Molecular regulation of NLRP3 inflammasome activation during parasitic infection.

Parasitic diseases are a serious global health concern, causing many common and severe infections, including Chagas disease, leishmaniasis, and schistosomiasis. The NLRP3 inflammasome belongs to the NLR (nucleotide-binding domain leucine-rich-repeat-containing proteins) family, which are cytosolic proteins playing key roles in the detection of pathogens. NLRP3 inflammasomes are activated in immune responses to Plasmodium, Leishmania, Toxoplasma gondii, Entamoeba histolytica, Trypanosoma cruzi, and other parasites. The role of NLRP3 is not fully understood, but it is a crucial component of the innate immune response to parasitic infections and its functions as a sensor triggering the inflammatory response to the invasive parasites. However, while this response can limit the parasites' growth, it can also result in potentially catastrophic host pathology. This makes it essential to understand how NLRP3 interacts with parasites to initiate the inflammatory response. Plasmodium hemozoin, Leishmania glycoconjugate lipophosphoglycan (LPG) and E. histolytica Gal/GalNAc lectin can stimulate NLRP3 activation, while the dense granule protein 9 (GRA9) of T. gondii has been shown to suppress it. Several other parasitic products also have diverse effects on NLRP3 activation. Understanding the mechanism of NLRP3 interaction with these products will help to develop advanced therapeutic approaches to treat parasitic diseases. This review summarizes current knowledge of the NLRP3 inflammasome's action on the immune response to parasitic infections and aims to determine the mechanisms through which parasitic molecules either activate or inhibit its action.

Tuft Cells: Detectors, Amplifiers, Effectors and Targets in Parasite Infection.

Tuft cells have recently emerged as the focus of intense interest following the discovery of their chemosensory role in the intestinal tract, and their ability to activate Type 2 immune responses to helminth parasites. Moreover, they populate a wide range of mucosal tissues and are intimately connected to immune and neuronal cells, either directly or through the release of pharmacologically active mediators. They are now recognised to fulfil both homeostatic roles, in metabolism and tissue integrity, as well as acting as the first sensors of parasite infection, immunity to which is lost in their absence. In this review we focus primarily on the importance of tuft cells in the intestinal niche, but also link to their more generalised physiological role and discuss their potential as targets for the treatment of gastrointestinal disorders.

Natural regulatory T cells increase significantly in pediatric patients with parasitic infections: Flow cytometry study.

Background: The most accepted definition of regulatory T cells (Tregs) relies on the expression of several biomarkers, including CD4, CD25, and transcription factor, Foxp3. The Tregs maintain tolerance to self-antigens and prevent autoimmune diseases. Aim: The purpose of this study was to determine the difference in natural Treg levels in Entamoeba histolytica, Schistosoma mansoni, Giardia lamblia, Enterobius vermicularis, and Hymenolepis nana infected patients. Setting and Design: Fifty-one pediatric subjects (29 males and 22 females) were recruited from a tertiary care hospital, and were divided into infected and non-infected (control) groups. The mean age of the subjects was 8.7 years. Materials and Methods: Blood samples were collected from infected and non-infected groups, and change in the level of Tregs in these subjects was investigated by flow cytometry. Statistical Analysis Used: The statistical analysis of data was performed by SPSS software. Quantitative data used in this study included mean and standard deviation. Data from the two groups were compared by the Student's t-test. The age of the patient and infection status were used for multivariate logistic regression analysis. Odds ratios (ORs) were estimated within a 95% confidence interval, and a P value of <0.05 was considered significant. Results and Conclusions: The levels of natural regulatory T cells, indicated by the biomarkers, CD4+, CD25+, and Foxp3+, increase significantly in patients infected by Entamoeba histolytica, Schistosoma mansoni, Giardia lamblia, Enterobius vermicularis, and Hymenolepis nana as compared to controls. They also increase in cases of mixed infection as compared to infection by a single parasite.

