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Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) ß, and under diabetic conditions, this IFNß-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.
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Proteínas de Transporte/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Macrófagos/fisiologia , Proteínas Nucleares/metabolismo , Idoso , Animais , Proteínas de Transporte/genética , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Fenótipo , Ácido Úrico/metabolismo , CicatrizaçãoRESUMO
BACKGROUND: Iron is crucial for growth and development, but excess iron is harmful. Neonatal mice have elevated concentrations of circulating iron, but the source of this iron is unclear. This lack of understanding makes it difficult to optimize early life iron balance. OBJECTIVES: Identify the origins of neonatal tissue-specific iron pools using dietary manipulation and cross-fostering murine models. METHODS: To determine whether tissue-specific neonatal iron was primarily acquired during gestation or after birth, pups born to iron-sufficient or iron-deficient dams were cross-fostered, and tissues were harvested at postnatal days 3-5 to measure iron content. A separate set of female mice were fed a diet enriched with the stable iron isotope 57 (57Fe) for 4 generations to replace naturally abundant liver iron isotope 56 (56Fe) stores with 57Fe. To quantify the proportions of neonatal iron acquired during gestation, pups born to dams with 56Fe or 57Fe stores were cross-fostered, and tissues were harvested at postnatal day 3-5 to determine 56Fe:57Fe ratios by inductively coupled plasma mass spectrometry. Finally, to quantify the proportion of neonatal iron acquired from the maternal diet, female mice with 56Fe or 57Fe stores switched diets upon mating, and pup tissues were harvested on P0 to determine 56Fe:57Fe ratios by inductively coupled plasma mass spectrometry. RESULTS: Perinatal iron deficiency resulted in smaller pups, and gestational iron deficiency resulted in lower neonatal serum and liver iron. Cross-fostering between dams with 56Fe and 57Fe stores demonstrated that ≤70% of neonatal serum, liver, and brain iron were acquired during gestation. Dietary manipulation experiments using dams with 56Fe and 57Fe stores showed that over half of neonatal serum, liver, and brain iron were from the dam's gestational diet rather than preconception iron stores. CONCLUSIONS: This study provides quantitative values for the sources of neonatal iron, which may inform approaches to optimize neonatal iron status.
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Animais Recém-Nascidos , Dieta , Ferro , Animais , Feminino , Gravidez , Camundongos , Ferro/metabolismo , Ferro/sangue , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Fenômenos Fisiológicos da Nutrição Materna , Ferro da Dieta/administração & dosagem , Masculino , Isótopos de FerroRESUMO
BACKGROUND: The induction of maternal inflammation in mice leads to fetal injury that is believed to be IL-6 dependent. The fetal inflammatory response, defined by elevated fetal or amniotic fluid IL-6, has been described as a potential mechanism for subsequent fetal injury. The role of maternal IL-6 production and signaling in the fetal IL-6 response is currently unclear. METHODS: Genetic and anti-IL-6 antibody strategies were used to systematically block the maternal IL-6 response during inflammation. Chorioamnionitis was induced using intraperitoneal injection of lipopolysaccharide (LPS) at mid gestation (E14.5) and late gestation (E18.5). This model was used in pregnant C57Bl/6 dams, IL6-/- dams, C57Bl/6 dams treated with anti-IL-6 (blocks both classical and trans-signaling) or anti-gp130 antibodies (blocks trans-signaling only) and IL6+/- dams. Six hours following LPS injection, maternal serum, placental tissue, amniotic fluid and fetal tissue or serum were collected. A bead-based multiplex assay was used to evaluate levels of IL-6, KC, IL-1ß, TNF, IL-10, IL-22, IFN-γ, IL-13 and IL-17A. RESULTS: Chorioamnionitis in C57Bl/6 dams was characterized by elevated maternal serum levels of IL-6, KC and IL-22 with litter loss during mid gestation. The fetal response to maternal inflammation in C57Bl/6 mice was primarily characterized by elevated levels of IL-6, KC and IL-22 in the placenta, amniotic fluid and fetus during both mid and late gestation. A global IL-6 knockout (IL6-/-) eradicated the maternal, placental, amniotic fluid and fetal IL-6 response to LPS during mid and late gestation and improved litter survival, while minimally influencing the KC or IL-22 responses. Blocking maternal classical IL-6 signaling in C57Bl/6 dams at the time of LPS exposure diminished the maternal, placental, amniotic fluid and fetal IL-6 response during mid and late gestation, while blocking maternal IL-6 trans-signaling only affected fetal IL-6 expression. To evaluate whether maternal IL-6 was crossing the placenta and reaching the fetus, IL-6+/- dams were utilized in the chorioamnionitis model. IL-6+/- dams mounted a systemic inflammatory response following injection with LPS, characterized by elevated IL-6, KC and IL-22. IL-6-/- pups born to IL6+/- dams had decreased amniotic fluid levels of IL-6 and undetectable levels of fetal IL-6 compared to IL-6+/+ littermate controls. CONCLUSION: The fetal response to systemic maternal inflammation is dependent upon maternal IL-6 signaling, but maternal IL-6 is not crossing the placenta and reaching the fetus at detectable levels.
