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Airway epithelial cells, which lines the respiratory mucosa is in direct contact with the environment. Airway epithelial cells are the primary target for rhinovirus and other inhaled pathogens. In response to rhinovirus infection, airway epithelial cells mount both pro-inflammatory responses and antiviral innate immune responses to clear the virus efficiently. Some of the antiviral responses include the expression of IFNs, endoplasmic reticulum stress induced unfolded protein response and autophagy. Airway epithelial cells also recruits other innate immune cells to establish antiviral state and resolve the inflammation in the lungs. In patients with chronic lung disease, these responses may be either defective or induced in excess leading to deficient clearing of virus and sustained inflammation. In this review, we will discuss the mechanisms underlying antiviral innate immunity and the dysregulation of some of these mechanisms in patients with chronic lung diseases.

Toxoplasma gondii is a worldwide prevalent parasite. The infection has been linked to variable inflammatory effects including neuroinflammation. Biochanin A (BCA) is an isoflavone, known for its anti-inflammatory and anti-oxidative properties. In this study, we examined the effect of BCA on the brain and liver inflammatory lesions in a murine model with chronic toxoplasmosis. Mice were divided in to six groups: non-infected control, non-infected BCA-treated, and four infected groups with Toxoplasmagondii Me49-type II cystogenic strain: infected control, BCA (50 mg/kg/day)-treated, combined BCA/cotrimoxazole-treated and cotrimoxazole (370 mg/kg/day) alone-treated. Gene expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS) was evaluated by quantitative real-time PCR in the brain and liver tissues. In the infected control group, an upregulation of TNF-α and IL-1β mRNA expression levels was found. However, a downregulation of iNOS expression was detected in the brain of infected control mice. In both BCA- and combined-treated groups, the brain and liver tissues showed significantly reduced inflammatory lesions compared to the infected control mice with inhibited TNF-α and IL-1β mRNA levels. The iNOS expression levels in the brain tissues of BCA group were significantly higher than the levels of the infected control group. BCA alone or combined significantly reduced T. gondii cyst count in the brain tissues. In conclusion, the anti-inflammatory activity of BCA was demonstrated in the brain tissues of mice with chronic toxoplasmosis with decreased TNF-α and IL-1β expression levels and increased iNOS expression levels.

Schistosomes are parasitic platyhelminths that currently infect >200 million people globally. The adult worms can live within the vasculature of their hosts for many years where they acquire all nutrients necessary for their survival and growth. In this work we focus on how Schistosoma mansoni parasites acquire and metabolize vitamin B6, whose active form is pyridoxal phosphate (PLP). We show here that live intravascular stage parasites (schistosomula and adult males and females) can cleave exogenous PLP to liberate pyridoxal. Of the three characterized nucleotide-metabolizing ectoenzymes expressed at the schistosome surface (SmAP, SmNPP5, and SmATPDase1), only SmAP hydrolyzes PLP. Heat-inactivated recombinant SmAP can no longer cleave PLP. Further, parasites whose SmAP gene has been suppressed by RNAi are significantly impaired in their ability to cleave PLP compared to controls. When schistosomes are incubated in murine plasma, they alter its metabolomic profile—the levels of both pyridoxal and phosphate increase over time, a finding consistent with the action of host-exposed SmAP acting on PLP. We hypothesize that SmAP-mediated dephosphorylation of PLP generates a pool of pyridoxal around the worms that can be conveniently taken in by the parasites to participate in essential, vitamin B6-driven metabolism. In addition, since host PLP‐dependent enzymes play active roles in inflammatory processes, parasite-mediated cleavage of this metabolite may serve to limit parasite-damaging inflammation. In this work we also identified schistosome homologs of enzymes that are involved in intracellular vitamin B6 metabolism. These are pyridoxal kinase (SmPK) as well as pyridoxal phosphate phosphatase (SmPLP-Ph) and pyridox(am)ine 5’-phosphate oxidase (SmPNPO) and cDNAs encoding these three enzymes were cloned and sequenced. The three genes encoding these enzymes all display high relative expression in schistosomula and adult worms suggestive of robust vitamin B6 metabolism in the intravascular life stages.

Schistosomes are parasitic flatworms that infect the vasculature of >200 million people around the world. These long-lived parasites do not appear to provoke blood clot formation or obvious inflammation around them . Proteins expressed at the host-parasite interface (such as alkaline phosphatase, SmAP) are likely key to these abilities. SmAP is a glycoprotein that hydrolyses the artificial substrate -nitrophenyl phosphate in a reaction that requires Mg and at an optimal pH of 9. SmAP additionally cleaves the nucleoside monophosphates AMP, CMP, GMP, and TMP, all with a similar Km (~600-650 μM). Living adult worms, incubated in murine plasma for 1 h, alter the plasma metabolome; a decrease in sphingosine-1-phosphate (S1P) is accompanied by an increase in the levels of its component parts-sphingosine and phosphate. To test the hypothesis that schistosomes can hydrolyze S1P (and not merely recruit or activate a host plasma enzyme with this function), living intravascular life-stage parasites were incubated with commercially obtained S1P and cleavage of S1P was detected. Parasites whose SmAP gene was suppressed using RNAi were impaired in their ability to cleave S1P compared to controls. In addition, recombinant SmAP hydrolyzed S1P. Since extracellular S1P plays key roles in controlling inflammation and platelet aggregation, we hypothesize that schistosome SmAP, by degrading S1P, can regulate the level of this bioactive lipid in the environment of the parasites to control these processes in the worm's local environment. This is the first report of any parasite being able to cleave S1P.

