COVID-19 mRNA Vaccines Induce Robust Levels of IgG but Limited Amounts of IgA Within the Oronasopharynx of Young Children.

Background: Understanding antibody responses to SARS-CoV-2 vaccination is crucial for refining COVID-19 immunization strategies. Generation of mucosal immune responses, including mucosal IgA, could be of potential benefit to vaccine efficacy; however, limited evidence exists regarding the production of mucosal antibodies following the administration of current mRNA vaccines to young children.

Methods: We measured the levels of antibodies against SARS-CoV-2 from a cohort of children under 5 years of age (n = 24) undergoing SARS-CoV-2 mRNA vaccination (serially collected, matched serum and saliva samples) or in a convenience sample of children under 5 years of age presenting to pediatric emergency department (nasal swabs, n = 103).

Bacterial Sphingolipids Exacerbate Colitis by Inhibiting ILC3-derived IL-22 Production.

Background & Aims: Gut bacterial sphingolipids, primarily produced by Bacteroidetes, have dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells. Patients with inflammatory bowel disease display altered sphingolipids profiles in fecal samples. However, how bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remains unclear.

COVID-19 mRNA vaccines induce robust levels of IgG but limited amounts of IgA within the oronasopharynx of young children.

Background: Understanding antibody responses to SARS-CoV-2 vaccination is crucial for refining COVID-19 immunization strategies. Generation of mucosal immune responses, including mucosal IgA, could be of potential benefit to vaccine efficacy, yet limited evidence exists regarding the production of mucosal antibodies following the administration of current mRNA vaccines to young children.

Methods: We measured the levels of antibodies against SARS-CoV-2 from a cohort of children under 5 years of age undergoing SARS-CoV-2 mRNA vaccination (serially collected, matched serum and saliva samples, N=116) or on convenience samples of children under 5 years of age presenting to a pediatric emergency department (nasal swabs, N=103).

An enhanced IL17 and muted type I interferon nasal epithelial cell state characterizes severe COVID-19 with fungal coinfection.

Unlabelled: Recent case reports and epidemiological data suggest that fungal infections represent an underappreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing data set characterizing the upper respiratory microenvironment during COVID-19 and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells.

Humoral profiles of toddlers and young children following SARS-CoV-2 mRNA vaccination.

Although young children generally experience mild symptoms following infection with SARS-CoV-2, severe acute and long-term complications can occur. SARS-CoV-2 mRNA vaccines elicit robust immunoglobulin profiles in children ages 5 years and older, and in adults, corresponding with substantial protection against hospitalizations and severe disease. Whether similar immune responses and humoral protection can be observed in vaccinated infants and young children, who have a developing and vulnerable immune system, remains poorly understood.

The IL-10 receptor inhibits cell extrinsic signals necessary for STAT1-dependent macrophage accumulation during colitis.

The loss of IL-10R function leads to severe early onset colitis and, in murine models, is associated with the accumulation of immature inflammatory colonic macrophages. We have shown that IL-10R-deficient colonic macrophages exhibit increased STAT1-dependent gene expression, suggesting that IL-10R-mediated inhibition of STAT1 signaling in newly recruited colonic macrophages might interfere with the development of an inflammatory phenotype. Indeed, STAT1 mice exhibit defects in colonic macrophage accumulation after Helicobacter hepaticus infection and IL-10R blockade, and this was phenocopied in mice lacking IFNγR, an inducer of STAT1 activation.

Severe COVID-19 is associated with fungal colonization of the nasopharynx and potent induction of IL-17 responses in the nasal epithelium.

Recent case reports and epidemiological data suggest fungal infections represent an under-appreciated complication among people with severe COVID-19. However, the frequency of fungal colonization in patients with COVID-19 and associations with specific immune responses in the airways remain incompletely defined. We previously generated a single-cell RNA-sequencing (scRNA-seq) dataset characterizing the upper respiratory microenvironment during COVID-19, and mapped the relationship between disease severity and the local behavior of nasal epithelial cells and infiltrating immune cells.

CCR2 promotes monocyte recruitment and intestinal inflammation in mice lacking the interleukin-10 receptor.

Macrophages are a heterogeneous population of mononuclear phagocytes abundantly distributed throughout the intestinal compartments that adapt to microenvironmental specific cues. In adult mice, the majority of intestinal macrophages exhibit a mature phenotype and are derived from blood monocytes. In the steady-state, replenishment of these cells is reduced in the absence of the chemokine receptor CCR2.

Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation.

Background: The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS.

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19.

SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper respiratory symptoms, suggesting potential to constrain viral pathology to the nasopharynx. Which cells SARS-CoV-2 primarily targets and how infection influences the respiratory epithelium remains incompletely understood.

Increased ACE2 Levels and Mortality Risk of Patients With COVID-19 on Proton Pump Inhibitor Therapy.

Introduction: Proton pump inhibitor (PPI) use was recently reported to be associated with increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and worse clinical outcomes. The underlying mechanism(s) for this association are unclear.

Methods: We performed a prospective study of hospitalized coronavirus disease 2019 (COVID-19) patients and COVID-negative controls to understand how PPI use may affect angiotensin-converting enzyme 2 (ACE2) expression and stool SARS-CoV-2 RNA.

Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.

Background And Aims: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation.

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19.

Infection with SARS-CoV-2, the virus that causes COVID-19, can lead to severe lower respiratory illness including pneumonia and acute respiratory distress syndrome, which can result in profound morbidity and mortality. However, many infected individuals are either asymptomatic or have isolated upper respiratory symptoms, which suggests that the upper airways represent the initial site of viral infection, and that some individuals are able to largely constrain viral pathology to the nasal and oropharyngeal tissues. Which cell types in the human nasopharynx are the primary targets of SARS-CoV-2 infection, and how infection influences the cellular organization of the respiratory epithelium remains incompletely understood.

Characterizing T cell subsets in the nasal mucosa of children with acute respiratory symptoms.

Background: In infants admitted to an ICU with respiratory failure, there is an association between the ratio of CD8 to CD4 T cells within the upper respiratory tract and disease severity. Whether this ratio is associated with respiratory disease severity within children presenting to a pediatric emergency department is not known.

Methods: We studied a convenience sample of 63 children presenting to a pediatric emergency department with respiratory symptoms.

Effects of Colonization of Gnotobiotic Swiss Webster Mice with .

(Hb) causes hepatitis in some strains of inbred mice. The current study confirmed that Hb directly causes portal hepatitis in outbred gnotobiotic Swiss Webster (SW) mice, as we previously reported for conventional SW mice. Hbmonoassociated SW mice also developed mild enterocolitis, expanded gut-associated lymphoid tissue (GALT), and tertiary lymphoid tissue in the lower bowel.

Generation of protective pneumococcal-specific nasal resident memory CD4 T cells via parenteral immunization.

The generation of tissue-resident memory T cells (T) is an essential aspect of immunity at mucosal surfaces, and it has been suggested that preferential generation of T is one of the principal advantages of mucosally administered vaccines. We have previously shown that antigen-specific, IL-17-producing CD4 T cells can provide capsular antibody-independent protection against nasal carriage of Streptococcus pneumoniae; but whether pneumococcus-responsive T are localized within the nasal mucosa and are sufficient for protection from carriage has not been determined. Here, we show that intranasal administration of live or killed pneumococci to mice generates pneumococcus-responsive IL-17A-producing CD4 mucosal T Furthermore, we show that these cells are sufficient to mediate long-lived, neutrophil-dependent protection against subsequent pneumococcal nasal challenge.

Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis.

Inflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs. However, the specific gene that controls disease susceptibility remains unknown.

WASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis.

Mutations in Wiskott-Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. Yet, how WASP mediates mucosal homeostasis is not fully understood. Here we show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance.

Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor.

Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota.

Inhibition of Inflammatory Gene Transcription by IL-10 Is Associated with Rapid Suppression of Lipopolysaccharide-Induced Enhancer Activation.

IL-10 limits the magnitude of inflammatory gene expression following microbial stimuli and is essential to prevent inflammatory disease; however, the molecular basis for IL-10-mediated inhibition remains elusive. Using a genome-wide approach, we demonstrate that inhibition of transcription is the primary mechanism for IL-10-mediated suppression in LPS-stimulated macrophages and that inhibited genes can be divided into two clusters. Genes in the first cluster are inhibited only if IL-10 is included early in the course of LPS stimulation and is strongly enriched for IFN-inducible genes.

Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency.

Interleukin 10 receptor (IL10R)-deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1β. We demonstrated that innate immune production of IL1β mediates colitis in IL10R-deficient mice.

Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3.

Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific "humanized" mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue.

Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function.

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells.