Bone marrow-derived mesenchymal stem cell ameliorates post-stroke enterobacterial translocation through liver-gut axis.

BACKGROUND: Enterobacterial translocation is a leading contributor to fatal infection among patients with acute ischaemic stroke (AIS). Accumulative evidence suggests that mesenchymal stem cell (MSC) effectively ameliorates stroke outcomes. Whether MSC could inhibit post-stroke enterobacterial translocation remains elusive. METHODS: Patients with AIS and healthy individuals were enrolled in the study. Mice subjected to transient middle cerebral artery occlusion were treated with bone marrow-derived MSC (BM-MSC) right after reperfusion. Enterobacterial translocation was evaluated with Stroke Dysbiosis Index and circulating endotoxin. Thickness of mucus was assessed with Alcian blue staining. Hepatic glucocorticoid (GC) metabolism was analysed with expression of HSD11B2, HSD11B1 and SRD5A1. RESULTS: We report that the gut mucus layer was attenuated after the stroke leading to pronounced enterobacterial translocation. The attenuation of the gut mucus was attributed to diminished mucin production by goblet cells in response to the elevated systemic GC after cerebral ischaemia. Transferred-BM-MSC restored the mucus thickness, thus preserving gut microbiota homeostasis and preventing enterobacterial invasion. Mechanistically, the transferred-BM-MSC stationed in the liver and enhanced peroxisome proliferator-activated receptor γ signalling in hepatocytes. Consequently, expression of HSD11B2 and SRD5A1 was increased while HSD11B1 expression was downregulated which promoted GC catabolism and subsequently restored mucin production. CONCLUSIONS: Our findings reveal that MSC transfer improves post-stroke gut barrier integrity and inhibits enterobacterial translocation by enhancing the hepatic GC metabolism thus representing a protective modulator of the liver-gut-brain axis in AIS.

Astrocyte-derived clusterin disrupts glial physiology to obstruct remyelination in mouse models of demyelinating diseases.

Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models.

Chronic Stress Exacerbates Cerebral Amyloid Angiopathy Through Promoting Neutrophil Extracellular Traps Formation.

Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in cerebral amyloid angiopathy patients but are usually considered as consequences of cerebral amyloid angiopathy pathology. Here, it is reported that chronic stress promotes cerebral amyloid angiopathy progression, which enhances deposition of amyloid protein beta (Aß) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in cerebral amyloid angiopathy development. Aß that accumulates in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET-dependent angiopathy. It is demonstrated that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate cerebral amyloid angiopathy severity in the context of chronic stress. Therefore, it is proposed that stress-associated psychological disorders and NETs are promising therapeutic targets in cerebral amyloid angiopathy.

Probiotics-regulated lithocholic acid suppressed B-cell differentiation in neuromyelitis optica spectrum disorder.

Intestinal microbes play a crucial role in gut health and the immune-mediated central nervous system through the "gut-brain" axis. However, probiotic safety and efficacy in Neuromyelitis optica spectrum disorder (NMOSD) are not well-explored. A pilot clinic trial for NMOSD with probiotic intervention revealed alterations in the microbiota (increased Anaerostipes, Bacteroides; decreased Granulicatella, Streptococcus, Rothia). Metabolite analysis showed elevated 2-methylbutyric and isobutyric acids, reduced lithocholic acid (LCA), and glycodeoxycholic acid (GDCA). Immune markers Interleukin (IL-7), vascular endothelial growth factor (VEGF-A), and B lymphocyte chemoattractant (BLC) decreased, while plasma cells and transitional B cells increased post-probiotics, suggesting potential immunomodulatory effects on NMOSD.

A comparative study of hypothalamic involvement in patients with myelin oligodendrocyte glycoprotein antibody-associated disease, neuromyelitis optica spectrum disorder, and multiple sclerosis.