Balancing the functions of DNA extracellular traps in intracellular parasite infections: implications for host defense, disease pathology and therapy.

The release of DNA to the extracellular milieu is a biological process referred to as etosis, which is involved in both physiological and pathological functions. Although the release of DNA extracellular traps (ETs) was initially attributed to innate immune cells such as neutrophils, eosinophils, and macrophages, recent studies have shown that T cells, as well as non-immune cells, are capable of releasing ETs. These structures were described primarily for their potential to trap and kill pathogens, presenting an important strategy of host defense. Intriguingly, these functions have been associated with intracellular pathogens such as the parasites Leishmania sp. and Trypanosoma cruzi, causative agents of leishmaniasis and Chagas disease, respectively. These are two devastating tropical diseases that lead to thousands of deaths every year. In an apparent contradiction, ETs can also induce and amplify inflammation, which may lead to worsening disease pathology. This has prompted the concept of targeting ETs' release as a means of controlling tissue destruction to treat human diseases. What is the best approach to prevent disease severity: inducing ETs to kill pathogens or preventing their release? In this Perspective article, we will discuss the importance of understanding ETs released by different cell types and the need to balance their potentially complementary functions. In addition, we will explore other functions of ETs and their translational applications to benefit individuals infected with intracellular parasites and other pathogens. Ultimately, a better understanding of the role of ETs in disease pathogenesis will provide valuable insights into developing novel therapies for human diseases.

CD4+ T cells regulate sickness-induced anorexia and fat wasting during a chronic parasitic infection.

Infections cause catabolism of fat and muscle stores. Traditionally, studies have focused on understanding how the innate immune system contributes to energy stores wasting, while the role of the adaptive immune system remains elusive. In the present study, we examine the role of the adaptive immune response in adipose tissue wasting and cachexia using a murine model of the chronic parasitic infection Trypanosoma brucei, the causative agent of sleeping sickness. We find that the wasting response occurs in two phases, with the first stage involving fat wasting caused by CD4+ T cell-induced anorexia and a second anorexia-independent cachectic stage that is dependent on CD8+ T cells. Fat wasting has no impact on host antibody-mediated resistance defenses or survival, while later-stage muscle wasting contributes to disease-tolerance defenses. Our work reveals a decoupling of adaptive immune-mediated resistance from the catabolic response during infection.

Basophils beyond allergic and parasitic diseases.

Basophils bind IgE via FcεRI-αßγ2, which they uniquely share only with mast cells. In doing so, they can rapidly release mediators that are hallmark of allergic disease. This fundamental similarity, along with some morphological features shared by the two cell types, has long brought into question the biological significance that basophils mediate beyond that of mast cells. Unlike mast cells, which mature and reside in tissues, basophils are released into circulation from the bone marrow (constituting 1% of leukocytes), only to infiltrate tissues under specific inflammatory conditions. Evidence is emerging that basophils mediate non-redundant roles in allergic disease and, unsuspectingly, are implicated in a variety of other pathologies [e.g., myocardial infarction, autoimmunity, chronic obstructive pulmonary disease, fibrosis, cancer, etc.]. Recent findings strengthen the notion that these cells mediate protection from parasitic infections, whereas related studies implicate basophils promoting wound healing. Central to these functions is the substantial evidence that human and mouse basophils are increasingly implicated as important sources of IL-4 and IL-13. Nonetheless, much remains unclear regarding the role of basophils in pathology vs. homeostasis. In this review, we discuss the dichotomous (protective and/or harmful) roles of basophils in a wide spectrum of non-allergic disorders.

Effect of parasitic infection on muscular function of dystrophin gene (Dmd) deficient mouse.

