Lymphocytic Choriomeningitis Research Articles

Delineating the transcriptional landscape and clonal diversity of virus-specific CD4+ T cells during chronic viral infection.

Although recent evidence indicates that CD4+ T cells responding to chronic viral infection are functionally heterogenous, our understanding of the developmental relationships between these subsets, and a determination of how their transcriptional landscape compares to their acute infection counterparts remains unclear. Additionally, whether cell-intrinsic factors such as TCR usage influence CD4+ T cell fate commitment during persistent infection has not previously been studied. Herein, we perform single-cell RNA sequencing (scRNA-seq) combined with single-cell T cell receptor sequencing (scTCR-seq) on virus-specific CD4+ T cells isolated from mice infected with chronic lymphocytic choriomeningitis virus (LCMV) infection. We identify several transcriptionally distinct states among the Th1, Tfh, and memory-like T cell subsets that form at the peak of infection, including the presence of a previously unrecognized Slamf7+ subset with cytolytic features. We further show that the relative distribution of these populations differs substantially between acute and persistent LCMV infection. Moreover, while the progeny of most T cell clones displays membership within each of these transcriptionally unique populations, overall supporting a one cell-multiple fate model, a small fraction of clones display a biased cell fate decision, suggesting that TCR usage may impact CD4+ T cell development during chronic infection. Importantly, comparative analyses further reveal both subset-specific and core gene expression programs that are differentially regulated between CD4+ T cells responding to acute and chronic LCMV infection. Together, these data may serve as a useful framework and allow for a detailed interrogation into the clonal distribution and transcriptional circuits underlying CD4+ T cell differentiation during chronic viral infection.

A Sampling of Highlights from the Literature.

Knockout of RASA2 enhances T-cell antitumor function (from Public Domain Vectors)Several immunosuppressive mechanisms limit the efficacy of adoptive T-cell therapies. Carnevale et al. performed six genome-wide CRISPR–Cas9 knock-out screens for regulators of T-cell resistance to immunosuppression by inhibitors of calcium and calcineurin, TGFβ, and regulatory T cells, identifying a role for RAS p21 protein activator 2 (RASA2) in each case. Knocking out RASA2A in human T cells, including T-cell receptor (TCR) and chimeric antigen receptor (CAR)–engineered T cells, enhances their antitumor function in vitro and in xenograft models of melanoma, osteosarcoma, and acute lymphoblastic leukemia. The data suggest ablation of RASA2 may enable the generation of more efficacious adoptive T-cell therapies.Carnevale J, …, Marson A. Nature 2022 August 24;609:174–82.CD62L+ TPEX cells mediate responses to anti–PD-1 (from NIAID via NIH Flickr)Precursors of exhausted T (TPEX) cells, characterized by expression of TCF1, mediate responsiveness to anti–PD-1. Following single-cell RNA sequencing of TPEX cell–enriched CD8+ T cells from mice chronically infected with lymphocytic choriomeningitis virus (LCMV), Tsui et al. stratify TPEX cells by expression of Sell, which encodes CD62L. The transcription factor MYB is required for the development of CD62L+ TPEX cells, which show enhanced capacity for self-renewal, multipotency, and long-term proliferation compared with CD62L– TPEX cells. CD62L+ TPEX cells are pivotal for responsiveness to anti–PD-1 in mice chronically infected with LCMV. Thus, it is vital that we better understand their role in T cell–mediated cancer immunotherapy.Tsui C, …, Kallies A. Nature 2022 August 17;609:354–60.iNKT cells outperform other cell therapies (from Todd van Hoosear via Flickr)The immune suppressive tumor microenvironment (TME) can curb responses to an array of cell-based therapies. Delfanti et al. demonstrate the utility of T-cell receptor (TCR)–engineered invariant natural killer T (iNKT) cells to overcome immune-suppressive barriers in the TME. The engineered iNKT cells act as bispecific effectors, bridging CD1d to MHC-restricted antigens on tumor cells, while also maintaining their known TME-modulating functions. Treatment with these cells outperforms nontransduced iNKT cells and CD8+ T cells expressing the same TCR, and efficacy can be boosted with addition of an iNKT-cell agonist. These data show that TCR-engineered iNKT cells could be a potential cell-based therapy for patients with cancer.Delfanti G, …, Casorati G. Sci Immunol 2022 August 19;7:sciimmunol.abn65.Targeting COX2+ fibroblasts can improve antitumor responses (from go digital via Flickr).How the premetastatic niche develops and what cell types in the metastasis-supporting organ are involved has not been fully elucidated. Gong et al. identify a subset of cyclooxygenase 2–positive (COX-2+) lung fibroblasts that modulate the function of multiple myeloid cell subsets, rendering them dysfunctional or immune suppressive. This process is enhanced by neutrophil-derived IL1β produced because of tumor-associated inflammation. In breast cancer models, targeting the COX2 pathway in these fibroblasts improves immunotherapy efficacy and reduces lung metastasis, highlighting how understanding the microenvironment of the premetastatic niche can facilitate identification of therapeutic targets to boost antitumor responses.Gong Z, …, Ren G. Immunity 2022 July 30;55:1483–1500.E9.In situ generation of CAR-macrophages effectively prevent GBM recurrence (from Christaras A via Wikimedia Commons)Recurrence of glioblastoma multiforme (GBM) after surgical resection is driven by residual glioma stem cells (GSC). Chen et al. developed a cavity-injectable hydrogel embedded with macrophage-targeted nanoporter particles that they used to deliver plasmids encoding a CD133-directed chimeric antigen receptor (CAR) to macrophages in situ following tumor resection in preclinical models. The CAR+ macrophages target GSCs and show antitumor activity in vitro and in vivo, including preventing recurrence of surgically resected GBM in an orthotopic patient-derived xenograft model. These findings suggest that the injectable CAR-macrophage platform may be an effective therapeutic strategy to improve long-term survival of GBM patients.Chen C, …, Jiang X. Sci Trans Med 2022 Aug 3;14:scitranslmed.abn1128.Tumor-reactive T cells exhibit signatures of activation indicative of their TCR avidity (from Takuma-sa via Wikimedia Commons)The impact of T-cell receptor (TCR) avidity on T-cell antitumor activity remains unclear. Through adoptive transfer of ultra-low (<1000) numbers of T cells with OVA-specific TCRs of varying avidity into mice bearing OVA-expressing tumors, Purcarea et al. found that tumor-reactive T cells in tissues outside of tumors express PD-1 proportional to the avidity of their TCR and to their protective capacity. Tumor-infiltrating and peripheral T cells isolated from human melanoma patients exhibit gene expression and phenotypic signatures of ex vivo TCR functionality and cytotoxicity, altogether presenting molecular markers of highly active tumor-specific T cells.Purcarea A, …, Schober K. Sci Immunol 2022 August 12;7:sciimmunol.abm207.

