Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus （HBV） infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors （TLRs） sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons （IFNs） and pro-inflammatory cytokines. Experimental results from in vitroand in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T- and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.

Adaptive immune response during hepatitis C virus infection

Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma.HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control.Liver damage and disease progression during HCV infection are driven by both viral and host factors.Specifically,adaptive immune response carries out an essential task in controllingnon-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery.HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion.To impair HCV-specific T cell reactivity,HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro-and antiapoptotic proteins.In this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

Dynamic analysis of a latent HIV infection model with CTL immune and antibody responses

This paper develops a mathematical model to investigate the Human Immunodeficiency Virus(HIV)infection dynamics.The model includes two transmission modes(cell-to-cell and cell-free),two adaptive immune responses(cytotoxic T-lymphocyte(CTL)and antibody),a saturated CTL immune response,and latent HIV infection.The existence and local stability of equilibria are fully characterized by four reproduction numbers.Through sensitivity analyses,we assess the partial rank correlation coefficients of these reproduction numbers and identify that the infection rate via cell-to-cell transmission,the number of new viruses produced by each infected cell during its life cycle,the clearance rate of free virions,and immune parameters have the greatest impact on the reproduction numbers.Additionally,we compare the effects of immune stimulation and cell-to-cell spread on the model's dynamics.The findings highlight the significance of adaptive immune responses in increasing the population of uninfected cells and reducing the numbers of latent cells,infected cells,and viruses.Furthermore,cell-to-cell transmission is identified as a facilitator of HIV transmission.The analytical and numerical results presented in this study contribute to a better understanding of HIV dynamics and can potentially aid in improving HIV management strategies.

Enhanced host immune responses in presence of HCV facilitate HBV clearance in coinfection

Hepatitis B virus(HBV)/Hepatitis C virus(HCV)coinfection is frequently observed because of the common infection routine.Despite the reciprocal inhibition exerted by HBV and HCV genomes,the coinfection of HBV and HCV is associated with more severe forms of liver diseases.However,the complexity of viral interference and underlying pathological mechanism is still unclarified.With the demonstration of absence of direct viral interplay,some in vitro studies suggest the indirect effects of viral-host interaction on viral dominance outcome.Here,we comprehensively investigated the viral replication and host immune responses which might mediate the interference between viruses in HBV/HCV coinfected Huh7-NTCP cells and immunocompetent HCV human receptors transgenic ICR mice.We found that presence of HCV significantly inhibited HBV replication in vitro and in vivo irrespective of the coinfection order,while HBV did not affect HCV replication.Pathological alteration was coincidently reproduced in coinfected mice.In addition to the participation of innate immune response,an involvement of HCV in up-regulating HBV-specific immune responses was described to facilitate HBV clearance.Our systems partially recapitulate HBV/HCV coinfection and unveil the uncharacterized adaptive anti-viral immune responses during coinfection,which renews the knowledge on the nature of indirect viral interaction during HBV/HCV coinfection.

MAP Kinases in Immune Responses

MAP kinases are evolutionarily conserved signaling regulators from budding yeast to mammals and play essential roles in both innate and adaptive immune responses.There are three main families of MAPKs in mammals.Each of them has its own activators,inactivators,substrates and scaffolds,which altogether form a fine signaling network in response to different extracellular or intracellular stimulation.In this review,we summarize recent advances in understanding of the regulation of MAP kinases and the roles of MAP kinases in innate and adaptive immune responses.Cellular & Molecular Immunology.2005;2(1):20-27.

COVID-19 and gut immunomodulation

The disease coronavirus disease 2019(COVID-19)is a severe respiratory illness that has emerged as a devastating health problem worldwide.The disease outcome is heterogeneous,and severity is likely dependent on the immunity of infected individuals and comorbidities.Although symptoms of the disease are primarily associated with respiratory problems,additional infection or failure of other vital organs are being reported.Emerging reports suggest a quite common co-existence of gastrointestinal(GI)tract symptoms in addition to respiratory symptoms in many COVID-19 patients,and some patients show just the GI symptoms.The possible cause of the GI symptoms could be due to direct infection of the epithelial cells of the gut,which is supported by the fact that(1)The intestinal epithelium expresses a high level of angiotensin-converting enzyme-2 and transmembrane protease serine 2 protein that are required for the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)entry into the cells;(2)About half of the severe COVID-19 patients show viral RNA in their feces and various parts of the GI tract;and(3)SARS-CoV-2 can directly infect gut epithelial cells in vitro(gut epithelial cells and organoids)and in vivo(rhesus monkey).The GI tract seems to be a site of active innate and adaptive immune responses to SARS-CoV-2 as clinically,stool samples of COVID-19 patients possess proinflammatory cytokines(interleukin 8),calprotectin(neutrophils activity),and immunoglobulin A antibodies.In addition to direct immune activation by the virus,impairment of GI epithelium integrity can evoke immune response under the influence of systemic cytokines,hypoxia,and changes in gut microbiota(dysbiosis)due to infection of the respiratory system,which is confirmed by the observation that not all of the GI symptomatic patients are viral RNA positive.This review comprehensively summarizes the possible GI immunomodulation by SARS-CoV-2 that could lead to GI symptoms,their association with disease severity,and potential therapeutic interventions.