BACKGROUND: Previous studies have reported many cases of Trichinella spiralis (T. spiralis) infection in normal skeletal muscle but there is little research on T. spiralis infection in abnormal muscle tissue. OBJECTIVE: To identify the effect of T. spiralis infection on muscular dystrophy, this study compared aspects of infection between normal (C57BL/10) and dystrophin-deficient Duchenne muscular dystrophy (DMD) mdx mice. METHOD: Infection rate was found to be lower in mdx mice than in C57BL/10 mice at early stages of infection; however, infection and inflammation in mdx mice persisted at later stages of infection while the infection rate and inflammation in C57BL/10 mice decreased gradually. The inflammation area was proportional to the degree of infection in both groups. Muscle strength was measured by the time of latency to fall in the wire-hanging test. Hanging time was shorter in the infected group than in the uninfected group in both C57BL/10 and mdx mice. RESULTS: Muscle strength was also reduced in mdx mice compared with C57BL/10 mice in both the un-infected and infected groups. The muscle intracellular cytokines TGF-ß and IL-6 were continuously expressed from early stage to late-stage infection. IL-10 was strongly expressed at the early stage of infection but decreased as the infection progressed. TNF-α expression remained stable from early to late-stage infection in mdx mice, while TNF-α was elevated only during early-stage infection in C57BL/10 mice. The degree of muscle damage was significantly higher in mdx mice than in C57BL/10 mice because of the high level of serum creatine kinase (CK). CONCLUSION: These results suggest that mdx mice continued in infection and inflammation until the late stages of disease, which was in contrast to the C57BL/10 mice that recovered to some extent in the late stage of infection. In addition, that dystrophin-deficient mice are not suitable for T. spiralis infection compared to normal mice, and the degree of inflammation may be worse in mdx mice.

Immune Cell-Derived Extracellular Vesicles in the Face of Pathogenic Infections.

Extracellular Vesicles (EVs) are a collection of vesicles released from cells that play an important role in intercellular communication. Microbial infections are known as one of the major problems in the medical field. Considering the increasing resistance of strains to routine drug treatments, the need for new therapies seems to be more than ever. Recent studies have shown that the EVs released from immune cells during microbial infections had anti-microbial effects or were able to induce neighbouring cells to display anti-microbial effects. This mini-review aimed to explore the latest studies on immune cell-derived EVs in viral, bacterial, fungal, and parasitic infections. Review of the literature demonstrated that specific cargos in EVs were involved in the fight against pathogenic infections. Additionally, the transport of appropriate bioactive molecules including miRNAs, mRNAs, and proteins via EVs could mediate the anti-microbial process. Thus, it could be a proof-of-principle that therapeutic approaches based on EVs derived from immune cells could offer a promising path forward, which is still in early stages and needs further assessments.

Lactate cross-talk in host-pathogen interactions.

Lactate is the main product generated at the end of anaerobic glycolysis or during the Warburg effect and its role as an active signalling molecule is increasingly recognised. Lactate can be released and used by host cells, by pathogens and commensal organisms, thus being essential for the homeostasis of host-microbe interactions. Infection can alter this intricate balance, and the presence of lactate transporters in most human cells including immune cells, as well as in a variety of pathogens (including bacteria, fungi and complex parasites) demonstrates the importance of this metabolite in regulating host-pathogen interactions. This review will cover lactate secretion and sensing in humans and microbes, and will discuss the existing evidence supporting a role for lactate in pathogen growth and persistence, together with lactate's ability to impact the orchestration of effective immune responses. The ubiquitous presence of lactate in the context of infection and the ability of both host cells and pathogens to sense and respond to it, makes manipulation of lactate a potential novel therapeutic strategy. Here, we will discuss the preliminary research that has been carried out in the context of cancer, autoimmunity and inflammation.

Tumor suppressor p53 regulates intestinal type 2 immunity.

The role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca2+ influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.

Immunometabolism: Towards a Better Understanding the Mechanism of Parasitic Infection and Immunity.

