 ± 28.3 exposed vs. 111.5 ± 26.1 unexposed, p = 0.03). Conclusion: For visual and hearing impairment, exposed and unexposed infants had similar incidences of cognitive and motor impairment. However, exposed infants had significantly lower locomotor scores than unexposed peers.

ERp57 chaperon protein protects neuronal cells from Aß-induced toxicity.

Alzheimer's disease (AD) is a neurodegenerative disorder whose main pathological hallmark is the accumulation of Amyloid-ß peptide (Aß) in the form of senile plaques. Aß can cause neurodegeneration and disrupt cognitive functions by several mechanisms, including oxidative stress. ERp57 is a protein disulfide isomerase involved in the cellular stress response and known to be present in the cerebrospinal fluid of normal individuals as a complex with Aß peptides, suggesting that it may be a carrier protein which prevents aggregation of Aß. Although several studies show ERp57 involvement in neurodegenerative diseases, no clear mechanism of action has been identified thus far. In this work, we gain insights into the interaction of Aß with ERp57, with a special focus on the contribution of ERp57 to the defense system of the cell. Here, we show that recombinant ERp57 directly interacts with the Aß25-35 fragment in vitro with high affinity via two in silico-predicted main sites of interaction. Furthermore, we used human neuroblastoma cells to show that short-term Aß25-35 treatment induces ERp57 decrease in intracellular protein levels, different intracellular localization, and ERp57 secretion in the cultured medium. Finally, we demonstrate that recombinant ERp57 counteracts the toxic effects of Aß25-35 and restores cellular viability, by preventing Aß25-35 aggregation. Overall, the present study shows that extracellular ERp57 can exert a protective effect from Aß toxicity and highlights it as a possible therapeutic tool in the treatment of AD.

Hammersmith Infant Neurological Examination in low-risk infants born very preterm: a longitudinal prospective study.

AIM: To describe the profile of global and single items of the Hammersmith Infant Neurological Examination (HINE) in a population of low-risk infants born very preterm during the first year of life. METHOD: The HINE was performed at 3, 6, 9, and 12 months' corrected age in a population of low-risk infants born preterm with a gestational age of fewer than 32 weeks and with normal or minimal changes on neuroimaging. RESULTS: A total of 174 infants born preterm (96 males, 78 females; mean gestational age = 27 weeks [SD = 1.8], range 23-31 weeks) fulfilled the inclusion criteria. The 10th centile cut-off score with median and range was reported for the HINE global and subsection scores. A progressive increase in global HINE scores was observed. Most of the single items, especially those related to tone, posture, and reflexes, showed progressive maturation. INTERPRETATION: Our results, which provide longitudinal data for single-item and global scores in a population of low-risk infants born very preterm, can be used as a reference in both clinical and research settings to monitor early neurological signs in these infants. These data could be used as normative data when examining low-risk infants born preterm.

Hammersmith Infant Neurological Examination in infants born at term: Predicting outcomes other than cerebral palsy.

AIM: We explored the ability of the Hammersmith Infant Neurological Examination (HINE) to identify cognitive performance delay at 2 years in a large cohort of infants born at term. METHOD: We conducted a retrospective study of infants born at term at risk of neurodevelopmental impairments assessed using the HINE between 3 and 12 months post-term age and compared them with a cohort of typically developing infants born at term. All infants performed a neurodevelopmental assessment at 2 years of age using the Mental Development Index (MDI) of the Bayley Scales of Infant Development, Second Edition; the presence of cerebral palsy (CP) was also reported. The infants were classified as being cognitively normal/mildly delayed or significantly delayed (MDI < 70). The predictive validity of HINE scores for significantly delayed cognitive performance, in infants with and without CP, was calculated using specific cut-off scores according to age at assessment. RESULTS: A total of 446 at-risk and 235 typically developing infants (345 males, 336 females; mean [SD] gestational age 38.7 weeks [1.4], range 37-43 weeks) were included. Of the at-risk infants, 408 did not have CP at 2 years; 243 had a normal/mild delayed MDI and 165 had an MDI less than 70. Of the at-risk infants, 38 developed CP. HINE scores showed a good sensitivity and specificity, mainly after 3 months, for identifying significantly delayed cognitive performance in infants without CP. In those with CP, the score was associated with their cognitive performance. The comparison group had the highest HINE scores. INTERPRETATION: The HINE provides evidence about the risk of delayed cognitive performance at age 2 years in infants born at term with and without CP.