Impact of SARS-CoV-2 on neuropsychiatric disorders

Evolving data show a variable expression of clinical neurological manifestations in patients suffering with coronavirus disease 2019(COVID-19)from early disease onset.The most frequent symptoms and signs are fatigue,dizziness,impaired consciousness,ageusia,anosmia,radicular pain,and headache,as well as others.Based on the high number of series of cases reported,there is evidence for the implication of the immune system in the pathological mechanism of COVID-19.Although the exact role of the immunological mechanism is not elucidated,two main mechanisms are suggested which implicate the direct effect of severe acute respiratory syndrome coronavirus 2 infection in the central nervous system and neuroinflammation.In the context of neurological manifestations associated with COVID-19,neuropsychiatric disorders show an exacerbation and are described by symptoms and signs such as depression,anxiety,mood alterations,psychosis,post-traumatic stress disorder,delirium,and cognitive impairment,which appear to be common in COVID-19 survivors.A worsened score on psychopathological measures is seen in those with a history of psychiatric comorbidities.We review the neuropsychiatric manifestations associated with COVID-19 and some critical aspects of the innate and adaptive immune system involved in mental health disorders occurring in COVID-19.

Hydroxyapatite nanoparticles drive the potency of Toll-like receptor 9 agonist for amplified innate and adaptive immune response

The potency of Toll-like receptor 9(TLR9)agonist to drive innate immune response was limited due to immune suppression or tolerance during TLR9 signaling activation in immune cells.Herein we addressed this problem by introducing hydroxyapatite nanoparticles(HANPs)to CpG ODN(CpG),a TLR9 agonist.The study revealed that HANPs concentration and durationdependently reprogramed the immune response by enhancing the secretion of immunostimulatory cytokines(tumor necrosis factorα(TNFα)or IL-6)while reducing the production of immunosuppressive cytokine(IL-10)in macrophages in response to CpG.Next,the enhanced immune response benefited from increased intracellular Ca2+in macrophage by the addition of HANPs.Further,we found exposure to HANPs impacted the mitochondrial function of macrophages in support of the synthesis of adenosine triphosphate(ATP),the production of nicotinamide adenine dinucleotide(NAD),and reactive oxygen species(ROS)in the presence or absence of CpG.In vaccinated mice model,only one vaccination with a mixture of CpG,HANPs,and OVA,a model antigen,allowed the development of a long-lasting balanced humoral immunity in mice without any histopathological change in the local injection site.Therefore,this study revealed that HANPs could modulate the intracellular calcium level,mitochondrial function,and immune response in immune cells,and suggested a potential combination adjuvant of HANPs and TLR9 agonist for vaccine development.

Impact of adaptive immune response and cellular infection on delayed virus dynamics with multi-stages of infected cells

In this investigation,we propose and analyze a virus dynamics model with multi-stages of infected cells.The model incorporates the effect of both humoral and cell-mediated immune responses.We consider two modes of transmissions,virus-to-cell and cell-to-cell.Multiple intracellular discrete-time delays have been integrated into the model.The incidence rate of infection as well as the generation and removal rates of all compartments are described by general nonlinear functions.Wc derive five threshold parameters which determine the existence of the equilibria of the model under consideration.A set of conditions on the general functions has been established which is sufficient to investigate the global stability of the five equilibria of the model.The global asymptotic stability of all equilibria is proven by utilizing Lyapunov function and LaSalle’s invariance principle.The theoretical results are illustrated by numerical simulations of the model with specific forms of the general functions.

A key role for PTP1B in dendritic cell maturation, migration, and T cell activation

Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells.They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues.Here,wedemonstrate thatmyeloid cell-specific genetic deletion of PTP1B(LysM PTP1B)leads to defects in lipopolysaccharide-driven bone marrow-derivedDC(BMDC)activation associated with increased levels of phosphorylated Stat3.We showthatmyeloid cell-specific PTP1Bdeletion also causes decreased migratory capacity of epidermal DC,aswell as reduced CCR7 expression and chemotaxis to CCL19 by BMDC.PTP1B deficiency in BMDC also impairs their migration in vivo.Further,immature LysM PTP1B BMDC display fewer podosomes,increased levels of phosphorylated Src at tyrosine 527,and loss of Src localization to podosome puncta.In co-culture with T cells,LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC.Finally,LysMPTP1BBMDCfail to present antigen to T cells as efficiently as controlBMDC.These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.

Interactions between the lung microbiome and host immunity in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease(COPD)is a common chronic respiratory disease and the third leading cause of death worldwide.Developments in next-generation sequencing technology have improved microbiome analysis,which is increasingly recognized as an important component of disease management.Similar to the gut,the lung is a biosphere containing billions of microbial communities.The lung microbiome plays an important role in regulating and maintaining the host immune system.The microbiome composition,metabolites of microorganisms,and the interactions between the lung microbiome and the host immunity profoundly affect the occurrence,development,treatment,and prognosis of COPD.In this review,we drew comparisons between the lung microbiome of healthy individuals and that of patients with COPD.Furthermore,we summarize the intrinsic interactions between the host and the overall lung microbiome,focusing on the underlying mechanisms linking the microbiome to the host innate and adaptive immune response pathways.Finally,we discuss the possibility of using the microbiome as a biomarker to determine the stage and prognosis of COPD and the feasibility of developing a novel,safe,and effective therapeutic target.

Neuroinflammation in cortical and meningeal pathology in multiple sclerosis:understanding from animal models

Multiple sclerosis(MS)is a neurodegenerative and inflammatory disease usually presenting with acute demyelinating events that can start as,or progress to,chronic damage.The development of animal experimental models,specific for each stage of MS will aid in the design of new drugs specific for the different forms of the disease.Animal models of experimental autoimmune encephalomyelitis successfully reflect the pathophysiological mechanisms of the early phases of MS.However,few models resemble the features of the progressive forms of MS such as cortical demyelination and meningeal inflammation.Recently,a few auspicious animal models recapitulating many of the characteristics of progressive MS,aimed at a better understanding of the pathology of these forms of the disease,have been developed.In this review,we will summarize the latest developments in animal models reflecting the cortical and meningeal pathological features of progressive MS,as well as their response to drugs specifically targeting these forms.