Innate Production Research Articles

Early Immune Initiation by Porcine Cells following Toxoplasma gondii Infection versus TLR Ligation.

Containment of acute Toxoplasma gondii infection is dependent on an efficient interferon gamma response. However, the earliest steps of immune response initiation immediately following exposure to the parasite have not been previously characterized in pigs. Murine and human myeloid cells produce large quantities of interleukin (IL)-12 during early T. gondii infection. We therefore examined IL-12 expression by porcine peripheral blood monocytes and dendritic cell (DC) subsets following toll-like receptor (TLR) ligation and controlled T. gondii tachyzoite infection. We detected IL-12p40 expression by porcine plasmacytoid DC, but not conventional or monocyte-derived DC following TLR ligation. Unexpectedly, we also observed considerable IL-12p40 production by porcine CD3– NKp46+ cells—a classical natural killer cell phenotype—following TLR ligation. However, in response to T. gondii exposure, no IL-12 production was observed by either DC or CD3– NKp46+ cells. Despite this, IL-18 production by DC-enriched peripheral blood mononuclear cells was detected following live T. gondii tachyzoite exposure. Only combined stimulation of porcine peripheral blood mononuclear cells with recombinant IL-12p70 and IL-18 induced innate interferon gamma production by natural killer cells, while T cells and myeloid cells did not respond. Therefore, porcine CD3– NKp46+ cells serve as important IL-12 producers following TLR ligation, while IL-18 likely plays a prominent role in early immune response initiation in the pig following T. gondii infection.

The Ecophysiological Performance and Traits of Genera within the Stichococcus-like Clade (Trebouxiophyceae) under Matric and Osmotic Stress.

Changes in water balance are some of the most critical challenges that aeroterrestrial algae face. They have a wide variety of mechanisms to protect against osmotic stress, including, but not limited to, downregulating photosynthesis, the production of compatible solutes, spore and akinete formation, biofilms, as well as triggering structural cellular changes. In comparison, algae living in saline environments must cope with ionic stress, which has similar effects on the physiology as desiccation in addition to sodium and chloride ion toxicity. These environmental challenges define ecological niches for both specialist and generalist algae. One alga known to be aeroterrestrial and euryhaline is Stichococcus bacillaris Nägeli, possessing the ability to withstand both matric and osmotic stresses, which may contribute to wide distribution worldwide. Following taxonomic revision of Stichococcus into seven lineages, we here examined their physiological responses to osmotic and matric stress through a salt growth challenge and desiccation experiment. The results demonstrate that innate compatible solute production capacity under salt stress and desiccation tolerance are independent of one another, and that salt tolerance is more variable than desiccation tolerance in the Stichococcus-like genera. Furthermore, algae within this group likely occupy similar ecological niches, with the exception of Pseudostichococcus.

Neuroimmune mechanisms of cognitive impairment in a mouse model of Gulf War illness

Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting approximately 30 percent of the nearly 700,000 Veterans of the 1991 Persian Gulf War. GWI-related chemical (GWIC) exposure promotes immune activation that correlates with cognitive impairment and other symptoms of GWI. However, the molecular mechanisms and signaling pathways linking GWIC to inflammation and neurological symptoms remain unclear. Here we show that acute exposure of murine macrophages to GWIC potentiates innate immune signaling and inflammatory cytokine production. Using an established mouse model of GWI, we report that neurobehavioral changes and neuroinflammation are attenuated in mice lacking the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) and NOD-, LRR- or pyrin domain-containing protein 3 (NLRP3) innate immune pathways. In addition, we report sex differences in response to GWIC, with female mice showing more pronounced cognitive impairment and hippocampal astrocyte hypertrophy. In contrast, male mice display a GWIC-dependent upregulation of proinflammatory cytokines in the plasma that is not present in female mice. Our results indicate that STING and NLRP3 are key mediators of the cognitive impairment and inflammation observed in GWI and provide important new information on sex differences in this model.

