Barrier Impairment and Type 2 Inflammation in Allergic Diseases: The Pediatric Perspective

Allergic diseases represent a global burden. Although the patho-physiological mechanisms are still poorly understood, epithelial barrier dysfunction and Th2 inflammatory response play a pivotal role. Barrier dysfunction, characterized by a loss of differentiation, reduced junctional integrity, and altered innate defence, underpins the pathogenesis of allergic diseases. Epithelial barrier impairment may be a potential therapeutic target for new treatment strategies Up now, monoclonal antibodies and new molecules targeting specific pathways of the immune response have been developed, and others are under investigation, both for adult and paediatric populations, which are affected by atopic dermatitis (AD), asthma, allergic rhinitis (AR), chronic rhinosinusitis with nasal polyps (CRSwNP), or eosinophilic esophagitis (EoE). In children affected by severe asthma biologics targeting IgE, IL-5 and against IL-4 and IL-13 receptors are already available, and they have also been applied in CRSwNP. In severe AD Dupilumab, a biologic which inhibits both IL-4 and IL-13, the most important cytokines involved in inflammation response, has been approved for treatment of patients over 12 years. While a biological approach has already shown great efficacy on the treatment of severe atopic conditions, early intervention to restore epithelial barrier integrity, and function may prevent the inflammatory response and the development of the atopic march.

Asylum-seeking children in shutdown: Neurobiological models

Asylum-seeking children presenting in the shutdown state have been the subject of much discussion and controversy—on both government and medical system levels—in Australia and in Sweden. In this article, we conceptualize the shutdown state as an evolutionary response to extreme threat. We adopt a neuroscience approach to present five plausible models for explaining this shutdown state, their strengths and shortcomings, and the overlaps between them. Model 1—the sustained autonomic arousal model—draws on polyvagal theory. Model 2—the innate-defence model—draws on research pertaining to animal and human innate defence responses. Model 3—the catatonia model—draws on clinical and research data with patients presenting with catatonia. Model 4—the hypometabolic model—draws on an emerging body of work pertaining to hypometabolic states in animals and humans. Model 5—the defence cascade model of dissociation—draws on clinical research pertaining to human trauma states that present as dissociation. At present, each of the models provides a plausible pathophysiological explanation—or a component of a potential pathophysiological explanation—and none of them, for the moment, has enough evidence to be either accepted or disregarded. We hope that our discussion of the models advances scientific discussion and opens up possibilities for effective treatment.

A A review of role of Rajanyadi Churna as potential immune-modulator in Kaumarabhritya

The present pandemic situation has alarmed mankind to formulate and implement effective and practical tools to defend and confront any unexpected breakout of infectious diseases. It emphasizes the need to correct and sharpen the innate immune mechanisms, particularly under the circumstances of long waiting periods and uncertainty with vaccines. Revisiting the Ayurvedic principle of agni and bala to correct and enhance innate defence mechanisms in ways that can make the body ready to defend any situation of challenge. The paper explores the possibilities of the use of Rajanyadi Churna in Kaumarabhritya.

Senescence and Host–Pathogen Interactions

Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host–pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease.

The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal respiratory infection by influenza A virus at epithelial surfaces

SummaryRespiratory viruses such as influenza A virus (IAV) and SARS-CoV-2 (Covid-19) cause pandemic infections where cytokine storm syndrome, lung inflammation and pneumonia lead to high mortality. Given the high social and economic cost of these viruses, there is an urgent need for a comprehensive understanding of how the airways defend against virus infection. Viruses entering cells by endocytosis are killed when delivered to lysosomes for degradation. Lysosome delivery is facilitated by non-canonical autophagy pathways that conjugate LC3 to endo-lysosome compartments to enhance lysosome fusion. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that non-canonical autophagy protects mice from lethal IAV infection of the airways. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity murine-adapted IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV infection was controlled within epithelial barriers where non-canonical autophagy slowed fusion of IAV with endosomes and reduced activation of interferon signalling. This was consistent with conditional mouse models and ex vivo analysis showing that protection against IAV infection of lung was independent of phagocytes and other leukocytes. This establishes non-canonical autophagy pathways in airway epithelial cells as a novel innate defence mechanism that can restrict IAV infection and lethal inflammation at respiratory surfaces.

Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections

Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children (N = 111) and adults (N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults (p = 0.01). NET presence was associated with higher CSF levels of CXCL1 (p < 0.001), CXCL6 (p = 0.007), CXCL8 (p = 0.003), CXCL10 (p < 0.001), MMP-9 (p = 0.002), TNF (p = 0.02), IL-6 (p < 0.001), and IL-17A (p = 0.03). NETs were associated with fever (p = 0.002) and correlated with polynuclear pleocytosis (rs = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation.

Supreme activity of gramicidin S against resistant, persistent and biofilm cells of staphylococci and enterococci

Three promising antibacterial peptides were studied with regard to their ability to inhibit the growth and kill the cells of clinical strains of Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium. The multifunctional gramicidin S (GS) was the most potent, compared to the membranotropic temporin L (TL), being more effective than the innate-defence regulator IDR-1018 (IDR). These activities, compared across 16 strains as minimal bactericidal and minimal inhibitory concentrations (MIC), are independent of bacterial resistance pattern, phenotype variations and/or biofilm-forming potency. For S. aureus strains, complete killing is accomplished by all peptides at 5 × MIC. For E. faecalis strains, only GS exhibits a rapid bactericidal effect at 5 × MIC, while TL and IDR require higher concentrations. The biofilm-preventing activities of all peptides against the six strains with the largest biofilm biomass were compared. GS demonstrates the lowest minimal biofilm inhibiting concentrations, whereas TL and IDR are consistently less effective. In mature biofilms, only GS completely kills the cells of all studied strains. We compare the physicochemical properties, membranolytic activities, model pharmacokinetics and eukaryotic toxicities of the peptides and explain the bactericidal, antipersister and antibiofilm activities of GS by its elevated stability, pronounced cell-penetration ability and effective utilization of multiple modes of antibacterial action.