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SUMMARYHuman alphaherpesvirus 1 (HSV-1) is a highly successful neurotropic pathogen that primarily infects the epithelial cells lining the orofacial mucosa. After primary lytic replication in the oral, ocular, and nasal mucosal epithelial cells, HSV-1 establishes life-long latency in neurons within the trigeminal ganglion. Patients with compromised immune systems experience frequent reactivation of HSV-1 from latency, leading to virus entry in the sensory neurons, followed by anterograde transport and lytic replication at the innervated mucosal epithelial surface. Although recurrent infection of the corneal mucosal surface is rare, it can result in a chronic immuno-inflammatory condition called herpetic stromal keratitis (HSK). HSK leads to gradual vision loss and can cause permanent blindness in severe untreated cases. Currently, there is no cure or successful vaccine to prevent latent or recurrent HSV-1 infections, posing a significant clinical challenge to managing HSK and preventing vision loss. The conventional clinical management of HSK primarily relies on anti-virals to suppress HSV-1 replication, anti-inflammatory drugs (such as corticosteroids) to provide symptomatic relief from pain and inflammation, and surgical interventions in more severe cases to replace damaged cornea. However, each clinical treatment strategy has limitations, such as local and systemic drug toxicities and the emergence of anti-viral-resistant HSV-1 strains. In this review, we summarize the factors and immune cells involved in HSK pathogenesis and highlight alternate therapeutic strategies for successful clinical management of HSK. We also discuss the therapeutic potential of immunoregulatory cytokines and immunometabolism modulators as promising HSK therapies against emerging anti-viral-resistant HSV-1 strains.
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The Varicella-zoster virus (VZV), classified as a neurotropic member of the Herpesviridae family, exhibits a characteristic pathogenicity, predominantly inducing varicella, commonly known as chickenpox, during the initial infectious phase, and triggering the reactivation of herpes zoster, more commonly recognized as shingles, following its emergence from a latent state. The pathogenesis of VZV-associated neuroinflammation involves a complex interplay between viral replication within sensory ganglia and immune-mediated responses that contribute to tissue damage and dysfunction. Upon primary infection, VZV gains access to sensory ganglia, establishing latent infection within neurons. During reactivation, the virus can spread along sensory nerves, triggering a cascade of inflammatory mediators, chemokines, and immune cell infiltration in the affected neural tissues. The role of both adaptive and innate immune reactions, including the contributions of T and B cells, macrophages, and dendritic cells, in orchestrating the immune-mediated damage in the central nervous system is elucidated. Furthermore, the aberrant activation of the natural defence mechanism, characterised by the dysregulated production of immunomodulatory proteins and chemokines, has been implicated in the pathogenesis of VZV-induced neurological disorders, such as encephalitis, myelitis, and vasculopathy. The intricate balance between protective and detrimental immune responses in the context of VZV infection emphasises the necessity for an exhaustive comprehension of the immunopathogenic mechanisms propelling neuroinflammatory processes. Despite the availability of vaccines and antiviral therapies, VZV-related neurological complications remain a significant concern, particularly in immunocompromised individuals and the elderly. Elucidating these mechanisms might facilitate the emergence of innovative immunomodulatory strategies and targeted therapies aimed at mitigating VZV-induced neuroinflammatory damage and improving clinical outcomes. This comprehensive understanding enhances our grasp of viral pathogenesis and holds promise for pioneering therapeutic strategies designed to mitigate the neurological ramifications of VZV infections.