Multiple brain abscesses in a newborn with Down syndrome: heart disease or meningeal infection?

Introduction: Cerebral abscess is a rare pathology in the newborn, most often secondary to meningeal involvement, but congenital heart disease is to be feared. Objectives: To review a case of multiple cerebral abscesses in the newborn with a doubtful diagnosis through a clinical case. Observation: Newborn at D6 of life, from a fullterm pregnancy, with a negative infectious anamnesis, admitted for fever at 38. The first one appeared at D4 of life, in whom the clinical examination found an icteric newborn, with a trisomic face, tachycardia at 180bpm, axial hypotonia, FANT and RS+, systolic cardiac murmur and light sub-costal draught. In front of this picture, a lumbar puncture was carried out objectifying a lymphocytic meningitis, At J8 of life, the newborn presented a convulsion, An ETF was carried out objectifying a hypoechogenic image with hyperchogenic border in cocarde evoking an abces confirmed by CT. The echocardium performed as part of the etiological workup, objective a single ventricle, CIA ostium primum large, IVC admission, single atrio ventricular valve, complete atrio ventricular canal, persistence of the ductus arteriosus and Coarctation of the aorta. The newborn was put on parenteral antibiotic therapy based on C3G meningeal dose + vancomycin + metronidazole by intravenous route then oral relay, with a scannographic control and neurological clinical evaluation. In front of this case, the question that arises: are his abscesses secondary to meningitis or to congenital heart disease? Conclusion: Brain abscess is a rare pathology, with heavy after-effects, and the prognosis of patients has improved thanks to the progress of imaging techniques, the use of ATB treatments, and minimally invasive neurosurgery. It is to be feared in front of congenital cardiopathies with right-left shunt.

PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program.