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Corioamnionite , Doenças Fetais , Animais , Feminino , Camundongos , Gravidez , Líquido Amniótico/metabolismo , Corioamnionite/metabolismo , Modelos Animais de Doenças , Doenças Fetais/metabolismo , Inflamação/metabolismo , Interleucina-6 , Lipopolissacarídeos , Placenta/metabolismoRESUMO
BACKGROUND: Chorioamnionitis alters neonatal immune responses. Gestational COVID-19 infection is associated with adverse pregnancy outcomes, but its impact on neonatal immunity is unclear. We hypothesized that gestational COVID-19 exposure would result in exaggerated neonatal immune responses, similar to chorioamnionitis-exposed neonates. METHODS: Term umbilical cord blood mononuclear cells (CBMCs) were isolated from neonates exposed to chorioamnionitis, gestational COVID-19 or unexposed controls. CBMCs were cultured and stimulated with heat-killed Escherichia coli, Streptococcus agalactiae or Staphylococcus epidermidis. A multiplexed protein assay was used to measure cytokine levels in cell culture supernatants and flow cytometry was used to evaluate cellular-level cytokine expression. RESULTS: Both chorioamnionitis-exposed and COVID-19 exposed CBMCs demonstrated upregulation of IL-1ß and IL-6 compared to unexposed CBMCs, while only COVID-19 exposure resulted in IL-8 upregulation. There were no differences between chorioamnionitis-exposed and COVID-19 exposed CBMCs when these groups were directly compared. Flow cytometry demonstrated immune cell subset specific differences in cytokine expression between the exposure groups. CONCLUSION: The fetal/neonatal response to maternal inflammation differed based on immune cell subset and etiology of inflammation, but the global neonatal cytokine responses were similar between exposure groups. This suggests that targeting perinatal inflammation rather than the specific etiology may be a possible therapeutic approach. IMPACT: Neonatal immune cells have similar pathogen-associated global cytokine responses, but different cell-level immune responses, following in-utero exposure to chorioamnionitis or COVID-19. This is the first study to directly compare immune responses between neonates exposed to chorioamnionitis and COVID-19. This suggests that the fetal/neonatal cellular response to perinatal inflammation differs based on the etiology and severity of maternal inflammation, but still results in a similar overall inflammatory profile regardless of the cause of perinatal inflammation.