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Herpesvirus Humano 3 , Humanos , Herpesvirus Humano 3/imunologia , Herpesvirus Humano 3/fisiologia , Herpesvirus Humano 3/patogenicidade , Herpes Zoster/virologia , Herpes Zoster/imunologia , Infecção pelo Vírus da Varicela-Zoster/imunologia , Infecção pelo Vírus da Varicela-Zoster/virologia , Doenças do Sistema Nervoso/virologia , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/etiologia , Animais , Varicela/virologia , Varicela/imunologia , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/virologiaRESUMO
Maintenance and activation of the immune system incur costs, not only in terms of substrates and energy but also via collateral oxidative damage to host cells or tissues during immune response. So far, associations between immune function and oxidative damage have been primarily investigated at intra-specific scales. Here, we hypothesized that pathogen-driven selection should favour the evolution of effective immunosurveillance mechanisms (e.g. major histocompatibility complex, MHC) and antioxidant defences to mitigate oxidative damage resulting from immune function. Using phylogenetically informed comparative approaches, we provided evidence for the correlated evolution of host oxidative physiology and MHC-based immunosurveillance in birds. Species selected for more robust MHC-based immunosurveillance (higher gene copy numbers and allele diversity) showed stronger antioxidant defences, although selection for MHC diversity still showed a positive evolutionary association with oxidative damage to lipids. Our results indicate that historical pathogen-driven selection for highly duplicated and diverse MHC could have promoted the evolution of efficient antioxidant mechanisms, but these evolutionary solutions may be insufficient to keep oxidative stress at bounds. Although the precise nature of mechanistic links between the MHC and oxidative stress remains unclear, our study suggests that a general evolutionary investment in immune function may require co-adaptations at the level of host oxidative metabolism.
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Aves , Complexo Principal de Histocompatibilidade , Estresse Oxidativo , Animais , Complexo Principal de Histocompatibilidade/genética , Aves/fisiologia , Aves/imunologia , Evolução Biológica , FilogeniaRESUMO
Natural killer (NK) cells include different subsets with diverse effector capacities that are poorly understood in the context of parasitic diseases. Here, we investigated inhibitory and activating receptor expression on NK cells in patients with cutaneous leishmaniasis (CL) and explored their phenotypic and functional heterogeneity based on CD57 and NKG2C expression. The expression of CD57 identified NK cells that accumulated in CL patients and exhibited features of senescence. The CD57+ cells exhibited heightened levels of the activating receptor NKG2C and diminished expression of the inhibitory receptor NKG2A. RNA sequencing analyses based on NKG2C transcriptome have revealed two distinct profiles among CL patients associated with cytotoxic and functional genes. The CD57+NKG2C+ subset accumulated in the blood of patients and presented conspicuous features of senescence, including the expression of markers such as p16, yH2ax, and p38, as well as reduced proliferative capacity. In addition, they positively correlated with the number of days until lesion resolution. This study provides a broad understanding of the NK cell biology during Leishmania infection and reinforces the role of senescent cells in the adverse clinical outcomes of CL.
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Antígenos CD57 , Senescência Celular , Células Matadoras Naturais , Leishmaniose Cutânea , Subfamília C de Receptores Semelhantes a Lectina de Células NK , Humanos , Leishmaniose Cutânea/imunologia , Células Matadoras Naturais/imunologia , Antígenos CD57/metabolismo , Antígenos CD57/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Senescência Celular/imunologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adulto JovemRESUMO
Vaccines have demonstrated remarkable effectiveness in protecting against COVID-19; however, concerns regarding vaccine-associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS-CoV-2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2-biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2-humanized mice with SARS-CoV-2 Spike protein adjuvanted with aluminum and CpG-ODN. Subsequently, we exposed them to increasing doses of SARS-CoV-2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4+ T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1-associated immunity against COVID-19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell-mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID-19 and to enhance vaccine formulations for broad protection and maximum safety.
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Vacinas contra COVID-19 , COVID-19 , Glicoproteína da Espícula de Coronavírus , Animais , Humanos , Camundongos , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Alumínio , Enzima de Conversão de Angiotensina 2 , Infecções Irruptivas , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2RESUMO
Guillain-Barré syndrome (GBS) is a potentially devastating yet treatable disorder. A classically postinfectious, immune-mediated, monophasic polyradiculoneuropathy, it is the leading global cause of acquired neuromuscular paralysis. In most cases, the immunopathological process driving nerve injury is ill-defined. Diagnosis of GBS relies on clinical features, supported by laboratory findings and electrophysiology. Although previously divided into primary demyelinating or axonal variants, this dichotomy is increasingly challenged, and is not endorsed by the recent European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) guidelines. Intravenous immunoglobulin and plasma exchange remain the primary modalities of treatment, regardless of the electrophysiological subtype. Most patients recover, but approximately one-third require mechanical ventilation, and 5% die. Disease activity and treatment response are currently monitored through interval neurological examination and outcome measures, and the potential role of fluid biomarkers is under ongoing scrutiny. Novel potential therapies for GBS are being explored but none have yet modified clinical practice. This review provides a comprehensive update on the pathological and clinical aspects of GBS for clinicians and scientists.
