Emerging Links between Microbiome Composition and Skin Immunology in Diaper Dermatitis: A Narrative Review

Diaper dermatitis is a common type of irritant contact dermatitis occurring in infants and toddlers. Its occurrence is triggered by an unfavorable environment under the diaper, damage to skin integrity by fecal enzyme degradation, overhydration and disruption of the lipid bilayer structure facilitating the entry of irritants and microorganisms. In diaper dermatitis development, the central proinflammatory cytokines are IL-1α, IL-8 and TNF-α. The initial release of IL-1α and TNF-α starts a further cascade of pro-inflammatory chemo- and cytokines, resulting in inflammation and erythema of the skin. A recently recognized factor in diaper dermatitis is the composition of the skin microbiome; common pathogenic strains Candida albicans and Staphylococcus aureus are associated with skin irritation. The resulting impaired microbiome composition produces a local inflammatory response and may thus worsen the initial dermatitis clinical presentation and subsequent healing. Introduction of probiotics is an attractive treatment for microbiome modulation, which has shown success in other skin conditions in adults and children. Probiotics are thought to work as a protective shield against irritants, maintain low skin pH, secrete beneficial metabolites, and block pathogen invasion. There is preliminary evidence that certain probiotics given orally or topically could be used as a gentle intervention in diaper dermatitis.

Immune response and pathogen invasion at the choroid plexus in the onset of cerebral toxoplasmosis

Background Toxoplasma gondii (T. gondii) is a highly successful parasite being able to cross all biological barriers of the body, finally reaching the central nervous system (CNS). Previous studies have highlighted the critical involvement of the blood–brain barrier (BBB) during T. gondii invasion and development of subsequent neuroinflammation. Still, the potential contribution of the choroid plexus (CP), the main structure forming the blood–cerebrospinal fluid (CSF) barrier (BCSFB) have not been addressed. Methods To investigate T. gondii invasion at the onset of neuroinflammation, the CP and brain microvessels (BMV) were isolated and analyzed for parasite burden. Additionally, immuno-stained brain sections and three-dimensional whole mount preparations were evaluated for parasite localization and morphological alterations. Activation of choroidal and brain endothelial cells were characterized by flow cytometry. To evaluate the impact of early immune responses on CP and BMV, expression levels of inflammatory mediators, tight junctions (TJ) and matrix metalloproteinases (MMPs) were quantified. Additionally, FITC-dextran was applied to determine infection-related changes in BCSFB permeability. Finally, the response of primary CP epithelial cells to T. gondii parasites was tested in vitro. Results Here we revealed that endothelial cells in the CP are initially infected by T. gondii, and become activated prior to BBB endothelial cells indicated by MHCII upregulation. Additionally, CP elicited early local immune response with upregulation of IFN-γ, TNF, IL-6, host-defence factors as well as swift expression of CXCL9 chemokine, when compared to the BMV. Consequently, we uncovered distinct TJ disturbances of claudins, associated with upregulation of MMP-8 and MMP-13 expression in infected CP in vivo, which was confirmed by in vitro infection of primary CP epithelial cells. Notably, we detected early barrier damage and functional loss by increased BCSFB permeability to FITC-dextran in vivo, which was extended over the infection course. Conclusions Altogether, our data reveal a close interaction between T. gondii infection at the CP and the impairment of the BCSFB function indicating that infection-related neuroinflammation is initiated in the CP.