BACKGROUND AND PURPOSE: We aimed to characterize hypothalamic involvement in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and compare it with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). METHODS: A retrospective study was performed to identify hypothalamic lesions in patients diagnosed with MOGAD, NMOSD, or MS from January 2013 to May 2020. The demographic, clinical, and radiological features were recorded. Hypothalamic dysfunction and prognosis were assessed through physical examination, biochemical testing, sleep monitoring, and magnetic resonance imaging. RESULTS: Hypothalamic lesions were observed in seven of 96 patients (7.3%) with MOGAD, 34 of 536 (6.3%) with NMOSD, and 16 of 356 (4.5%) with MS (p = 0.407). The time from disease onset to development of hypothalamic lesions was shortest in MOGAD (12 months). The frequency of bilateral hypothalamic lesions was the lowest in MOGAD (p = 0.008). The rate of hypothalamic dysfunction in MOGAD was 28.6%, which was lower than that in NMOSD (70.6%) but greater than that in MS patients (18.8%; p = 0.095 and p = 0.349, respectively). Hypothalamic dysfunction in MOGAD manifests as hypothalamic-pituitary-adrenal axis dysfunction and hypersomnia. The proportion of complete regression of hypothalamic lesions in MOGAD (100%) was much greater than that in NMOSD (41.7%) and MS patients (18.2%; p = 0.007 and p = 0.001, respectively). An improvement in hypothalamic dysfunction was observed in all MOGAD patients after immunotherapy. CONCLUSIONS: MOGAD patients have a relatively high incidence of asymptomatic hypothalamic lesions. The overall prognosis of patients with hypothalamic involvement is good in MOGAD, as the lesions completely resolve, and dysfunction improves after immunotherapy.

Teriflunomide Promotes Blood-Brain Barrier Integrity by Upregulating Claudin-1 via the Wnt/ß-catenin Signaling Pathway in Multiple Sclerosis.

The blood-brain barrier (BBB) and tight junction (TJ) proteins maintain the homeostasis of the central nervous system (CNS). The dysfunction of BBB allows peripheral T cells infiltration into CNS and contributes to the pathophysiology of multiple sclerosis (MS). Teriflunomide is an approved drug for the treatment of MS by suppressing lymphocytes proliferation. However, whether teriflunomide has a protective effect on BBB in MS is not understood. We found that teriflunomide restored the injured BBB in the EAE model. Furthermore, teriflunomide treatment over 6 months improved BBB permeability and reduced peripheral leakage of CNS proteins in MS patients. Teriflunomide increased human brain microvascular endothelial cell (HBMEC) viability and promoted BBB integrity in an in vitro cell model. The TJ protein claudin-1 was upregulated by teriflunomide and responsible for the protective effect on BBB. Furthermore, RNA sequencing revealed that the Wnt signaling pathway was affected by teriflunomide. The activation of Wnt signaling pathway increased claudin-1 expression and reduced BBB damage in cell model and EAE rats. Our study demonstrated that teriflunomide upregulated the expression of the tight junction protein claudin-1 in endothelial cells and promoted the integrity of BBB through Wnt signaling pathway.

Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model.

Accumulation of amyloid beta protein (Aß) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aß and produce disease-modifying mediators. Herein, we report that Aß40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.

Bone Marrow Mesenchymal Stem Cell-Derived Dermcidin-Containing Migrasomes enhance LC3-Associated Phagocytosis of Pulmonary Macrophages and Protect against Post-Stroke Pneumonia.

Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post-stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM-MSC) downregulate bacterial load in the lungs of stroke mice models. RNA-sequencing of the lung from BM-MSC-treated stroke models indicates that BM-MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM-MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration-dependent extracellular vesicles. With liquid chromatography-tandem mass spectrometry (LC-MS/MS), the result shows that BM-MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3-associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM-MSC is a promising therapeutic candidate against post-stroke pneumonia, with dual functions of anti-infection and immunol modulation, which is more than a match for antibiotics treatment.