Allotransplantation Is Associated With Exacerbation of CD8 T-Cell Senescence: The Particular Place of the Innate CD8 T-Cell Component.

Immunosenescence is a physiological process that is associated with changes in the immune system, particularly among CD8 T-cells. Recent studies have hypothesized that senescent CD8 T-cells are produced with chronologic age by chronic stimulation, leading to the acquisition of hallmarks of innate-like T-cells. While conventional CD8 T-cells are quite well characterized, CD8 T-cells sharing features of NK cells and memory CD8 T-cells, are a newly described immune cell population. They can be distinguished from conventional CD8 T-cells by their combined expression of panKIR/NKG2A and Eomesodermin (E), a unique phenotype closely associated with IFN-γ production in response to innate stimulation. Here, we first provided new evidence in favor of the innate character of panKIR/NKG2A(+) E(+) CD8 T-cells in normal subjects, documenting their position at an intermediate level in the innateness gradient in terms of both innate IFN-γ production and diminished mitochondrial mass. We also revealed that CD8 E(+) panKIR/NKG2A(+) T-cells, hereafter referred to as Innate E(+) CD8 T-cells, exhibit increased senescent (CD27(-) CD28(-)) phenotype, compared to their conventional memory counterparts. Surprisingly, this phenomenon was not dependent on age. Given that inflammation related to chronic viral infection is known to induce NK-like marker expression and a senescence phenotype among CD8 T-cells, we hypothesized that innate E(+) CD8 T-cells will be preferentially associated with exacerbated cellular senescence in response to chronic alloantigen exposure or CMV infection. Accordingly, in a pilot cohort of stable kidney allotransplant recipients, we observed an increased frequency of the Innate E(+) CD8 T-cell subset, together with an exacerbated senescent phenotype. Importantly, this phenotype cannot be explained by age alone, in clear contrast to their conventional memory counterparts. The senescent phenotype in CD8 T-cells was further increased in cytomegalovirus (CMV) positive serology transplant recipients, suggesting that transplantation and CMV, rather than aging by itself, may promote an exacerbated senescent phenotype of innate CD8 T-cells. In conclusion, we proposed that kidney transplantation, via the setting of inflammatory stimuli of alloantigen exposure and CMV infection, may exogenously age the CD8 T-cell compartment, especially its innate component. The physiopathological consequences of this change in the immune system remain to be elucidated.

The role of micronutrient and immunomodulation effect in the vaccine era of COVID-19.

Different dietary nutrients have distinct effects, including enhancing immune response activity and supporting mucous membrane integrity. These effects are critical in fighting against pathogenic agents, which cover coronavirus disease 2019 (COVID-19), the coronavirus disease that shuts down globally. Recent researches have shown that micronutrient deficiency is commonly associated with compromised immune responses, respiratory tract infections, or even susceptibility to COVID-19. The relationship between Vit A and infection is its role in mucosal epithelium integrity (skin and mucous membrane), the supplementation could be an option for assisted-treating the SARS-CoV-2 virus and a possible prevention of lung infection. Vit C/ascorbic acid stimulates oxygen radical scavenging activity of the skin and enhances epithelial barrier function. Ascorbic acid alone or with other natural compounds (baicalin and theaflavin) may inhibit the expression of angiotensin-converting enzyme II in human small alveolar epithelial cells and limited the entry of SARS-CoV-2. Vitamin D receptors can be expressed by immune cells, and different immune cells (macrophages, monocytes, dendritic cells, T cells, and B cells) can convert Vit D into its active form 1,25-(OH)2 D. Oral vitamin D intake can be a readily way to restrict the viral infection through downregulation of ACE2 receptor and to attenuate the disease severity by decreasing the frequency of cytokine storm and pulmonary pro-inflammatory response. Vit E supports T-cell mediated functions, optimization of Th1 response, and suppression of Th2 response. Vitamin E supplementation can lower the production of superoxides and may favors the antioxidants and benefit the progress of COVID-19 treatment. Zinc plays an essential role in both innate and adaptive immune systems and cytokine production, and Zinc-dependent viral enzymes to initiate the infectious process have proved the Zinc levels are directly associated with symptoms relieved of COVID-19. Iron is an essential component of enzymes involved in the activation of immune cells, lower iron levels predispose to severe symptoms of SARS-CoV-2, and monitoring the status can predict the disease severity and mortality. Selenium participates in the adaptive immune response by supporting antibody production and development. Deficiency can reduce antibody concentration, decreased cytotoxicity of NK cells, compromised cellular immunity, and an attenuated response to vaccination. The COVID-19 vaccines including three broad categories, protein-based vaccines, gene-based vaccines (mRNA vaccines and DNA vaccines), combination of gene and protein-based vaccines. Micronutrients are involved in immunity from the virus entering the human to innate immune response and adaptive immune response. Micronutrients are indispensable in immune response of vaccination.