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Síndrome de Guillain-Barré , Síndrome de Guillain-Barré/terapia , Síndrome de Guillain-Barré/fisiopatologia , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/imunologia , Humanos , Troca Plasmática/métodos , Imunoglobulinas Intravenosas/uso terapêuticoRESUMO
Impaired T-cell responses to mitogens and high T-cell activation marker (TAM) expression on Mycobacterium tuberculosis-specific T-cells characterize immunopathology in patients with tuberculosis (TB). In a study of patients with TB (n = 60) and asymptomatic contacts (controls, n = 37), we found that TB patients had higher CD38+ T-cell proportions specific for M. tuberculosis protein (PPDMtb), yet total proportions of PPDMtb-specific T-cells were comparable. Notably, both activated (CD38+) and total IFN-γ+ T-cells from TB patients had lower mitogen (phytohemagglutinin, PHA)-induced responses. This impaired mitogen response improved the classification efficacy of the TAM-TB assay, especially employing the PPD/PHA-induced T-cell ratio.
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Mycobacterium tuberculosis , Tuberculose , Humanos , Mitógenos/farmacologia , Tuberculina , Linfócitos T , Antígenos de BactériasRESUMO
Cardiomyopathy syndrome (CMS) caused by piscine myocarditis virus (PMCV) is a severe cardiac disease in Atlantic salmon (Salmo salar) and one of the leading causes of morbidity and mortality in the Norwegian aquaculture industry. Previous research suggest a variation in individual susceptibility to develop severe disease, however the role of the immune response in determining individual outcome of CMS is poorly understood particularly in cases where fish are also challenged by stress. The present study's aim was therefore to characterize cardiac transcriptional responses to PMCV infection in Atlantic salmon responding to infection under stressful conditions with a high versus low degree of histopathological damage. The study was performed as a large-scale controlled experiment of Atlantic salmon smolts from pre-challenge to 12 weeks post infection (wpi) with PMCV, during which fish were exposed to intermittent stressors. RNA sequencing (RNAseq) was used to compare the heart transcriptome of high responders (HR) with atrium histopathology score '4' and low responders (LR) with score '0.5' at 12 wpi. A high-throughput quantitative PCR (qPCR) analysis was used to compare immune gene transcription between individuals sampled at 6, 9 and 12 wpi. Based on RNAseq and qPCR results, RNAscope in situ hybridization (ISH) was performed for visualization of IFN-γ - and IFNb producing immune cells in affected heart tissue. Compared to LR, the transcription of 1592 genes was increased in HR at 12 wpi. Of these genes, around. 40 % were immune-related, including various chemokines, key antiviral response molecules, and genes. associated with a Th1 pro-inflammatory immune response. Further, the qPCR analysis confirmed. increased immune gene transcription in HR at both 9 and 12 wpi, despite a decrease in PMCV. transcription between these time points. Interestingly, increased IFNb transcription in HR suggests the. presence of high-quantity IFN secreting cells in the hearts of these individuals. Indeed, RNAscope. confirmed the presence of IFN-γ and IFNb-positive cells in the heart ventricle of HR but not LR. To conclude, our data indicate that in severe outcomes of PMCV infection various chemokines attract leucocytes to the salmon heart, including IFN-γ and IFNb-secreting cells, and that these cells play important roles in maintaining persistent antiviral responses and a sustained host immunopathology despite decreasing heart viral transcription.