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Neonatal CD4+ T cells have reduced or delayed T-cell receptor (TCR) signaling responses compared with adult cells, but the mechanisms underlying this are poorly understood. This study tested the hypothesis that human neonatal naïve CD4+ TCR signaling and activation deficits are related to differences in H3K4me3 patterning and chromatin accessibility. Following initiation of TCR signaling using anti-CD3/anti-CD28 beads, adult naïve CD4+ T cells demonstrated increased CD69, phospho-CD3ε and interleukin (IL)-2, tumor necrosis factor-α (TNF-α), interferon-γ and IL-17A compared with neonatal cells. By contrast, following TCR-independent activation using phorbol myristate acetate (PMA)/ionomycin, neonatal cells demonstrated increased expression of CD69, IL-2 and TNF-α and equivalent phospho-ERK compared with adult cells. H3K4me3 chromatin immunoprecipitation-sequencing (ChIP-seq) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) were performed on separate cohorts of naïve CD4+ T cells from term neonates and adults, and RNA-seq data from neonatal and adult naïve CD4+ T cells were obtained from the Blueprint Consortium. Adult cells demonstrated overall increased chromatin accessibility and a higher proportion of H3K4me3 sites associated with open chromatin and active gene transcription compared with neonatal cells. Adult cells demonstrated increased mRNA expression of the TCR-associated genes FYN, ITK, CD4, LCK and LAT, which was associated with increased H3K4me3 at the FYN and ITK gene loci and increased chromatin accessibility at the CD4, LCK and LAT loci. These findings indicate that neonatal TCR-dependent defects in activation are epigenetically regulated and provide a potentially targetable mechanism to enhance neonatal CD4+ T-cell responses.
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Linfócitos T CD4-Positivos , Cromatina , Adulto , Cromatina/metabolismo , Histonas , Humanos , Recém-Nascido , Ativação Linfocitária/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Epigenetic regulation of transcription is a collective term that refers to mechanisms known to regulate gene transcription without changing the underlying DNA sequence. These mechanisms include DNA methylation and histone tail modifications which influence chromatin accessibility, and microRNAs that act through post-transcriptional gene silencing. Epigenetics is known to regulate a variety of biological processes, and the role of epigtenetics in immunity and immune-mediated diseases is becoming increasingly recognized. While DNA methylation is the most widely studied, each of these systems play an important role in the development and maintenance of appropriate immune responses. There is clear evidence that epigenetic mechanisms contribute to developmental stage-specific immune responses in a cell-specific manner. There is also mounting evidence that prenatal exposures alter epigenetic profiles and subsequent immune function in exposed offspring. Early life exposures that are associated with poor long-term health outcomes also appear to impact immune specific epigenetic patterning. Finally, each of these epigenetic mechanisms contribute to the pathogenesis of a wide variety of diseases that manifest during childhood. This review will discuss each of these areas in detail. IMPACT: Epigenetics, including DNA methylation, histone tail modifications, and microRNA expression, dictate immune cell phenotypes. Epigenetics influence immune development and subsequent immune health. Prenatal, perinatal, and postnatal exposures alter immune cell epigenetic profiles and subsequent immune function. Numerous pediatric-onset diseases have an epigenetic component. Several successful strategies for childhood diseases target epigenetic mechanisms.
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Epigênese Genética , Imunidade , Criança , Metilação de DNA , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Processamento de Proteína Pós-TraducionalRESUMO
BACKGROUND: Early-life wheezing-associated respiratory infection with human rhinovirus (RV) is associated with asthma development. RV infection of 6-day-old immature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with the expansion of IL-13-producing type 2 innate lymphoid cells (ILC2s) and dependent on IL-25 and IL-33. We examined regulation of this asthma-like phenotype by IL-1ß. METHODS: Six-day-old wild-type or NRLP3-/- mice were inoculated with sham or RV-A1B. Selected mice were treated with IL-1 receptor antagonist (IL-1RA), anti-IL-1ß, or recombinant IL-1ß. RESULTS: Rhinovirus infection induced Il25, Il33, Il4, Il5, Il13, muc5ac, and gob5 mRNA expression, ILC2 expansion, mucus metaplasia, and airway hyperresponsiveness. RV also induced lung mRNA and protein expression of pro-IL-1ß and NLRP3 as well as cleavage of caspase-1 and pro-IL-1ß, indicating inflammasome priming and activation. Lung macrophages were a major source of IL-1ß. Inhibition of IL-1ß signaling with IL-1RA, anti-IL-1ß, or NLRP3 KO increased RV-induced type 2 cytokine immune responses, ILC2 number, and mucus metaplasia, while decreasing IL-17 mRNA expression. Treatment with IL-1ß had the opposite effect, decreasing IL-25, IL-33, and mucous metaplasia while increasing IL-17 expression. IL-1ß and IL-17 each suppressed Il25, Il33, and muc5ac mRNA expression in cultured airway epithelial cells. Finally, RV-infected 6-day-old mice showed reduced IL-1ß mRNA and protein expression compared to mature mice. CONCLUSION: Macrophage IL-1ß limits type 2 inflammation and mucous metaplasia following RV infection by suppressing epithelial cell innate cytokine expression. Reduced IL-1ß production in immature animals provides a mechanism permitting asthma development after early-life viral infection.