Human Newborn Monocytes Demonstrate Distinct BCG-Induced Primary and Trained Innate Cytokine Production and Metabolic Activation In Vitro.

BackgroundNewborns exhibit distinct immune responses and are at high risk of infection. Neonatal immunization with BCG, the live attenuated vaccine against tuberculosis (TB), is associated with broad protection against a range of unrelated pathogens, possibly reflecting vaccine-induced training of innate immune cells (“innate memory”). However, little is known regarding the impact of age on BCG-induced innate responses.ObjectiveEstablish an age-specific human monocyte in vitro training platform to characterize and compare BCG-induced primary and memory cytokine responses and immunometabolic shifts.Design/MethodsHuman neonatal and adult CD33-selected monocytes were stimulated for 24h with RPMI (control) or BCG (Danish strain) in 10% autologous serum, washed and cultured for 5 additional days, prior to re-stimulation with the TLR4 agonist LPS for another 24h. Supernatants were collected at Day 1 (D1) to measure primary innate responses and at Day 7 (D7) to assess memory innate responses by ELISA and multiplex cytokine and chemokine assays. Lactate, a signature metabolite increased during trained immunity, was measured by colorimetric assay.ResultsCytokine production by human monocytes differed significantly by age at D1 (primary, BCG 1:750 and 1:100 vol/vol, p<0.0001) and D7 (innate memory response, BCG 1:100 vol/vol, p<0.05). Compared to RPMI control, newborn monocytes demonstrated greater TNF (1:100, 1:10 vol/vol, p<0.01) and IL-12p40 (1:100 vol/vol, p<0.05) production than adult monocytes (1:100, p<0.05). At D7, while BCG-trained adult monocytes, as previously reported, demonstrated enhanced LPS-induced TNF production, BCG-trained newborn monocytes demonstrated tolerization, as evidenced by significantly diminished subsequent LPS-induced TNF (RPMI vs. BCG 1:10, p <0.01), IL-10 and CCL5 production (p<0.05). With the exception of IL-1RA production by newborn monocytes, BCG-induced monocyte production of D1 cytokines/chemokines was inversely correlated with D7 LPS-induced TNF in both age groups (p<0.0001). Compared to BCG-trained adult monocytes, newborn monocytes demonstrated markedly impaired BCG-induced production of lactate, a metabolite implicated in immune training in adults.ConclusionsBCG-induced human monocyte primary- and memory-innate cytokine responses were age-dependent and accompanied by distinct immunometabolic shifts that impact both glycolysis and training. Our results suggest that immune ontogeny may shape innate responses to live attenuated vaccines, suggesting age-specific approaches to leverage innate training for broad protection against infection.

Prostaglandin E2 amplifies IL-17 production by γδ Tcells during barrier inflammation.