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Cardiomiopatias , Doenças dos Peixes , Salmo salar , Totiviridae , Animais , Totiviridae/genética , Cardiomiopatias/genética , Imunidade Adaptativa , Quimiocinas , AntiviraisRESUMO
The mission of this review is to identify immune-damaging participants involved in antiviral immunoinflammatory lesions. We argue these could be targeted and their activity changed selectively by maneuvers that, at the same time, may not diminish the impact of components that help resolve lesions. Ideally, we need to identify therapeutic approaches that can reverse ongoing lesions that lack unwanted side effects and are affordable to use. By understanding the delicate balance between immune responses that cause tissue damage and those that aid in resolution, novel strategies can be developed to target detrimental immune components while preserving the beneficial ones. Some strategies involve rebalancing the participation of immune components using various approaches, such as removing or blocking proinflammatory T cell products, expanding regulatory cells, restoring lost protective cell function, using monoclonal antibodies (moAb) to counteract inhibitory molecules, and exploiting metabolic differences between inflammatory and immuno-protective responses. These strategies can help reverse ongoing viral infections. We explain various approaches, from model studies and some clinical evidence, that achieve innate and adaptive immune rebalancing, offering insights into potential applications for controlling chronic viral-induced lesions.
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Anticorpos Monoclonais , Pirimetamina , Humanos , Anticorpos Monoclonais/uso terapêutico , SulfadiazinaRESUMO
INTRODUCTION: This review summarizes our current understanding of the respiratory microbiome in COPD and Bronchiectasis. We explore the interplay between microbial communities, host immune responses, disease pathology, and treatment outcomes. AREAS COVERED: We detail the dynamics of the airway microbiome, its influence on chronic respiratory diseases, and analytical challenges. Relevant articles from PubMed and Medline (January 2010-March 2024) were retrieved and summarized. We examine clinical correlations of the microbiome in COPD and bronchiectasis, assessing how current therapies impact upon it. The potential of emerging immunotherapies, antiinflammatories and antimicrobial strategies is discussed, with focus on the pivotal role of commensal taxa in maintaining respiratory health and the promising avenue of microbiome remodeling for disease management. EXPERT OPINION: Given the heterogeneity in microbiome composition and its pivotal role in disease development and progression, a shift toward microbiome-directed therapeutics is appealing. This transition, from traditional 'pathogencentric' diagnostic and treatment modalities to those acknowledging the microbiome, can be enabled by evolving crossdisciplinary platforms which have the potential to accelerate microbiome-based interventions into routine clinical practice. Bridging the gap between comprehensive microbiome analysis and clinical application, however, remains challenging, necessitating continued innovation in research, diagnostics, trials, and therapeutic development pipelines.
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Bronquiectasia , Microbiota , Doença Pulmonar Obstrutiva Crônica , Humanos , Bronquiectasia/microbiologia , Bronquiectasia/imunologia , Bronquiectasia/terapia , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/terapia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Progressão da Doença , Resultado do Tratamento , Animais , ImunoterapiaRESUMO
Oral candidiasis (OC), a prevalent opportunistic infection of the oral mucosa, presents a considerable health challenge, particularly in individuals with compromised immune responses, advanced age, and local predisposing conditions. A considerable part of the population carries Candida in the oral cavity, but only few develop OC. Therefore, the pathogenesis of OC may depend on factors other than the attributes of the fungus, such as host factors and other predisposing factors. Mucosal trauma and inflammation compromise epithelial integrity, fostering a conducive environment for fungal invasion. Molecular insights into the immunocompromised state reveal dysregulation in innate and adaptive immunity, creating a permissive environment for Candida proliferation. Detailed examination of Candida species (spp.) and their virulence factors uncovers a nuanced understanding beyond traditional C. albicans focus, which embrace diverse Candida spp. and their strategies, influencing adhesion, invasion, immune evasion, and biofilm formation. Understanding the pathophysiological microenvironments in OC is crucial for the development of targeted therapeutic interventions. This review aims to unravel the diverse pathophysiological microenvironments influencing OC development focusing on microbial, host, and predisposing factors, and considers Candida resistance to antifungal therapy. The comprehensive approach offers a refined perspective on OC, seeking briefly to identify potential therapeutic targets for future effective management.