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Infecções por Picornaviridae , Rhinovirus , Animais , Citocinas , Imunidade Inata , Linfócitos , Metaplasia , Camundongos , MucoRESUMO
Sepsis from Escherichia coli expressing the K1 antigen is a leading cause of death in neonates. In a murine model, E. coli K1 grew rapidly in the peritoneal cavity of neonatal mice, causing fatal disease. In contrast, adult mice cleared the infection. Neonatal mice mounted a rapid and equivalent antimicrobial immune response compared to adult mice. Interestingly, peritoneal fluid from neonatal mice contained significantly more total iron than that of adult mice, which was sufficient to support enhanced E. coli growth. Transient iron overload in adult mice infected with E. coli resulted in 100% mortality. Maternal diet-induced mild iron deficiency decreased offspring peritoneal iron, decreased bacterial growth, and conferred protection against sepsis. Taken together, neonatal susceptibility to E. coli K1 sepsis is enhanced by a localized excess of peritoneal iron that allows for unchecked bacterial growth. Targeting this excess iron may provide a new therapeutic target in human patients.
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Bacteriemia/microbiologia , Infecções por Escherichia coli/microbiologia , Escherichia coli/efeitos dos fármacos , Ferro/farmacologia , Animais , Animais Recém-Nascidos , Antibacterianos , Antígenos de Bactérias/metabolismo , Modelos Animais de Doenças , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/patogenicidade , Infecções por Escherichia coli/mortalidade , Feminino , Ferro da Dieta , Masculino , Camundongos , Cavidade Peritoneal , Polissacarídeos Bacterianos/metabolismo , GravidezRESUMO
OBJECTIVE: Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that is critical for proper healing, however, in diabetes mellitus, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown. APPROACH AND RESULTS: Here, we characterized the kinetics and function of Ly6CHi [Lin- (CD3-CD19-NK1.1-Ter-119-) Ly6G-CD11b+] and Ly6CLo [Lin- (CD3-CD19-NK1.1-Ter-119-) Ly6G-CD11b+] monocyte/macrophage subsets in normal and diabetic wounds. Using flow-sorted tdTomato-labeled Ly6CHi monocyte/macrophages, we show Ly6CHi cells transition to a Ly6CLo phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6CHi cells that fail transition to Ly6CLo. The second wave of Ly6CHi cells in diabetic wounds corresponded to a spike in MCP-1 (monocyte chemoattractant protein-1) and selective administration of anti-MCP-1 reversed the second Ly6CHi influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq-based transcriptome profiling was performed on flow-sorted Ly6CHi [Lin-Ly6G-CD11b+] and Ly6CLo [Lin-Ly6G-CD11b+] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6CHi cells demonstrated differences in proinflammatory and profibrotic genes compared with controls. CONCLUSIONS: Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11b+Ly6CHi monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds.