Interleukin-17 (IL-17)-producing γδ (γδ17) Tcells are innate-like lymphocytes that contribute to protective anti-microbial responses but are also implicated in pathogenic inflammation at barrier sites. Understanding tissue-specific signals that regulate this subset is important to boost host defense mechanisms, but also to mitigate immunopathology. Here, we demonstrate that prostaglandin E2 (PGE2), a cyclooxygenase-dependent member of the eicosanoid family, directly enhances cytokine production by circulating and tissue-specific γδ17 Tcells invitro. Gain- and loss-of-function invivo approaches further reveal that although provision of PGE2 amplifies psoriasiform inflammation, ablation of host mPGES1-dependent PGE2 synthesis is dispensable for cutaneous γδ17 Tcell activation. By contrast, loss of endogenous PGE2 production or depletion of the gut microbiota compromises intestinal γδ17 Tcell responses and increases disease severity during experimental colitis. Together, our results demonstrate how a lipid mediator can synergize with tissue-specific signals to enhance innate lymphocyte production of IL-17 during barrier inflammation.

TLR2 and TLR4 mRNA expression levels in liver transplant patients with acute rejection

Toll-like receptors (TLRs) have important role in transplant outcomes by activating the innate immune system and production of pro-inflammatory cytokines, leading to graft rejection. We assessed the expression level of TL2 and TLR4 in acute rejection (AR) on the 1st and 7th-day post-transplantation. TLR2 and TLR4 expressions were evaluated by real-time PCR in both the AR group (n = 50) and non-AR (n = 50), compared with the control group. Also, the correlation of the expression levels of TLRs between both the 1st and 7th day was analyzed. ROC curve analysis was used to determine the cut-off value for TLRs expression. TLR4 mRNA expression was significantly up-regulated in AR patients vs. the controls on the 1st day (p ≤ 0.05) and it was down-regulated in non-AR vs. controls on the 1st day (p ≤ 0.05). Also, TLR4 expression had decreased in both AR and non-AR groups vs. control on the 7th day (p ≤ 0.05). Both TLR2 and TLR4 expression in comparison to non-AR had increased in the AR group on the 7th day (p ≤ 0.05). TLR2 expression positively correlated between 1st and 7th day in AR (r = 0.3, (p ≤ 0.05) and non-AR group (r = 0.2, p ≤ 0.05). ROC curve analysis showed a cut-off value of TLR2 up to 0.98 with sensitivity 71.05 (95%CI = 54.1–84.6) and specificity 63.27 (95%CI = 48.3–76.6) that could distinguish between AR and non-AR group (p ≤ 0.05). The data support that both TLR2 and TLR4 expression have an effective role in AR after liver transplantation and could be used as possible biomarkers for AR to choose better therapeutic strategies based on immunological aspects.

The role of sirtuin 1 on the induction of trained immunity

Sirtuin 1 (SIRT1) has been described to modify immune responses by modulation of gene transcription. As transcriptional reprogramming is the molecular substrate of trained immunity, a de facto innate immune memory, we investigated the role of SIRT1 in the induction of trained immunity. We identified various SIRT1 genetic single nucleotide polymorphisms affecting innate and adaptive cytokine production of human peripheral blood mononuclear cells (PBMCs) in response to various stimuli on the one hand, and in vitro induction of trained immunity on the other hand. Furthermore, inhibition of SIRT1 upregulated pro-inflammatory innate cytokine production upon stimulation of PBMCs. However, inhibition of SIRT1 in vitro had no effect on cytokine responses upon induction of trained immunity, while activation of SIRT1 mildly modified trained immunity responses. In conclusion, SIRT1 modifies innate cytokine production by PBMCs in response to various microbes, but has only a secondary role for BCG and β-glucan-induced trained immunity responses.

Targeted Mitochondrial Therapy With Over-Expressed MAVS Protein From Mesenchymal Stem Cells: A New Therapeutic Approach for COVID-19.