Targeting L-Selectin Lymphocytes to Deliver Immunosuppressive Drug in Lymph Nodes for Durable Multiple Sclerosis Treatment.

Inflammation induced by autoreactive CD4+ T lymphocytes is a major factor in the pathogenesis of multiple sclerosis (MS). Immunosuppressive drugs, such as FTY720, are subsequently developed to prevent the migration of CD4+ T lymphocytes to the central nervous system (CNS). However, these immunosuppressive drugs have limited accumulation in lymph nodes (LNs), resulting in poor efficacy. Here, this work develops a nanoplatform for delivering immunosuppressive drugs to LNs for durable MS treatment. Human CD47 peptide and L-selectin targeting aptamer are modified on the nanoparticles encapsulated with FTY720 (clnFTY) for self-passivation and the targeting of L-selectin on lymphocytes, a homing receptor for T-cells entering LNs. Using this natural process, clnFTY nanoparticles efficiently deliver FTY720 to LNs and delay disease progression in experimental autoimmune encephalomyelitis (EAE) mice following a single dose treatment over a 42-day observational period. Considering the daily dosing requirement of FTY720, this strategy greatly improves its therapeutic efficiency. The ability of clnFTY nanoparticles to target lymphocytes, reduce sphingosine-1-phosphate receptor 1 (S1PR1) expression, and suppress inflammatory cytokines release are demonstrated in clinical blood samples from MS patients. Taken together, this study demonstrates that targeted LNs delivery may greatly extend the treatment cycle of immunosuppressive drugs for durable MS treatment.

FOXP3+ macrophage represses acute ischemic stroke-induced neural inflammation.

Proper termination of cell-death-induced neural inflammation is the premise of tissue repair in acute ischemic stroke (AIS). Macrophages scavenge cell corpses/debris and produce inflammatory mediators that orchestrate immune responses. Here, we report that FOXP3, the key immune-repressive transcription factor of Tregs, is conditionally expressed in macrophages in stroke lesion. FOXP3 ablation in macrophages results in detrimental stroke outcomes, emphasizing the beneficial role of FOXP3+ macrophages. FOXP3+ macrophages are distinct from the M1 or M2 subsets and display superactive efferocytic capacity. With scRNAseq and analysis of FOXP3-bound-DNA isolated with CUT & RUN, we show that FOXP3 facilitates macrophage phagocytosis through enhancing cargo metabolism. FOXP3 expression is controlled by macroautophagic/autophagic protein degradation in resting macrophages, while initiation of LC3-associated phagocytosis (LAP) competitively occupies the autophagic machineries, and thus permits FOXP3 activation. Our data demonstrate a distinct set of FOXP3+ macrophages with enhanced scavenging capability, which could be a target in immunomodulatory therapy against AIS.Abbreviations: ADGRE1/F4/80: adhesion G protein-coupled receptor E1; AIF1/Iba1: allograft inflammatory factor 1; AIS: acute ischemic stroke; ARG1: arginase 1; ATP: adenosine triphosphate; BECN1/Beclin1: Beclin 1, autophagy related; BMDM: bone marrow-derived macrophages; CKO: conditional knockout; CSF1/M-CSF: colony stimulating factor 1 (macrophage); CSF2/GM-CSF: colony stimulating factor 2; CSF3/G-CSF: colony stimulating factor 3; CUT & RUN: cleavage under targets and release using nuclease; CyD: cytochalasin D; DAMP: danger/damage-associated molecular pattern; DIL: dioctadecyl-3,3,3,3-tetramethylin docarbocyanine; ELISA: enzyme linked immunosorbent assay; GO: Gene Ontology; FCGR3/CD16: Fc receptor, IgG, low affinity III; HMGB1: high mobility group box 1; IFNG/IFNγ: interferon gamma; IP: immunoprecipitation; KEGG: Kyoto Encyclopedia of Genes and Genomes; ITGAM/CD11b: integrin subunit alpha M; ITGAX/CD11c: integrin subunit alpha X; LAP: LC3-associated phagocytosis; LC-MS: liquid chromatography-mass spectrometry; LPS: lipopolysaccharide; MRC1/CD206: mannose receptor, C type 1; O4: oligodendrocyte marker O4; PBMC: peripheral blood mononuclear cells; RBC: red blood cells; PTPRC/CD45: protein tyrosine phosphatase, receptor type, C; RBFOX3/NeuN: RNA binding protein, fox 1 homolog (C. elegans) 3; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; scRNAseq: single cell RNA sequencing; SQSTM1/p62 (sequestosome 1); TGFB/TGFß: transforming growth factor, beta; tMCAO: transient middle cerebral artery occlusion; TNF/TNFα: tumor necrosis factor; Treg: regulatory T cell.