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Antígenos Ly/metabolismo , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Inflamação/sangue , Macrófagos/metabolismo , Monócitos/metabolismo , Úlcera Cutânea/sangue , Cicatrização , Animais , Plasticidade Celular , Quimiocina CCL2/metabolismo , Doença Crônica , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/fisiopatologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Fibrose , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Mediadores da Inflamação/metabolismo , Cinética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Transdução de Sinais , Úlcera Cutânea/genética , Úlcera Cutânea/patologiaRESUMO
Sepsis survivors are at high risk for infection-related rehospitalization and mortality for years following the resolution of the acute septic event. These infection-causing microorganisms generally do not cause disease in immunocompetent hosts, suggesting that the post-septic immune response is compromised. Given the importance of CD4 T cells in the development of long-lasting protective immunity, we analyzed their post-septic function. Here we showed that sepsis induced chronic increased and non-specific production of IL-17 by CD4 T cells, resulting in the inability to mount an effective immune response to a secondary pneumonia challenge. Altered cell function was associated with metabolic reprogramming, characterized by mitochondrial dysfunction and increased glycolysis. This metabolic reprogramming began during the acute septic event and persisted long after sepsis had resolved. Our findings reveal cell metabolism as a potential therapeutic target. Given the critical role of cell metabolism in the physiological and pathophysiological processes of immune cells, these findings reveal a potential new therapeutic target to help mitigate sepsis survivors' susceptibility to secondary infections.
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Neonatal capillary leak syndrome (CLS) is a rare, but life-threatening condition following neonatal sepsis or inflammatory injury. The objective of this study was to describe a standardized treatment approach for CLS that improves mortality and neonatal outcomes. A retrospective cohort study of 10 infants born at 22 to 26 weeks of gestation who developed CLS following a significant inflammatory insult was performed. Time to diagnosis and treatment approaches over 2 epochs were recorded and described. In epoch 2, with increased clinical awareness of CLS and implementation of a standardized treatment approach, there was a non-statistically significant decrease in the time to treatment with a significant decrease in mortality. An early targeted treatment approach for neonatal CLS can decrease mortality rates in this highly morbid condition.
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Protoporphyria is a subtype of porphyria characterized primarily by painful phototoxic skin reactions after light exposure at specific wavelengths. Historically, phototherapy is not contraindicated in patients with protoporphyria since there have not been any reports of phototoxic reactions. However, patients with protoporphyria are advised to avoid direct sunlight. In this case report, we describe a neonate not known to have X-linked protoporphyria who received phototherapy for 1 to 2 hours. Within hours after initiation of phototherapy, this neonate developed a life-threatening reaction consisting of rash over the distribution of phototherapy, acute liver failure with coagulopathy, diffuse hypotonia with diaphragmatic failure, and subsequent acute respiratory failure that required mechanical ventilation. As in this case, patients with protoporphyria-related acute liver failure can have signs and symptoms similar to that of an acute hepatic porphyria attack. Neither neonatal reactions to phototherapy nor liver failure temporally associated with phototherapy have been reported in patients with X-linked protoporphyria. Early recognition of this entity is crucial in light of potential life-threatening complications. Therefore, providers must react quickly when neonates have abnormal reactions to phototherapy and consider protoporphyria in the differential diagnosis.
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Fototerapia , Humanos , Recém-Nascido , Fototerapia/efeitos adversos , Fototerapia/métodos , Masculino , Protoporfiria Eritropoética/terapia , Protoporfiria Eritropoética/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Falência Hepática Aguda/terapia , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/diagnósticoRESUMO
Evidence from in vitro studies and observational human disease data suggest the complement system plays a significant role in SARS-CoV-2 pathogenesis, although how complement dysregulation develops in patients with severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501YMA30) and a mouse model of severe COVID-19, we identify significant serologic and pulmonary complement activation following infection. We observed C3 activation in airway and alveolar epithelia, and in pulmonary vascular endothelia. Our evidence suggests that while the alternative pathway is the primary route of complement activation, components of both the alternative and classical pathways are produced locally by respiratory epithelial cells following infection, and increased in primary cultures of human airway epithelia in response to cytokine exposure. This locally generated complement response appears to precede and subsequently drive lung injury and inflammation. Results from this mouse model recapitulate findings in humans, which suggest sex-specific variance in complement activation, with predilection for increased C3 activity in males, a finding that may correlate with more severe disease. Our findings indicate that complement activation is a defining feature of severe COVID-19 in mice and lay the foundation for further investigation into the role of complement in COVID-19.