The SARS-CoV-2, the virus that causes COVID-19, has infected millions of people worldwide. The symptoms of this disease are primarily due to pulmonary involvement, uncontrolled tissue inflammation, and inadequate immune response against the invader virus. Impaired interferon (IFN) production is one of the leading causes of the immune system’s inability to control the replication of the SARS-CoV-2. Mitochondria play an essential role in developing and maintaining innate cellular immunity and IFN production. Mitochondrial function is impaired during cellular stress, affecting cell bioenergy and innate immune responses. The mitochondrial antiviral-signaling protein (MAVS), located in the outer membrane of mitochondria, is one of the key elements in engaging the innate immune system and interferon production. Transferring healthy mitochondria to the damaged cells by mesenchymal stem cells (MSCs) is a proposed option for regenerative medicine and a viable treatment approach to many diseases. In addition to mitochondrial transport, these cells can regulate inflammation, repair the damaged tissue, and control the pathogenesis of COVID-19. The immune regulatory nature of MSCs dramatically reduces the probability of an immune rejection. In order to induce an appropriate immune response against the SARS-CoV-2, we hypothesize to donate mitochondria to the host cells of the virus. We consider MSCs as an appropriate biological carrier for mitochondria. Besides, enhancing the expression of MAVS protein in MSCs and promoting the expression of SARS-CoV-2 viral spike protein as a specific ligand for ACE2+ cells will improve IFN production and innate immune responses in a targeted manner.

Balloon cells promote immune system activation in focal cortical dysplasia type 2b.

AimsFocal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells (BCs) in FCD 2b. While pro‐epileptogenic immune system activation and inflammatory responses are commonly detected in both subtypes, it is unknown what contextual role BCs play.MethodsThe present study employed RNA sequencing of surgically resected brain tissue from FCD 2a (n = 11) and FCD 2b (n = 20) patients compared to autopsy control (n = 9) focusing on three immune system processes: adaptive immunity, innate immunity and cytokine production. This analysis was followed by immunohistochemistry on a clinically well‐characterised FCD 2 cohort.ResultsDifferential expression analysis revealed stronger expression of components of innate immunity, adaptive immunity and cytokine production in FCD 2b than in FCD 2a, particularly complement activation and antigen presentation. Immunohistochemical analysis confirmed these findings, with strong expression of leukocyte antigen I and II in FCD 2b as compared to FCD 2a. Moreover, T‐lymphocyte tissue infiltration was elevated in FCD 2b. Expression of markers of immune system activation in FCD 2b was concentrated in subcortical white matter. Lastly, antigen presentation was strongly correlated with BC load in FCD 2b lesions.ConclusionWe conclude that, next to mutation‐driven mTOR activation and seizure activity, BCs are crucial drivers of inflammation in FCD 2b. Our findings indicate that therapies targeting inflammation may be beneficial in FCD 2b.

Transcriptome analysis of primary chicken cells infected with infectious bronchitis virus strain K047-12 isolated in Korea.

Infectious bronchitis virus (IBV), an avian coronavirus, is highly contagious. Chickens with IBV infection develop acute pathogenesis in multiple organs, including the respiratory and urogenital tracts. Frequent recombination in the spike (S) glycoprotein gene has made vaccine strategies ineffective. To understand IBV pathogenesis, we analyzed the genetic distance between Korean IBV isolates and other coronaviruses, including SARS-CoV-2. To obtain comprehensive information about early immune responses such as innate cytokine production and associated immune regulation during IBV infection, we infected primary chicken embryonic kidney cells and performed transcriptome analysis. We observed that the functional pathways of innate immunity are regulated and confirmed expression of genes that coordinate early immune responses. Understanding the immune profile of the host cell may assist in vaccine development.

Peripheral blood basophils are the main source for early interleukin-4 secretion upon in vitro stimulation with Culicoides allergen in allergic horses