Melatonin Offers Dual-Phase Protection to Brain Vessel Endothelial Cells in Prolonged Cerebral Ischemia-Recanalization Through Ameliorating ER Stress and Resolving Refractory Stress Granule.

Ischemic-reperfusion injury limits the time window of recanalization therapy in cerebral acute ischemic stroke (AIS). Brain vessel endothelial cells (BVECs) form the first layer of the blood-brain barrier (BBB) and are thus the first sufferer of ischemic-reperfusion disorder. The current study demonstrates that melatonin can reduce infarct volume, alleviate brain edema, ameliorate neurological deficits, and protect BBB integrity in prolonged-stroke mice. Here, we demonstrate that endoplasmic reticulum (ER)-associated injury contributes to BVEC death in the dural phase of reperfusion after prolonged ischemia. When encountering ischemia, ER stress arises, specifically activating PERK-EIF2α signaling and the subsequent programmed cell death. Prolonged ischemia leads stress granules (SGs) to be refractory, which remain unresolved and accumulate in ER during recanalization. During reperfusion, refractory SGs activate PKR-EIF2α and further exacerbate BVEC injury. We report that melatonin treatment downregulates ER stress in the ischemic period and enhances dissociation of the refractory SGs during reperfusion, thus offering dual-phase protection to BVECs in prolonged cerebral stroke. Mechanistically, melatonin enhances autophagy in BVECs, which preserves ER function and resolves refractory SGs. We, therefore, propose that melatonin is a potential treatment to extend the time window of delayed recanalization therapy in AIS.

Neutrophil Nanovesicle Protects against Experimental Autoimmune Encephalomyelitis through Enhancing Myelin Clearance by Microglia.

Timely clearance of myelin debris is the premise of neuroinflammation termination and tissue regeneration in multiple sclerosis (MS). Microglia are the main scavengers of myelin debris in MS lesions, but its phagocytic capability is limited in MS patients. Here, we develop neutrophil-derived nanovesicles (NNVs) to enhance the efficiency of myelin debris clearance in microglia for MS therapy. RNA sequencing (RNAseq) results demonstrate that NNVs treatment ameliorates lesional neuroinflammation of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Consequently, EAE mice exhibit favorable neurological functions and white matter integrity after NNVs treatment. Specifically, NNVs treatment upregulates the expression of nuclear factor E2-related factor 2 (NRF2) in microglia, as revealed by Assay for Transposase Accessible Chromatin using sequencing (ATACseq). We also demonstrate that NRF2 can activate the transcription of RUBCN (RUN domain and cysteine-rich domain containing Beclin 1-interacting protein), which in turn enhances LC3-associated phagocytosis (LAP) in microglia. As a result, myelin debris engulfed by microglia can be efficiently catabolized in NNVs-treated EAE mice without obvious side effects. Together, this study proves that NNVs can modulate neuroinflammation by clearing myelin debris and is a promising MS treatment strategy.

Anemoside B4 ameliorates experimental autoimmune encephalomyelitis in mice by modulating inflammatory responses and the gut microbiota.