Apoplastic CBM1-interacting proteins bind conserved carbohydrate binding module 1 motifs in fungal hydrolases to counter pathogen invasion

When infecting plants, fungal pathogens secrete cell wall degrading enzymes (CWDEs) that break down cellulose and hemicellulose, the primary components of plant cell walls. Some fungal CWDEs contain a unique domain, named the carbohydrate binding module (CBM), that facilitates their access to polysaccharides. However, little is known about how plants counteract pathogen degradation of their cell walls. Here, we show that the rice cysteine-rich repeat secretion protein OsCBMIP binds to and inhibits xylanase MoCel10A of the blast fungus pathogen Magnaporthe oryzae, interfering with its access to the rice cell wall and degradation of rice xylan. We found binding of OsCBMIP to various CBM1-containing enzymes, suggesting it has a general role in inhibiting the catalytic activities of fungal enzymes. OsCBMIP is localized to the apoplast, and its expression is strongly induced in leaves infected with M. oryzae. Remarkably, knockdown of OsCBMIP reduced rice defense against M. oryzae, demonstrating that inhibition of CBM1-containing fungal enzymes by OsCBMIP is crucial for rice defense. We also identified additional CBMIP-related proteins from Arabidopsis thaliana and Setaria italica, indicating that a wide range of plants counteract pathogens through this mechanism.

TOXICITY MEDIATED OXIDATIVE STRESS AND ITS MITIGATION STRATEGIES IN CROP PLANTS

Oxidative stress occurs in plant due to various environmental stressors like drought, high temperature, pathogen invasion, heavy metals, pesticides etc. when plant faces these conditions, reactive oxygen species (ROS) are produced in the chloroplast, mitochondria, plasma membrane, peroxisomes, ER and cell wall due to the leakage of electrons. Depending upon its concentration the role of ROS is decided if less then it will act as a signaling molecule but if in excess it will damage the cellular machinery of plants as the production of species like free radicals would take place. Though to combat these stress plants have antioxidant defense machinery which include enzymatic and non- enzymatic which lower down the level of ROS. Through genetic engineering more tolerant plants are produced which include modification of key genes like transcription factors. In this review article the molecular physiology of plants is discussed where in the factors contributing to stress including biotic and abiotic factors and various mitigation strategies.

‘Candidatus Liberibacter asiaticus’-Encoded BCP Peroxiredoxin Suppresses Lipopolysaccharide-Mediated Defense Signaling and Nitrosative Stress in Planta

The lipopolysaccharides (LPS) of Gram-negative bacteria trigger a nitrosative and oxidative burst in both animals and plants during pathogen invasion. Liberibacter crescens strain BT-1 is a surrogate for functional genomic studies of the uncultured pathogenic ‘Candidatus Liberibacter’ spp. that are associated with severe diseases such as citrus greening and potato zebra chip. Structural determination of L. crescens LPS revealed the presence of a very long chain fatty acid (VLCFA) modification. L. crescens LPS pretreatment suppressed growth of Xanthomonas perforans on non-host tobacco (Nicotiana benthamiana) and X. citri subsp. citri on host citrus (Citrus sinensis, confirming bioactivity of L. crescens LPS in activation of systemic acquired resistance (SAR). L. crescens LPS elicited a rapid burst of nitric oxide (NO) in suspension cultured tobacco cells. Pharmacological inhibitor assays confirmed that arginine-utilizing NO synthase (NOS) activity was the primary source of NO generation elicited by L. crescens LPS. LPS treatment also resulted in biological markers of NO-mediated SAR activation, including an increase in the glutathione (GSH) pool, callose deposition and activation of the salicylic acid (SA) and azelaic acid (AzA) signaling networks. Transient expression of ‘Ca. L. asiaticus’ BCP peroxiredoxin in tobacco compromised AzA signaling, a prerequisite for LPS-triggered SAR. Western blot analyses revealed that ‘Ca. L. asiaticus’ BCP peroxiredoxin prevented peroxynitrite-mediated tyrosine nitration in tobacco. ‘Ca. L. asiaticus’ BCP peroxiredoxin (a) attenuates NO-mediated SAR signaling and (b) scavenges peroxynitrite radicals, which would facilitate repetitive cycles of ‘Ca. L. asiaticus’ acquisition and transmission by fecund psyllids throughout the limited flush period in citrus.

Innate Receptors Expression by Lung Nociceptors: Impact on COVID-19 and Aging

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition via innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.