As a relatively successful pathogen, several parasites can establish long-term infection in host. This "harmonious symbiosis" status relies on the "precise" manipulation of host immunity and metabolism, however, the underlying mechanism is still largely elusive. Immunometabolism is an emerging crossed subject in recent years. It mainly discusses the regulatory mechanism of metabolic changes on reprogramming the key transcriptional and post-transcriptional events related to immune cell activation and effect, which provides a novel insight for understanding how parasites regulate the infection and immunity in hosts. The present study reviewed the current research progress on metabolic reprogramming mechanism exploited by parasites to modulate the function in various immune cells, highlighting the future exploitation of key metabolites or metabolic events to clarify the underlying mechanism of anti-parasite immunity and design novel intervention strategies against parasitic infection.

The Autophagy Machinery in Human-Parasitic Protists; Diverse Functions for Universally Conserved Proteins.

Autophagy is a eukaryotic cellular machinery that is able to degrade large intracellular components, including organelles, and plays a pivotal role in cellular homeostasis. Target materials are enclosed by a double membrane vesicle called autophagosome, whose formation is coordinated by autophagy-related proteins (ATGs). Studies of yeast and Metazoa have identified approximately 40 ATGs. Genome projects for unicellular eukaryotes revealed that some ATGs are conserved in all eukaryotic supergroups but others have arisen or were lost during evolution in some specific lineages. In spite of an apparent reduction in the ATG molecular machinery found in parasitic protists, it has become clear that ATGs play an important role in stage differentiation or organelle maintenance, sometimes with an original function that is unrelated to canonical degradative autophagy. In this review, we aim to briefly summarize the current state of knowledge in parasitic protists, in the light of the latest important findings from more canonical model organisms. Determining the roles of ATGs and the diversity of their functions in various lineages is an important challenge for understanding the evolutionary background of autophagy.

A Mitocentric View of the Main Bacterial and Parasitic Infectious Diseases in the Pediatric Population.

Infectious diseases occur worldwide with great frequency in both adults and children. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins to the complexes of the electron transport chain, (ii) mitochondrial genome (depletion, deletions, and point mutations) and mitochondrial dynamics (fusion and fission), (iii) membrane potential, (iv) apoptotic regulation, (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with great impact on children's quality of life, even resulting in death. As such, bacterial agents are frequently associated with loss of mitochondrial membrane potential and cytochrome c release, ultimately leading to mitochondrial apoptosis by activation of caspases-3 and -9. Using Rayyan QCRI software for systematic reviews, we explore the association between mitochondrial alterations and pediatric infections including (i) bacterial: M. tuberculosis, E. cloacae, P. mirabilis, E. coli, S. enterica, S. aureus, S. pneumoniae, N. meningitidis and (ii) parasitic: P. falciparum. We analyze how these pediatric infections and their treatments may lead to mitochondrial deterioration in this especially vulnerable population, with the intention of improving both the understanding of these diseases and their management in clinical practice.

Pathomechanisms in the Kidneys in Selected Protozoan Parasitic Infections.

Leishmaniasis, malaria, toxoplasmosis, and acanthamoebiasis are protozoan parasitic infections. They remain important contributors to the development of kidney disease, which is associated with increased patients' morbidity and mortality. Kidney injury mechanisms are not fully understood in protozoan parasitic diseases, bringing major difficulties to specific therapeutic interventions. The aim of this review is to present the biochemical and molecular mechanisms in kidneys infected with Leishmania spp., Plasmodium spp., Toxoplasma gondii, and Acanthamoeba spp. We present available mechanisms of an immune response, oxidative stress, apoptosis process, hypoxia, biomarkers of renal injury in the serum or urine, and the histopathological changes of kidneys infected with the selected parasites. Pathomechanisms of Leishmania spp. and Plasmodium spp. infections have been deeply investigated, while Toxoplasma gondii and Acanthamoeba spp. infections in the kidneys are not well known yet. Deeper knowledge of kidney involvement in leishmaniasis and malaria by presenting their mechanisms provides insight into how to create novel and effective treatments. Additionally, the presented work shows gaps in the pathophysiology of renal toxoplasmosis and acanthamoebiasis, which need further research.