BACKGROUND: Anemoside B4 (AB4) is a representative component of Pulsatilla decoction that is used in traditional Chinese medicine for treating inflammatory conditions. It is not known whether AB4 has beneficial effects on multiple sclerosis (MS). METHODS: In the present study, we examined the preventative and therapeutic effects of AB4, and the possible mechanism by which it protects female mice against experimental autoimmune encephalomyelitis (EAE). RESULTS: Preventative treatment with AB4 (given orally at 100 and 200 mg/kg for 18 days) reduced the clinical severity of EAE significantly (from 3.6 ± 1.3 to 1.8 ± 1.5 and 1.6 ± 0.6, respectively), and inhibited demyelination and inflammatory infiltration of the spinal cord. In the therapeutic protocol, oral administration of 200 mg/kg AB4 for 21 days after initiation of EAE significantly alleviated disease severity (from 2.6 ± 1.3 to 0.9 ± 0.6) and was as effective as the clinically used drug fingolimod (0.3 ± 0.6). Furthermore, both doses of AB4 significantly inhibited mRNA expression of TNF-α, IL-6, and IL-17, and STAT3 activation, in the spinal cord; and the ex vivo and iv vitro AB4 treatment markedly inhibited secretion of the three cytokines from lymphocytes of EAE mice upon in vitro restimulation. In addition, AB4 reversed the changes in the composition of the intestinal microbiome observed in EAE mice. CONCLUSION: We reveal for the first time that AB4 protects against EAE by modulating inflammatory responses and the gut microbiota, demonstrating that AB4 may have potential as a therapeutic agent for treating MS in humans.

Gut Microbiome and Bile Acid Metabolism Induced the Activation of CXCR5+ CD4+ T Follicular Helper Cells to Participate in Neuromyelitis Optica Spectrum Disorder Recurrence.

From the perspective of the role of T follicular helper (Tfh) cells in the destruction of tolerance in disease progression, more attention has been paid to their role in autoimmunity. To address the role of Tfh cells in neuromyelitis optica spectrum disorder (NMOSD) recurrence, serum C-X-C motif ligand 13 (CXCL13) levels reflect the effects of the Tfh cells on B-cell-mediated humoral immunity. We evaluated the immunobiology of the CXCR5+CD4+ Tfh cells in 46 patients with NMOSD, including 37 patients with NMOSD with an annual recurrence rate (ARR) of<1 and 9 patients with NMOSD with an ARR of ≥1. Herein, we reported several key observations. First, there was a lower frequency of circulating Tfh cells in patients with an ARR of<1 than in those with an ARR of ≥1 (P< 0.05). Second, the serum CXCL13 levels were downregulated in individuals with an ARR<1 (P< 0.05), processing the ability to promote Tfh maturation and chemotaxis. Third, the level of the primary bile acid, glycoursodeoxycholic acid (GUDCA), was higher in patients with NMOSD with an ARR of<1 than in those with NMOSD with an ARR of ≥1, which was positively correlated with CXCL13. Lastly, the frequency of the Tfh precursor cells decreased in the spleen of keyhole limpet haemocyanin-stimulated animals following GUDCA intervention. These findings significantly broaden our understanding of Tfh cells and CXCL13 in NMOSD. Our data also reveal the potential mechanism of intestinal microbiota and metabolites involved in NMOSD recurrence.

Serum NfL associated with anti-NMDA receptor encephalitis.