EXAMEN NEUROLÓGICO INFANTIL DE HAMMERSMITH EN BEBÉS NACIDOS A TÉRMINO: SU USO PARA PREDECIR OTRAS CONDICIONES ADEMÁS DE LA PARÁLISIS CEREBRAL: OBJETIVO: Valoramos la capacidad del examen neurológico infantil de Hammersmith (HINE) para identificar el retraso en el rendimiento cognitivo a los 2 años en una cohorte grande de bebés nacidos a término. MÉTODO: Realizamos un estudio retrospectivo de bebés nacidos a término con riesgo de trastornos del desarrollo neurológico evaluados mediante el HINE entre los 3 y los 12 meses de edad postérmino y los comparamos con una cohorte de bebés nacidos a término con un desarrollo típico. Todos los bebés realizaron una evaluación del desarrollo neurológico a los 2 años de edad utilizando el Índice de Desarrollo Mental (MDI) de las Escalas de Desarrollo Infantil de Bayley, Segunda Edición; también se informó la presencia de parálisis cerebral (PC). Los bebés se clasificaron como cognitivamente normales/levemente con retreaso o significativamente con retraso (MDI < 70). La validez predictiva de las puntuaciones HINE para el rendimiento cognitivo con retraso significativo, en bebés con y sin parálisis cerebral, se calculó utilizando puntuaciones de corte específicas según la edad en la evaluación. RESULTADOS: Se incluyeron un total de 446 lactantes en riesgo y 235 con desarrollo normal (345 varones, 336 mujeres; edad gestacional media [DE] 38,7 semanas [1,4], rango de 37 a 43 semanas). De los lactantes en riesgo, 408 no tenían parálisis cerebral a los 2 años; 243 tenían un MDI con retraso normal/leve y 165 tenían un MDI inferior a 70. De los bebés en riesgo, 38 desarrollaron PC. Las puntuaciones HINE mostraron una buena sensibilidad y especificidad, principalmente después de 3 meses, para identificar un rendimiento cognitivo severo en lactantes sin PC. En aquellos con PC, la puntuación se asoció con su rendimiento cognitivo. El grupo de comparación tuvo las puntuaciones HINE más altas. INTERPRETACIÓN: El HINE proporciona evidencia sobre el riesgo de retraso en el rendimiento cognitivo a los 2 años de edad en bebés nacidos a término con y sin parálisis cerebral.

Short- and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 in utero or during the perinatal period: preliminary findings.

The long-term outcomes of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life are still unknown. We performed a single-center, prospective, observational study of newborns born from mothers with microbiologically confirmed SARS-CoV-2 infection in pregnancy or at time of delivery. Infants were offered a multidisciplinary follow-up consisting of nasopharyngeal Polymerase Chain Reaction test at birth and at 48-72 h of life, auxological growth and neurological development, serologic testing, and audiological and ophthalmological assessments. One-hundred ninety-eight mothers and 199 newborns were enrolled. Of the 199 newborns, 171 underwent nasopharyngeal swab, four (2.3%) and two (1.15%) children tested positive at birth and 48-72 h of life, respectively. None had SARS-CoV-2 related symptoms. Auxologic and neurologic development were normal in all children during follow-up. Nine out of 59 infants had SARS-CoV-2 IgG at 3 months of life, which was associated with a positive nasopharyngeal swab at birth (P = 0.04). Twenty seven out of 143 (18.8%) newborns had pathologic transitory evoked otoacoustic emissions at birth, although 14/27 repeated after 1 month were normal. Audiological evaluation was completed with Auditory Brainstem Response between the third and sixth month of life in 34 children, showing in all normal hearing threshold. The ophthalmological evaluation found retinal vascular anomalies in 3/20 (15%) children, immature visual acuity in 5/20 (25%) children, and reduced distance attention in 6/20 cases (30%). CONCLUSIONS: Our study showed that the neonatal and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life are mostly positive, with the exception of ophthalmologic findings which, in a preliminary cohort, were abnormal in about 15% of cases. Further prospective, longitudinal studies are needed to better understand the clinical outcomes of children exposed to SARS-CoV-2 in utero and in the early postnatal life. WHAT IS KNOWN: • In utero mother-to-child transmission of SARS-CoV-2 has been documented by several independent studies. • Neonatal COVID-19 is a systemic disease that can be severe, although rarely. WHAT IS NEW: • Newborns exposed in utero to SARS-CoV-2 have mostly a normal auxological, audiological, and neurological development during the first months of life. • Fundus fluorescein angiography revealed that up to 5% of newborns exposed in utero to SARS-CoV2 can show retinal and choroidal abnormalities, including peripheral hypofluorescence of the choroid and increased vascular tortuosity.