Schistosomes (blood flukes) can survive in the bloodstream of their hosts for many years. We hypothesize that proteins on their host-interactive surface impinge on host biochemistry to help ensure their long-term survival. Here, we focus on a surface ectoenzyme of Schistosoma mansoni, designated SmNPP5. This ~53 kDa glycoprotein is a nucleotide pyrophosphatase/phosphodiesterase that has been previously shown to: (1) cleave adenosine diphosphate (ADP) and block platelet aggregation; and (2) cleave nicotinamide adenine dinucleotide (NAD) and block NAD-induced T cell apoptosis in vitro. T cell apoptosis can additionally be driven by extracellular adenosine triphosphate (ATP). In this work, we show that adult S. mansoni parasites can inhibit this process. Further, we demonstrate that recombinant SmNPP5 alone can both cleave ATP and impede ATP-induced T cell killing. As immunomodulatory regulatory T cells (Tregs) are especially prone to the induction of these apoptotic pathways, we hypothesize that the schistosome cleavage of both NAD and ATP promotes Treg survival and this helps to create a less immunologically hostile environment for the worms in vivo.

The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL-11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing–remitting multiple sclerosis (RRMS) have an increased frequency of IL-11⁺ monocytes, IL-11⁺ and IL-11R⁺ CD4⁺ lymphocytes, and IL-11R⁺ neutrophils in comparison to matched healthy controls. IL-11⁺ and granulocyte-macrophage colony-stimulating factor (GM-CSF)⁺ monocytes, CD4⁺ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single-cell RNA sequencing, revealed the highest number of differentially expressed genes in classical monocytes, including up-regulated NFKB1, NLRP3, and IL1B. All CD4⁺ cell subsets had increased expression of S100A8/9 alarmin genes involved in NLRP3 inflammasome activation. In IL-11R⁺-sorted cells from the CSF, classical and intermediate monocytes significantly up-regulated the expression of multiple NLRP3 inflammasome–related genes, including complement, IL18, and migratory genes (VEGFA/B) in comparison to blood-derived cells. Therapeutic targeting of this pathway with αIL-11 mAb in mice with RR experimental autoimmune encephalomyelitis (EAE) decreased clinical scores, CNS inflammatory infiltrates, and demyelination. αIL-11 mAb treatment decreased the numbers of NFκBp65⁺, NLRP3⁺, and IL-1β⁺ monocytes in the CNS of mice with EAE. The results suggest that IL-11/IL-11R signaling in monocytes represents a therapeutic target in RRMS.

Purpose The autophagy process is critical for cell survival, homeostasis, and functions. Autophagy deregulation was linked to several liver diseases; however, little is known about autophagy status during schistosomiasis and praziquantel (PZQ) treatment. This study is exploring autophagy status during schistosomiasis and praziquantel treatment in the hepatocytes, macrophages, and hepatic stellate cells (HSCs) in mice, and linking the variations in these levels to the parasitic parameters. Methods CD-1 Swiss female albino mice were allocated into three groups: negative control, Schistosoma mansoni ( S. mansoni )-infected, and the third group was S. mansoni- infected and treated with PZQ. Liver sections were stained for autophagy markers (LC3 and P62) by immunohistochemistry. Results At 12 weeks post infection, P62 increased in S. mansoni -infected mice in hepatocytes, macrophages, and HSCs compared to negative controls ( P  = 0.038, P  < 0.001, P  = 0.004, respectively) and decreased in PZQ-treated group compared to S. mansoni -infected mice in hepatocytes and macrophages only ( P  < 0.001, P  = 0.004, respectively). LC3 displayed higher levels in S. mansoni- infected mice compared to negative controls in hepatocytes, macrophages, and HSCs ( P  = 0.01, P  < 0.001, P  < 0.001, respectively), while in PZQ-treated group, it decreased in macrophages and HSCs compared to S. mansoni -infected mice ( P  = 0.016, P  < 0.001, respectively). Correlations were found between the number of eggs and autophagy status, mostly in HSCs. Conclusion Schistosomiasis inhibits autophagy in hepatocytes, macrophages, and HSCs, while PZQ treatment reverses autophagy levels in hepatocytes and macrophages, but not in HSCs. More research is needed to understand the autophagy behavior in HSCs during different stages of schistosomiasis to promote development of autophagy-based anti-fibrotic drugs.

T Regulatory T cells (Tregs) from patients with relapsing-remitting multiple sclerosis (RRMS) exhibit impaired suppressive function, yet the underlying molecular mechanisms remain elusive. Single-cell RNA sequencing (scRNAseq) of sorted Tregs from RRMS patients and matched healthy controls (HCs) revealed down-regulation of type I IFN (IFN) and IL-27 signaling pathways in RRMS Tregs. These Tregs showed reduced expression of IFN-stimulated genes (ISGs) ( ), as well as key mediators of Treg suppressive function ( ), all suggesting a key role of decreased IFN signaling in RRMS Treg dysfunction. To therapeutically target IFN signaling pathways and improve Treg suppressive functions, we used cGAMP-loaded microparticles (MPs) to activate the stimulator of IFN genes (STING) in experimental autoimmune encephalomyelitis (EAE). cGAMP-MP treatment ameliorated EAE via induction of Tregs expressing IL-27R, IL-10, TGF-b, and Granzyme B. This effect was abolished in Treg-specific IL-27R (Treg ) knockout mice, confirming that IL-27 signaling is essential for Treg suppression. IL-27 stimulation of RRMS-derived Tregs restored expression of IFN pathway genes ( ) and Treg suppressive genes ( ). Thus, we propose that IL-27 pre-stimulation may restore their suppressive function and migration (via and ) to the central nervous system (CNS) in future clinical trials.