INTRODUCTION: Neurofilament light chains (NfL) have been reported as potential markers for neuronal-axonal injury in neuroinflammatory diseases. In the current study, we describe serum NfL levels as a prognostic marker for anti-N-methyl-D-aspartate receptor encephalitis (NMDARE). METHODS: Serum levels of NfL of 64 patients with anti-NMDARE and 84 healthy controls were measured by Simoa. The anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score, Modified Rankin Scale (mRS) scores, and clinical and cerebrospinal fluid parameters were evaluated in patients with anti-NMDARE. Meanwhile, we performed a receiver-operator characteristic analysis to assess the power of the serum NFL in predicting the 1-year functional status. RESULTS: Serum NfL levels were significantly elevated in patients with anti-NMDARE compared to healthy controls (p < 0.001, padjusted < 0.001), especially in patients with severe impairments (mRS > 3 vs ≤ 3, p = 0.035) or with limited response to treatment (vs. favorable outcome, p = 0.011). Serum NFL was positively associated with the initial admission mRS (r = 0.23, p = 0.072) and 1-year mRS (r = 0.29, p = 0.018). The AUC of serum NfL and NEOS score for 1-year poor functional status was 0.697 (95% CI 0.527-0.866, p = 0.011), 0.753 (95% CI 0.616-0.890, p = 0.001), respectively. Furthermore, AUC of the combination of serum NfL and NEOS was 0.815 (95% CI 0.680-0.950, p < 0.001). CONCLUSION: Our findings show that serum NfL levels evaluated in anti-NMDAR encephalitis may be a good predictor of the risk of 1-year poor functional status.

Hypothalamic lesions in neuromyelitis optica spectrum disorders: exploring a scoring system based on magnetic resonance imaging.

PURPOSE: We propose a scoring system for early diagnosis of sleep abnormalities in neuromyelitis optica spectrum disorders (NMOSD) with hypothalamic lesions based on magnetic resonance imaging (MRI). MATERIALS AND METHODS: We evaluated MRI features of 45 patients with hypothalamic lesions identified from two cohorts. Univariate logistic regression analysis identified factors associated with sleepiness, which were subsequently used to develop a scoring system. Interrater reliability was determined using intraclass correlation coefficient (ICC). Correlations between scores and clinical features were analyzed. RESULTS: In total, 48.9% of 45 patients with hypothalamic lesions exhibited sleepiness. The number of involved slices, maximum width/length of hypothalamic lesions, and boundaries extending beyond the hypothalamus were associated with sleepiness (all p < 0.05). The sensitivity and specificity of the scoring system were 68.2% and 87.0%, respectively. The ICC values for the maximum width and length measurement of hypothalamic lesions were 0.82 and 0.81, respectively. Daily sleep time and Epworth sleepiness scale scores were positively correlated with MRI-based scores (p < 0.05, 95% confidence interval (CI) 0.69-0.93 and p < 0.05, 95% CI 0.55-0.88, respectively). CONCLUSION: A scoring system based on MRI features was developed to provide diagnosis of sleepiness in NMOSD with hypothalamic lesions earlier than other measures.

Infection against infection: parasite antagonism against parasites, viruses and bacteria.

BACKGROUND: Infectious diseases encompass a large spectrum of diseases that threaten human health, and coinfection is of particular importance because pathogen species can interact within the host. Currently, the antagonistic relationship between different pathogens during concurrent coinfections is defined as one in which one pathogen either manages to inhibit the invasion, development and reproduction of the other pathogen or biologically modulates the vector density. In this review, we provide an overview of the phenomenon and mechanisms of antagonism of coinfecting pathogens involving parasites. MAIN BODY: This review summarizes the antagonistic interaction between parasites and parasites, parasites and viruses, and parasites and bacteria. At present, relatively clear mechanisms explaining polyparasitism include apparent competition, exploitation competition, interference competition, biological control of intermediate hosts or vectors and suppressive effect on transmission. In particular, immunomodulation, including the suppression of dendritic cell (DC) responses, activation of basophils and mononuclear macrophages and adjuvant effects of the complement system, is described in detail. CONCLUSIONS: In this review, we summarize antagonistic concurrent infections involving parasites and provide a functional framework for in-depth studies of the underlying mechanisms of coinfection with different microorganisms, which will hasten the development of promising antimicrobial alternatives, such as novel antibacterial vaccines or biological methods of controlling infectious diseases, thus relieving the overwhelming burden of ever-increasing antimicrobial resistance.