Interleukin-4 (IL-4) is a key cytokine secreted by type 2 T helper (Th2) cells that orchestrates immune responses during allergic reactions. Human and mouse studies additionally suggest that basophils have a unique role in the regulation of allergic diseases by providing initial IL-4 to drive T cell development towards the Th2 phenotype. Equine Culicoides hypersensitivity (CH) is a seasonal immunoglobulin E (IgE)-mediated allergic dermatitis in horses in response to salivary allergens from Culicoides (Cul) midges. Here, we analyzed IL-4 production in peripheral blood mononuclear cells (PBMC) of CH affected (n = 8) and healthy horses (n = 8) living together in an environment with natural Cul exposure. During Cul exposure when allergic horses had clinical allergy, IL-4 secretion from PBMC after stimulation with Cul extract was similar between healthy and CH affected horses. In contrast, allergic horses had higher IL-4 secretion from PBMC than healthy horses during months without allergen exposure. In addition, allergic horses had increased percentages of IL-4+ cells after Cul stimulation compared to healthy horses, while both groups had similar percentages of IL-4+ cells following IgE crosslinking. The IL-4+ cells were subsequently characterized using different cell surface markers as basophils, while very few allergen-specific CD4+ cells were detected in PBMC after Cul extract stimulation. Similarly, IgE crosslinking by anti-IgE triggered basophils to produce IL-4 in all horses. PMA/ionomycin consistently induced high percentages of IL-4+ Th2 cells in both groups confirming that T cells of all horses studied were capable of IL-4 production. In conclusion, peripheral blood basophils produced high amounts of IL-4 in allergic horses after stimulation with Cul allergens, and allergic horses also maintained higher basophil percentages throughout the year than healthy horses. These new findings suggest that peripheral blood basophils may play a yet underestimated role in innate IL-4 production upon allergen activation in horses with CH. Basophil-derived IL-4 might be a crucial early signal for immune induction, modulating of immune responses towards Th2 immunity and IgE production.

Induction of Serum Amyloid A3 in Mouse Mammary Epithelial Cells Stimulated with Lipopolysaccharide and Lipoteichoic Acid.

Simple SummarySerum amyloid A (SAA) is an acute phase protein present in mammals and birds. Based on the amino acid sequence, SAA has been classified into isoforms SAA1–4 in mice. Previously, it was reported that after the stimulation with bacterial antigens, the expression of the Saa3 mRNA was induced more strongly than that of the Saa1 mRNA in mouse epithelia, including colonic and alveolar epithelial cells, indicating that SAA3 plays a role in the local response. However, the contribution of SAA3 to the local response in mouse mammary epithelium, where mastitis occurs due to bacterial infection, has not been completely determined yet. In this study, to clarify whether mouse SAA3 has a role in the defense against bacterial infection in mouse mammary epithelium, normal murine mammary gland (NMuMG) epithelial cells were stimulated with lipopolysaccharide (LPS) and lipoteichoic acid (LTA). LPS and LTA significantly enhanced mRNA expression level of the Saa3 gene but not that of Saa1. Furthermore, LPS induced SAA3 protein expression more strongly than LTA. Our data indicate that SAA3 expression in mouse mammary epithelial cells was increased by the stimulation with bacterial antigens, suggesting that SAA3 is involved in the defense against bacterial infection in mouse mammary epithelium.In this study, to establish whether serum amyloid A (SAA) 3 plays a role in the defense against bacterial infection in mouse mammary epithelium, normal murine mammary gland (NMuMG) epithelial cells were stimulated with lipopolysaccharide (LPS) and lipoteichoic acid (LTA). LPS and LTA significantly enhanced mRNA expression level of the Saa3 gene, whereas no significant change was observed in the Saa1 mRNA level. Furthermore, LPS induced SAA3 protein expression more strongly than LTA, whereas neither LPS nor LTA significantly affected SAA1 protein expression. These data indicate that the expression of SAA3 in mouse mammary epithelial cells was increased by the stimulation with bacterial antigens. SAA3 has been reported to stimulate neutrophils in the intestinal epithelium and increase interleukin-22 expression, which induces activation of the innate immune system and production of antibacterial proteins, such as antimicrobial peptides. Therefore, collectively, these data suggest that SAA3 is involved in the defense against bacterial infection in mouse mammary epithelium.