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Corioamnionite , Nascimento Prematuro , Feminino , Humanos , Recém-Nascido , Lipopolissacarídeos , Monócitos , Gravidez , Staphylococcus epidermidisAssuntos
Pesquisa Biomédica/tendências , Pediatria/educação , Pediatria/organização & administração , Adulto , Idoso , Escolha da Profissão , Feminino , Humanos , Masculino , Michigan , Pessoa de Meia-Idade , National Institute of Child Health and Human Development (U.S.) , Pediatras/provisão & distribuição , Pediatria/tendências , Sociedades Médicas , Estados Unidos , UniversidadesRESUMO
OBJECTIVES: Determine if chronologic age and/or chorioamnionitis exposure alter normal serum cytokine and chemokine levels in uninfected preterm neonates during their initial NICU stay. STUDY DESIGN: A 7-plex immunoassay measured levels of serum IL-1ß, IL-6, IL-8, IL-10, TNF-α, CCL2, and CCL3 longitudinally from chorioamnionitis-exposed and unexposed preterm neonates under 33 weeks' gestation. RESULTS: Chorioamnionitis-exposed and unexposed preterm neonates demonstrated differences in the trends of IL-1ß, IL-6, IL-8, IL-10, TNF-α, and CCL2 over the first month of life. The unexposed neonates demonstrated elevated levels of these inflammatory markers in the first two weeks of life with a decrease by the third week of life, while the chorioamnionitis-exposed neonates demonstrated differences over time without a predictable pattern. Chorioamnionitis-exposed and unexposed neonates demonstrated altered IL-10 and TNF-α trajectories over the first twelve weeks of life. CONCLUSION: Chorioamnionitis induces a state of immune dysregulation in preterm neonates that persists beyond the immediate neonatal period.
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Corioamnionite , Citocinas , Recém-Nascido , Gravidez , Feminino , Humanos , Interleucina-10 , Interleucina-6 , Fator de Necrose Tumoral alfa , Interleucina-8RESUMO
Preterm delivery can be precipitated by preeclampsia or infection, and preterm infants are at heightened risk of postnatal infection. Little is known about the ontogeny of inflammatory biomarkers in extremely preterm infants. We hypothesized that suspected prenatal infection (clinical chorioamnionitis or spontaneous preterm labor) and clinically diagnosed postnatal infection would be associated with unique biomarker signatures, and those patterns would be influenced by the degree of prematurity. Venous blood was collected daily for the first week and weekly for up to 14 additional weeks from 142 neonates born at 22-32 weeks gestation. A custom array was utilized to measure monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). C-reactive protein (CRP) levels were obtained from the electronic medical record. Independent of gestational age, MCP-1 was significantly increased (p < 0.001) in association with maternal preeclampsia, but MCP-1 was decreased (p < 0.01), and CRP was increased (p < 0.01) in the presence of chorioamnionitis with funisitis. IL-6 and CRP were both increased in infants diagnosed with postnatal infection, with peak levels observed on days 2 and 3, respectively. In conclusion, suspected prenatal and postnatal infections and non-infectious complications of pregnancy are associated with unique biomarker profiles, independent of gestational age, including over a 2-fold increase in MCP-1 among newborns of mothers with preeclampsia. Further, in those clinically diagnosed with a postnatal infection in the absence of antenatal infection concerns, IL-6 increases before CRP, emphasizing a potential role for expanded biomarker screening if antibiotics are initially avoided in infants delivered for maternal indications.