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Despite major global efforts to eliminate tuberculosis, which is caused by Mycobacterium tuberculosis (Mtb), this disease remains as a major plague of humanity. Several factors associated with the host and Mtb interaction favor the infection establishment and/or determine disease progression. The Early Secreted Antigenic Target 6 kDa (ESAT-6) is one of the most important and well-studied mycobacterial virulence factors. This molecule has been described to play an important role in the development of tuberculosis-associated pathology by subverting crucial components of the host immune responses. This review highlights the main effector mechanisms by which ESAT-6 modulates the immune system, directly impacting cell fate and disease progression.
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Mycobacterium tuberculosis , Tuberculose , Humanos , Antígenos de Bactérias , Proteínas de Bactérias , Progressão da DoençaRESUMO
Shortly after the establishment of African swine fever virus (ASFV) genotype II in 2007, cases of acute fatal infection were observed. However, after several years of circulation in the Eurasian region, the clinical signs of the disease changed. Currently, this disease can occur acutely, subclinically, chronically, or asymptomatically. Cases of the complete recovery of infected pigs, and the disappearance of ASFV from their tissues and secretions have been described. This form of the disease first appeared in Armenia at the end of 2011. This virus was described and identified as the Dilijan2011IMB strain. The goal of our research was to study the main features of clinical, pathological, immunological, virological, and genetic parameters involved in the development of new forms of African swine fever (ASF). Chronic ASF was characterized with low titers of the virus and a decrease in the intensity of hemadsorption. Additionally, a reduced intensity in clinical symptoms and pathoanatomical results was noted. The absolute, but not the relative number of immune cells changes; the neutropenia (in bone marrow and spleen), lymphopenia (in bone marrow), lymphocytosis (only in spleen), lymphoid cell depletion (in bone marrow), and pancytopenia (in bone marrow) observed in the chronic form of ASF were less pronounced compared to in the acute form. When comparing the late stage of chronic ASF to the acute form, the key cytological indicators in the spleen, lymph nodes, and blood were less severe in the chronic stage. Bone marrow failure in the chronic form, expressed in a pronounced decrease in all cell types, generally coincided with the data in the acute form of ASF. The same data were obtained after assessing serum TNF-alpha levels. Thus, we can conclude that the chronic form of ASF occurs due to a less pronounced immune response, as well as a decrease in virus titers in the blood and tissues of infected pigs.
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7An efficient immune system must provide protection against a broad range of pathogens without causing excessive collateral tissue damage. While immune effectors have been well characterized, we know less about the resilience mechanisms protecting the host from its own immune response. Antimicrobial peptides (AMPs) are small, cationic peptides that contribute to innate defenses by targeting negatively charged membranes of microbes. While protective against pathogens, AMPs can be cytotoxic to host cells. Here, we reveal that a family of stress-induced proteins, the Turandots, protect the Drosophila respiratory system from AMPs, increasing resilience to stress. Flies lacking Turandot genes are susceptible to environmental stresses due to AMP-induced tracheal apoptosis. Turandot proteins bind to host cell membranes and mask negatively charged phospholipids, protecting them from cationic pore-forming AMPs. Collectively, these data demonstrate that Turandot stress proteins mitigate AMP cytotoxicity to host tissues and therefore improve their efficacy.
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Proteínas de Drosophila , Drosophila , Animais , Drosophila/metabolismo , Peptídeos Antimicrobianos , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/farmacologia , Imunidade Inata/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismoRESUMO
Atopic dermatitis (AD) is a common inflammatory and pruritic allergic skin disease in humans and dogs worldwide. The pathogenesis of AD is multifactorial, immunologically complex, and may involve genetic factors, epidermal barrier dysfunction, microbiome changes, immune dysregulation, and allergic sensitization. Across species, prevalence of AD is on the rise. At present, there is no cure for canine AD (CAD). The treatment for CAD is multifaceted and aimed at controlling the pruritus, associated inflammation, and infections, repairing the skin barrier function, and dietary management. This review presents data on prevalence, impact, and complex immunological interactions in AD with a focus on subsequent management of the disease in the canine population. A multimodal approach for management of CAD to address varying clinical signs and responses to therapies is discussed.