Building back colonic crypts

Mucosal Immunology Restoration of the colonic epithelium after mucosal injury depends on cell renewal initiated by intestinal stem cells (ISCs) and their progeny. Stromal cells near the base of colonic crypts secrete trophic factors for ISCs, but regulation of this process by proinflammatory mediators is not well understood. Cox et al. used mouse models of pathogen- or chemical-induced epithelial damage to investigate the contribution of interleukin-1 (IL-1) and its receptor (IL-1R1) to epithelial restitution. IL-1 release set off a signaling pathway supporting ISC renewal and proliferation and promoted innate lymphoid cell production of IL-22, a cytokine supporting colonocyte proliferation. These findings illustrate the need to consider the desirable regenerative properties of IL-1 when designing therapeutic approaches for chronic inflammatory diseases. Sci. Immunol. 6 , eabe8856 (2021).

Beryllium-specific CD4+ T cells induced by chemokine neoantigens perpetuate inflammation.

Discovering dominant epitopes for T cells, particularly CD4+ T cells, in human immune-mediated diseases remains a significant challenge. Here, we used bronchoalveolar lavage (BAL) cells from HLA-DP2-expressing patients with chronic beryllium disease (CBD), a debilitating granulomatous lung disorder characterized by accumulations of beryllium-specific (Be-specific) CD4+ T cells in the lung. We discovered lung-resident CD4+ T cells that expressed a disease-specific public CDR3β T cell receptor motif and were specific to Be-modified self-peptides derived from C-C motif ligand 4 (CCL4) and CCL3. HLA-DP2-CCL/Be tetramer staining confirmed that these chemokine-derived peptides represented major antigenic targets in CBD. Furthermore, Be induced CCL3 and CCL4 secretion in the lungs of mice and humans. In a murine model of CBD, the addition of LPS to Be oxide exposure enhanced CCL4 and CCL3 secretion in the lung and significantly increased the number and percentage of CD4+ T cells specific for the HLA-DP2-CCL/Be epitope. Thus, we demonstrate a direct link between Be-induced innate production of chemokines and the development of a robust adaptive immune response to those same chemokines presented as Be-modified self-peptides, creating a cycle of innate and adaptive immune activation.

IL-33 promotes innate lymphoid cell-dependent IFN-γ production required for innate immunity to Toxoplasma gondii.

IL-33 is an alarmin required for resistance to the parasite Toxoplasma gondii, but its role in innate resistance to this organism is unclear. Infection with T. gondii promotes increased stromal cell expression of IL-33, and levels of parasite replication correlate with release of IL-33 in affected tissues. In response to infection, a subset of innate lymphoid cells (ILC) emerges composed of IL-33R+ NK cells and ILC1s. In Rag1-/-mice, where NK cells and ILC1 production of IFN-γ mediate innate resistance to T. gondii, the loss of the IL-33R resulted in reduced ILC responses and increased parasite replication. Furthermore, administration of IL-33 to Rag1-/- mice resulted in a marked decrease in parasite burden, increased production of IFN-γ, and the recruitment and expansion of inflammatory monocytes associated with parasite control. These protective effects of exogenous IL-33 were dependent on endogenous IL-12p40 and the ability of IL-33 to enhance ILC production of IFN-γ. These results highlight that IL-33 synergizes with IL-12 to promote ILC-mediated resistance to T. gondii.

The vesicular trafficking system component MIN7 is required for minimizing Fusarium graminearum infection.

Plants have developed intricate defense mechanisms, referred to as innate immunity, to defend themselves against a wide range of pathogens. Plants often respond rapidly to pathogen attack by the synthesis and delivery to the primary infection sites of various antimicrobial compounds, proteins, and small RNA in membrane vesicles. Much of the evidence regarding the importance of vesicular trafficking in plant-pathogen interactions comes from studies involving model plants whereas this process is relatively understudied in crop plants. Here we assessed whether the vesicular trafficking system components previously implicated in immunity in Arabidopsis play a role in the interaction with Fusarium graminearum, a fungal pathogen well-known for its ability to cause Fusarium head blight disease in wheat. Among the analysed vesicular trafficking mutants, two independent T-DNA insertion mutants in the AtMin7 gene displayed a markedly enhanced susceptibility to F. graminearum. Earlier studies identified this gene, encoding an ARF-GEF protein, as a target for the HopM1 effector of the bacterial pathogen Pseudomonas syringae pv. tomato, which destabilizes MIN7 leading to its degradation and weakening host defenses. To test whether this key vesicular trafficking component may also contribute to defense in crop plants, we identified the candidate TaMin7 genes in wheat and knocked-down their expression through virus-induced gene silencing. Wheat plants in which TaMin7 genes were silenced displayed significantly more Fusarium head blight disease. This suggests that disruption of MIN7 function in both model and crop plants compromises the trafficking of innate immunity signals or products resulting in hypersusceptibility to various pathogens.