Pathogen invasion-dependent tissue reservoirs and plasmid-encoded antibiotic degradation boost plasmid spread in the gut

Many plasmids encode antibiotic resistance genes. Through conjugation, plasmids can be rapidly disseminated. Previous work identified gut luminal donor/recipient blooms and tissue-lodged plasmid-bearing persister cells of the enteric pathogen Salmonella enterica serovar Typhimurium (S.Tm) that survive antibiotic therapy in host tissues, as factors promoting plasmid dissemination among Enterobacteriaceae. However, the buildup of tissue reservoirs and their contribution to plasmid spread await experimental demonstration. Here, we asked if re-seeding-plasmid acquisition-invasion cycles by S.Tm could serve to diversify tissue-lodged plasmid reservoirs, and thereby promote plasmid spread. Starting with intraperitoneal mouse infections, we demonstrate that S.Tm cells re-seeding the gut lumen initiate clonal expansion. Extended spectrum beta-lactamase (ESBL) plasmid-encoded gut luminal antibiotic degradation by donors can foster recipient survival under beta-lactam antibiotic treatment, enhancing transconjugant formation upon re-seeding. S.Tm transconjugants can subsequently re-enter host tissues introducing the new plasmid into the tissue-lodged reservoir. Population dynamics analyses pinpoint recipient migration into the gut lumen as rate-limiting for plasmid transfer dynamics in our model. Priority effects may be a limiting factor for reservoir formation in host tissues. Overall, our proof-of-principle data indicates that luminal antibiotic degradation and shuttling between the gut lumen and tissue-resident reservoirs can promote the accumulation and spread of plasmids within a host over time.

γδ T cell IFNγ production is directly subverted by Yersinia pseudotuberculosis outer protein YopJ in mice and humans

Yersinia pseudotuberculosis is a foodborne pathogen that subverts immune function by translocation of Yersinia outer protein (Yop) effectors into host cells. As adaptive γδ T cells protect the intestinal mucosa from pathogen invasion, we assessed whether Y. pseudotuberculosis subverts these cells in mice and humans. Tracking Yop translocation revealed that the preferential delivery of Yop effectors directly into murine Vγ4 and human Vδ2+ T cells inhibited anti-microbial IFNγ production. Subversion was mediated by the adhesin YadA, injectisome component YopB, and translocated YopJ effector. A broad anti-pathogen gene signature and STAT4 phosphorylation levels were inhibited by translocated YopJ. Thus, Y. pseudotuberculosis attachment and translocation of YopJ directly into adaptive γδ T cells is a major mechanism of immune subversion in mice and humans. This study uncovered a conserved Y. pseudotuberculosis pathway that subverts adaptive γδ T cell function to promote pathogenicity.

Innate Lymphoid Cells in Response to Intracellular Pathogens: Protection Versus Immunopathology

Innate lymphoid cells (ILCs) are a heterogeneous group of cytokine-producing lymphocytes which are predominantly located at mucosal barrier surfaces, such as skin, lungs, and gastrointestinal tract. ILCs contribute to tissue homeostasis, regulate microbiota-derived signals, and protect against mucosal pathogens. ILCs are classified into five major groups by their developmental origin and distinct cytokine production. A recently emerged intriguing feature of ILCs is their ability to alter their phenotype and function in response to changing local environmental cues such as pathogen invasion. Once the pathogen crosses host barriers, ILCs quickly activate cytokine production to limit the spread of the pathogen. However, the dysregulated ILC responses can lead to tissue inflammation and damage. Furthermore, the interplay between ILCs and other immune cell types shapes the outcome of the immune response. Recent studies highlighted the important role of ILCs for host defense against intracellular pathogens. Here, we review recent advances in understanding the mechanisms controlling protective and pathogenic ILC responses to intracellular pathogens. This knowledge can help develop new ILC-targeted strategies to control infectious diseases and immunopathology.