Neurodevelopmental Outcomes in Preterm Infants Receiving a Multicomponent vs. a Soybean-Based Lipid Emulsion: 24 Month Follow-Up of a Randomized Controlled Trial.

BACKGROUND: Few studies in the literature have analyzed the long-term neurodevelopmental outcomes of the administration of a multicomponent versus a soybean-based lipid emulsion (LE) in preterm infants receiving parenteral nutrition (PN). A recent randomized controlled trial conducted in our unit provided evidence of better growth in head circumference during the hospital stay in those who received a multicomponent LE. METHODS: This is a 24 month follow-up study of preterm infants, previously enrolled in a randomized trial, who received a multicomponent LE (SMOFlipid®) or a standard soybean-based one (Intralipid®). We evaluated neurodevelopmental outcomes at 24 months of corrected age (CA) in the two groups. RESULTS: Ninety-three children were followed up to the age of 24 months CA. Due to the peculiar time frame of the SARS-CoV-2 pandemic, neurodevelopmental outcomes were evaluated only in 77 children: 37 in the SMOFlipid® group and 40 in the Intralipid® group. No differences in major disability rates or in Griffith's evaluation were found between the two groups. CONCLUSIONS: In our population study, the administration of a multicomponent LE containing fish oil, compared to a soybean-based LE, had no significant effects on neurodevelopmental outcomes in preterm infants at 24 months CA.

Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection.

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.

The special unfolded protein response in plasma cells.

The high rate of antibody production places considerable metabolic and folding stress on plasma cells (PC). Not surprisingly, they rely on the unfolded protein response (UPR), a universal signaling, and transcriptional network that monitors the health of the secretory pathway and mounts cellular responses to stress. Typically, the UPR utilizes three distinct stress sensors in the ER membrane, each regulating a subset of targets to re-establish homeostasis. PC use a specialized UPR scheme-they preemptively trigger the UPR via developmental signals and suppress two of the sensors, PERK and ATF6, relying on IRE1 alone. The specialized PC UPR program is tuned to the specific needs at every stage of development-from early biogenesis of secretory apparatus, to massive immunoglobulin expression later. Furthermore, the UPR in PC integrates with other pathways essential in a highly secretory cell-mTOR pathway that ensures efficient synthesis, autophagosomes that recycle components of the synthetic machinery, and apoptotic signaling that controls cell fate in the face of excessive folding stress. This specialized PC program is not shared with other secretory cells, for reasons yet to be defined. In this review, we give a perspective into how and why PC need such a unique UPR program.

Innate Immune Response to SARS-CoV-2 Infection: From Cells to Soluble Mediators.

The vulnerability of humankind to SARS-CoV-2 in the absence of a pre-existing immunity, the unpredictability of the infection outcome, and the high transmissibility, broad tissue tropism, and ability to exploit and subvert the immune response pose a major challenge and are likely perpetuating the COVID-19 pandemic. Nevertheless, this peculiar infectious scenario provides researchers with a unique opportunity for studying, with the latest immunological techniques and understandings, the immune response in SARS-CoV-2 naïve versus recovered subjects as well as in SARS-CoV-2 vaccinees. Interestingly, the current understanding of COVID-19 indicates that the combined action of innate immune cells, cytokines, and chemokines fine-tunes the outcome of SARS-CoV-2 infection and the related immunopathogenesis. Indeed, the emerging picture clearly shows that the excessive inflammatory response against this virus is among the main causes of disease severity in COVID-19 patients. In this review, the innate immune response to SARS-CoV-2 infection is described not only in light of its capacity to influence the adaptive immune response towards a protective phenotype but also with the intent to point out the multiple strategies exploited by SARS-CoV-2 to antagonize host antiviral response and, finally, to outline inborn errors predisposing individuals to COVID-19 disease severity.