Probiotics/Prebiotics in Viral Respiratory Infections: Implication for Emerging Pathogens

Viral respiratory infections could result in perturbation of the gut microbiota due to a probable cross-talk between lungs and gut microbiota. This can affect pulmonary health and the gastrointestinal system. This review aimed to discuss the impact of probiotics/prebiotics and supplements on the prevention and treatment of respiratory infections, especially emerging pathogens. The data were searched in PubMed, Scopus, Google Scholar, Google Patents, and The Lens-Patent using keywords of probiotics and viral respiratory infections in the title, abstract, and keywords. Probiotics consumption could decrease the susceptibility to viral respiratory infections, such as COVID-19 and simultaneously enhance vaccine efficiency in infectious disease prevention through the immune system enhancement. Probiotics improve the gut microbiota and the immune system via regulating the innate system response and production of anti-inflammatory cytokines. Moreover, treatment with probiotics contributes to intestinal homeostasis restitution under antibiotic pressure and decreasing the risk of secondary infections due to viral respiratory infections. Probiotics present varied performances in different conditions; thus, promoting their efficacy through combining with supplements (prebiotics, postbiotics, nutraceuticals, berberine, curcumin, lactoferrin, minerals, and vitamins) is important. Several supplements reported to enhance the probiotics' efficacy and their mechanisms as well as probiotics- related patents are summarized in this review. Using nanotechnology and microencapsulation techniques can also improve probiotics' efficiency. Given the global challenge of COVID-19, probiotic/prebiotic and following nutritional guidelines should be regarded seriously. Additionally, their role as an adjuvant in vaccination for immune response augmentation needs attention.

Inhibition of Autophagy Does Not Affect Innate Cytokine Production in Human Lung Epithelial Cells During Respiratory Syncytial Virus Infection.

Human respiratory syncytial virus (RSV) is one of the major causes of childhood acute lower respiratory tract infection worldwide. Autophagy is an intracellular pathway involved in nutrient recycling. Recently, autophagy has been reported to play a role in regulating host cytokine response to several viruses, including vesicular stomatitis virus and human immunodeficiency virus. Previous in vivo studies using mouse model has shown that inhibition of autophagy reduces RSV-induced cytokine production. However, the role of autophagy in modulating RSV-induced cytokine response in human cells has not been reported. We investigated the role of autophagy in regulating the production of the cytokines C-X-C motif ligand 8 (CXCL8) and C-C motif ligand 5 (CCL5), in RSV-infected human bronchial epithelium BEAS-2B cells. Fluorescent microscopic analysis showed that RSV infection induced autophagosome formation in BEAS-2B cells. This autophagy inducing ability of RSV was further confirmed by flow cytometry. The effects of pharmacological inhibition of autophagy by SAR405 or chloroquine on cell death and cytokine release were quantified using lactate dehydrogenase assay and enzyme-linked immunosorbent assay (ELISA), respectively. We found that SAR405 or chloroquine did not cause cell death. Importantly, ELISA analysis showed that pharmacological inhibition of autophagy by SAR405 or chloroquine did not affect the productions of both CXCL5 and CXCL8. In contrast to the previous studies using mouse model, our data suggest that pharmacological inhibition of autophagy may not be a suitable strategy in controlling RSV-induced airway inflammation.