Exploiting the pro-resolving actions of glucocorticoid-induced proteins Annexin A1 and GILZ in infectious diseases.

For decades, glucocorticoids (GC) have been used to treat several inflammatory conditions, including chronic and autoimmune diseases, due to their potent anti-inflammatory properties. In the context of infectious diseases, the use of GCs may be effective as adjuvant to antibiotic therapy by controlling excessive inflammatory responses resulting in better outcome in some cases. However, the use of GCs has been associated with a vast number of side effects, including increased probability of immunosuppression and consequent risk of opportunistic infection. Glucocorticoid-induced leucine zipper (GILZ) and Annexin A1 (AnxA1) are GC-induced proteins intrinsically involved with the anti-inflammatory functions of GCs without the associated adverse metabolic effects. Recent studies have shown that these GC-proteins exhibit pro-resolving effects. An essential characteristic of pro-resolving molecules is their ability to coordinate the resolution of inflammation and promote host defense in most experimental models of infection. Although the role of GILZ and AnxA1 in the context of infectious diseases remain to be better explored, herein we provide an overview of the emerging functions of these GC-proteins obtained from pre-clinical models of infectious diseases.

Neurological Infection, Kynurenine Pathway, and Parasitic Infection by Neospora caninum.

Neuroinflammation is one of the most frequently studied topics of neurosciences as it is a common feature in almost all neurological disorders. Although the primary function of neuroinflammation is to protect the nervous system from an insult, the complex and sequential response of activated glial cells can lead to neurological damage. Depending on the type of insults and the time post-insult, the inflammatory response can be neuroprotective, neurotoxic, or, depending on the glial cell types, both. There are multiple pathways activated and many bioactive intermediates are released during neuroinflammation. One of the most common one is the kynurenine pathway, catabolizing tryptophan, which is involved in immune regulation, neuroprotection, and neurotoxicity. Different models have been used to study the kynurenine pathway metabolites to understand their involvements in the development and maintenance of the inflammatory processes triggered by infections. Among them, the parasitic infection Neospora caninum could be used as a relevant model to study the role of the kynurenine pathway in the neuroinflammatory response and the subset of cells involved.

The Roles of Type I Interferon in Co-infections With Parasites and Viruses, Bacteria, or Other Parasites.

Parasites, bacteria, and viruses pose serious threats to public health. Many parasite infections, including infections of protozoa and helminths, can inhibit inflammatory responses and impact disease outcomes caused by viral, bacterial, or other parasitic infections. Type I interferon (IFN-I) has been recognized as an essential immune effector in the host defense against various pathogens. In addition, IFN-I responses induced by co-infections with different pathogens may vary according to the host genetic background, immune status, and pathogen burden. However, there is only limited information on the roles of IFN-I in co-infections with parasites and viruses, bacteria, or other parasites. This review summarizes some recent findings on the roles of IFN-I in co-infections with parasites, including Leishmania spp., Plasmodium spp., Eimeria maxima, Heligmosomoides polygyrus, Brugia malayi, or Schistosoma mansoni, and viruses or bacteria and co-infections with different parasites (such as co-infection with Neospora caninum and Toxoplasma gondii, and co-infection with Plasmodium spp. and H. polygyrus). The potential mechanisms of host responses associated with co-infections, which may provide targets for immune intervention and therapies of the co-infections, are also discussed.

The role of MUC2 mucin in intestinal homeostasis and the impact of dietary components on MUC2 expression.

MUC2 mucin is an important secretory protein found in the human gut. Recent studies indicated that MUC2 mucin plays a role in the protection of gut barrier, the regulation of microbiome homeostasis and the prevention of diseases. In this review, the physiological properties of MUC2 mucin and its interactions with the intestinal microbiome are firstly discussed. Its roles in intestinal diseases including inflammatory bowel disease, colorectal cancer and parasitic infections are concluded. We also reviewed dietary components known to have modulative effects on MUC2 mucin expression, such as polysaccharides, amino acids and polyphenols.