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Clostridium septicum is one of the major causative agents of clostridial dermatitis (CD), an emerging disease of turkeys, characterized by sudden deaths and necrotic dermatitis. Despite its economic burden on the poultry industry, the immunopathological changes and pathogen-specific immune responses are poorly characterized. Here, we used three strains of C. septicum, namely Str. A1, Str. B1 and Str. C1, isolated from CD field outbreaks, to experimentally infect turkeys to evaluate local (skin and muscle) and systemic (spleen) pathological and immunological responses. Results showed that while all three strains produced an acute disease, Str. A1 and B1 caused significantly higher mortality when compared to Str. C1. Gross and histopathology evaluation showed that birds infected with Str. A1 and B1 had severe inflammatory, edematous, granulomatous and necrotic lesions in the skin, muscle and spleen, while these lesions produced by Str. C1 were relatively less severe and mostly confined to skin and/or muscle. Immune gene expression in these tissues showed that Str. B1-infected birds had significantly higher expression of interleukin (IL)-1ß, IL-6 and interferon (IFN)γ genes compared to uninfected control, suggesting a robust inflammatory response both locally as well as systemically. The transcription of IL-1ß and IFNγ in the muscle or spleen of Str. A1-infected birds and IL-1ß in the skin of Str. C1-infected group was also significantly higher than control. Additionally, Str. A1 or B1-infected groups also had significantly higher IL-4 transcription in these tissues, while birds infected with all three strains developed C. septicum-specific serum antibodies. Furthermore, splenic cellular immunophenotyping in the infected turkeys showed a marked reduction in CD4+ cells. Collectively, it can be inferred that host responses against C. septicum involve an acute inflammatory response along with antibody production and that the disease severity seem to depend on the strain of C. septicum involved in CD in turkeys.
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Infecções por Clostridium , Clostridium septicum , Dermatite , Doenças das Aves Domésticas , Humanos , Animais , Clostridium septicum/fisiologia , Infecções por Clostridium/veterinária , Perus , Clostridium , Inflamação/veterinária , Dermatite/veterinária , ImunidadeRESUMO
Objective: We aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the in vivo regulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an in vivo lupus mouse model and an in vitro coculture model using human PBMCs. Method: We first induced lupus-like disease in T cell specific Rictor, a key component of mTORC2, deficient mice by topical application of imiquimod (IMQ) and monitored disease development. Next, we investigated the changes of mTORC2 signaling and immunological phenotypes in type I IFNAR deficient Lpr mice. We then tested the beneficial effects of anti-Rictor antisense oligonucleotide (Rictor-ASO) in a mouse model of lupus: MRL/lpr mice. Finally, we examined the beneficial effects of RICTOR-ASO on SLE patients' PBMCs using an in vitro T-B cell coculture assay. Results: T cell specific Rictor deficient mice have reduced age-associated B cells, plasma cells and germinal center B cells, and less autoantibody production than WT mice following IMQ treatment. IFNAR1 deficient Lpr mice have reduced mTORC2 activity in CD4+ T cells accompanied by restored CD4+ T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation. In vivo Rictor-ASO treatment improves renal function and pathology in MRL/lpr mice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay, RICTOR-ASO significantly reduce immunoglobulin and autoantibodies production (P < 0.05). Conclusion: Targeting mTORC2 could be a promising therapeutic for SLE.
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Mosquito-borne viral infections are on the rise worldwide and can lead to severe symptoms such as haemorrhage, encephalitis, arthritis or microcephaly. A protective immune response following mosquito-borne viral infections requires the generation of a controlled and balanced immune response leading to viral clearance without immunopathology. Here, regulatory T cells play a central role in restoring immune homeostasis. In current review, we aim to provide an overview and summary of the phenotypes of FOXP3+ Tregs in various mosquito-borne arboviral disease, their association with disease severity and their functional characteristics. Furthermore, we discuss the role of cytokines and Tregs in the immunopathogenesis of mosquito-borne infections. Lastly, we discuss possible novel lines of research which could provide additional insight into the role of Tregs in mosquito-borne viral infections in order to develop novel therapeutic approaches or vaccination strategies.