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This study investigates sex-associated systemic innate immune differences by examining bone marrow-derived dendritic cells (BMDCs). BMDC grown from 7-day-old mice show enhanced type-I interferon (IFN) signaling in female compared to male BMDC. Upon respiratory syncytial virus (RSV) infection of 7-day-old mice, a significantly altered phenotype of BMDC at 4 weeks post-infection is observed in a sex-dependent manner. The alterations include heightened Ifnb/ interleukin (Il12a) and enhanced IFNAR1+ expression in BMDC from early-life RSV-infected female mice that leads to increased IFN-γ production by T cells. Phenotypic differences were verified upon pulmonary sensitization whereby EL-RSV male-derived BMDC promoted enhanced T helper 2/17 responses and exacerbated disease upon RSV infection while EL-RSV/F BMDC sensitization was relatively protective. Assay for transposase-accessible chromatin using sequencing analysis (ATAC-seq) demonstrated that EL-RSV/F BMDC had enhanced chromatin accessibility near type-I immune genes with JUN, STAT1/2, and IRF1/8 transcription factors predicted to have binding sites in accessible regions. Importantly, ATAC-seq of human cord blood-derived monocytes displayed a similar sex-associated chromatin landscape with female-derived monocytes having more accessibility in type-I immune genes. These studies enhance our understanding of sex-associated differences in innate immunity by epigenetically controlled transcriptional programs amplified by early-life infection in females via type-I immunity.
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Interferon Tipo I , Infecções por Vírus Respiratório Sincicial , Masculino , Camundongos , Feminino , Humanos , Animais , Montagem e Desmontagem da Cromatina , Imunidade Inata , Pulmão , Interferon Tipo I/metabolismo , Cromatina/genética , Cromatina/metabolismoRESUMO
Information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in premature infants remains limited. Early in the pandemic, several studies reported that the risk of infection in infants was relatively small and that affected infants had a milder disease than what was seen in adults. Since the increase of the delta variant (SARS-CoV-2 B.1.617.2) within the population, there have been increased reports of more severe disease in infants. We present 3 cases of premature, very low birth weight infants with confirmed SARS-CoV-2 infection who presented with significant hyperglycemia and bone marrow dysfunction. Two infants had presumed vertical transmission, and 1 infant was infected by respiratory transmission. Despite the mode of transmission, symptom onset and duration were similar in all infants. All resolved with symptomatic management. In the context of the continuing pandemic, evaluation for SARS-CoV-2 infection should be considered in premature very low birth weight infants who demonstrate certain patterns of acute metabolic and hematologic abnormalities.
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COVID-19 , Hiperglicemia , Leucopenia , Complicações Infecciosas na Gravidez , Nascimento Prematuro , Trombocitopenia , Adulto , COVID-19/diagnóstico , Feminino , Humanos , Hiperglicemia/diagnóstico , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Transmissão Vertical de Doenças Infecciosas , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , SARS-CoV-2RESUMO
OBJECTIVE: There is a clear need for improved biomarkers to diagnose HIV/TB coinfection. Although numerous tests can identify the existence of both of these microbes within the host, a parallel assessment of the host response to HIV/TB coinfection may prove as useful confirmation in cases where microbiological tests are inconclusive. To this end we assessed the levels of Notch ligands found in serum samples of patients with TB, HIV or HIV/TB coinfection. The Notch system is involved in almost every stage of development, including the maturation of the immune response. Upon exposure to a pathogen, the innate immune system will increase expression of Notch ligands Delta-like 1 and Delta-like 4. Previous research has demonstrated that Notch ligand expression is increased on monocytes from patients diagnosed with tuberculosis. We hypothesized that if Notch ligands were present in the peripheral blood of individuals diagnosed with TB, they may serve as a novel marker for infection.Design: Serum samples from patients with HIV, TB or HIV/TB coinfection were compared to serum from uninfected individuals to determine levels of DLL1 and DLL4 in a case controlled study. METHODS: DLL1 and DLL4 were measured by ELISA. Linear regression with post tests were used to determine if levels of DLL1 and DLL4 were increased in individuals with HIV/TB coinfection as compared to individuals infected with either HIV or TB or healthy controls. RESULTS: Delta-like 1 and Delta-like 4 were significantly increased in the serum of patients with HIV and HIV/ M. tuberculosis coinfection compared to other groups. CONCLUSIONS: Assessment of Notch ligands in peripheral blood may enhance the diagnosis of individuals with active TB that are co-infected with HIV. The study will also need to be validated in in a larger cohort.