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Infecções por Arbovirus , Arbovírus , Culicidae , Encefalite , Microcefalia , Viroses , Animais , Humanos , Linfócitos T Reguladores , Mosquitos VetoresRESUMO
COVID-19 is of special concern to immunocompromised individuals, including organ transplant recipients. However, the exact implications of COVID-19 for the immunocompromised host remain unclear. Existing theories regarding this matter are controversial and mainly based on clinical observations. Here, the postmortem histopathology, immunopathology, and viral presence in various tissues of a kidney transplant recipient with COVID-19 were compared to those of 2 nontransplanted patients with COVID-19 matched for age, sex, length of intensive care unit stay, and admission period in the pandemic. None of the tissues of the kidney transplant recipient demonstrated the presence of SARS-CoV-2. In lung tissues of both controls, some samples showed viral positivity with high Ct values with quantitative reverse transcription polymerase chain reaction. The lungs of the kidney transplant recipient and controls demonstrated similar pathology, consisting of acute fibrinous and organizing pneumonia with thrombosis and an inflammatory response with T cells, B cells, and macrophages. The kidney allograft and control kidneys showed a similar pattern of interstitial lymphoplasmacytic infiltration. No myocarditis could be observed in the hearts of the kidney transplant recipient and controls, although all cases contained scattered lymphoplasmacytic infiltrates in the myocardium, pericardium, and atria. The brainstems of the kidney transplant recipient and controls showed a similar pattern of lymphocytic inflammation with microgliosis. This research report highlights the possibility that, based on the results obtained from this single case, at time of death, the immune response in kidney transplant recipients with long-term antirejection immunosuppression use prior to severe illness is similar to nontransplanted deceased COVID-19 patients.
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COVID-19 , Transplante de Rim , Humanos , SARS-CoV-2 , Transplante de Rim/efeitos adversos , Relatório de Pesquisa , Terapia de Imunossupressão/métodosRESUMO
Chlamydiae are obligate intracellular bacterial pathogens that may cause genital pathology via induction of destructive host immune responses. Human-adapted Chlamydia trachomatis causes inflammatory disease in human hosts but is easily cleared in mice, and mouse-adapted Chlamydia muridarum establishes a productive and pathogenic infection in murine hosts. While numerous anti-chlamydial host resistance factors have been discovered in mice and humans alike, little is known about host factors promoting host fitness independent of host resistance. Here, we show that interferon-inducible immunity-related GTPase M (Irgm) proteins function as such host factors ameliorating infection-associated sequalae in the murine female genital tract, thus characterizing Irgm proteins as mediators of disease tolerance. Specifically, we demonstrate that mice deficient for all three murine Irgm paralogs (pan-Irgm-/-) are defective for cell-autonomous immunity to C. trachomatis, which correlates with an early and transient increase in bacterial burden and sustained hyperinflammation in vivo. In contrast, upon infection of pan-Irgm-/- mice with C. muridarum, bacterial burden is unaffected, yet genital inflammation and scarring pathology are nonetheless increased, demonstrating that Irgm proteins can promote host fitness without altering bacterial burden. Additionally, pan-Irgm-/- mice display increased granulomatous inflammation in genital Chlamydia infection, implicating Irgm proteins in the regulation of granuloma formation and maintenance. These findings demonstrate that Irgm proteins regulate pathogenic immune responses to Chlamydia infection in vivo, establishing an effective infection model to examine the immunoregulatory functions and mechanisms of Irgm proteins. IMPORTANCE: In response to genital Chlamydia infection, the immune system mounts a proinflammatory response to resist the pathogen, yet inflammation must be tightly controlled to avoid collateral damage and scarring to host genital tissue. Variation in the human IRGM gene is associated with susceptibility to autoinflammatory diseases but its role in ameliorating inflammatory diseases caused by infections is poorly defined. Here, we use mice deficient for all three murine Irgm paralogs to demonstrate that Irgm proteins not only provide host resistance to Chlamydia infections but also limit associated inflammation in the female genital tract. In particular, we find that murine Irgm expression prevents granulomatous inflammation, which parallels inflammatory diseases associated with variants in human IRGM. Our findings therefore establish genital Chlamydia infection as a useful model to study the roles for Irgm proteins in both promoting protective immunity and limiting pathogenic inflammation.