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1+IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+T cells that resemble highly functional effector CD8+T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1+IL-2 combination therapy. There is considerable interest in PD-1+IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.

The Pan-ErbB tyrosine kinase inhibitor afatinib inhibits multiple steps of the mammarenavirus life cycle

The mammarenavirus Lassa virus (LASV) causes a life-threatening acute febrile disease, Lassa fever (LF). To date, no US Food and Drug Administration (FDA)-licensed medical countermeasures against LASV are available. This underscores the need for the development of novel anti-LASV drugs. Here, we screen an FDA-approved drug library to identify novel anti-LASV drug candidates using an infectious-free cell line expressing a functional LASV ribonucleoprotein (vRNP), where levels of vRNP-directed reporter gene expression serve as a surrogate for vRNP activity. Our screen identified the pan-ErbB tyrosine kinase inhibitor afatinib as a potent inhibitor of LASV vRNP activity. Afatinib inhibited multiplication of lymphocytic choriomeningitis virus (LCMV) a mammarenavirus closely related to LASV. Cell-based assays revealed that afatinib inhibited multiple steps of the LASV and LCMV life cycles. Afatinib also inhibited multiplication of Junín virus vaccine strain Candid#1, indicating that afatinib can have antiviral activity against a broad range of human pathogenic mammarenaviruses.

Directly injected lentiviral vector-based T cell vaccine protects mice against acute and chronic viral infection.

Lentiviral vector-based dendritic cell vaccines induce protective T cell responses against viral infection and cancer in animal models. In this study, we tested whether preventative and therapeutic vaccination could be achieved by direct injection of antigen-expressing lentiviral vector, obviating the need for ex vivo transduction of dendritic cells. Injected lentiviral vector preferentially transduced splenic dendritic cells and resulted in long-term expression. Injection of a lentiviral vector encoding an MHC class I-restricted T cell epitope of lymphocytic choriomeningitis virus (LCMV) and CD40 ligand induced an antigen-specific cytolytic CD8+ T lymphocyte response that protected the mice from infection. The injection of chronically infected mice with a lentiviral vector encoding LCMV MHC class I and II T cell epitopes and a soluble programmed cell death 1 microbody rapidly cleared the virus. Vaccination by direct injection of lentiviral vector was more effective in sterile alpha motif and HD-domain containing protein 1-knockout (SAMHD1-knockout) mice, suggesting that lentiviral vectors containing Vpx, a lentiviral protein that increases the efficiency of dendritic cell transduction by inducing the degradation of SAMHD1, would be an effective strategy for the treatment of chronic disease in humans.

Visualizing lymphocytic choriomeningitis virus infection in cells and living mice

SummaryMammarenavirus are a large family of enveloped negative-strand RNA viruses that include several agents responsible for severe hemorrhagic fevers. Until now, no FDA-licensed drug has been admitted for treating an arenavirus infection, and only few effective anti-arenavirus drugs have been tested in vivo. In this work, we designed a recombinant reporter arenavirus lymphocytic choriomeningitis virus that stably expressed nanoluciferase (LCMV-Nluc). The LCMV-Nluc was proved to share similar biological properties with wild-type LCMV and the Nluc intensity reliably reflected viral replication both in vitro and in vivo. Replication of the Nluc-encoding virus in living mice can be visualized by real-time bioluminescent imaging, and bioluminescence can be detected in a variety of organs of infected mice. This work provides a novel approach that enables real-time study of the arenavirus infection and is a convenient and valuable tool for screening of compounds that are active against arenaviruses in vitro and in living mice.

Lymphocytic choriomeningitis virus: An under-recognized congenital teratogen.

BACKGROUNDLymphocytic choriomeningitis virus (LCMV) is a neglected rodent-borne arenavirus associated with transplacental transmission and fetal infection. AIMTo summarize the epidemiological, clinical, and diagnostic features of reported patients with congenital LCMV infection.METHODSA literature search was conducted in PubMed, Medline, Google Scholar, and ResearchGate. The keywords used were ‘congenital lymphocytic choriomeningitis virus,’ and 48 studies were included. In addition, we conducted a relevant search by Reference Citation Analysis (RCA) (https://www.referencecitationanalysis.com).RESULTSThe results have shown 27 reports of congenital LCMV infection in 86 patients, with 52.73% of them being males. Patients presented with chorioretinitis (83.53%), hydrocephalus (54.12%), and psychomotor retardation or developmental delay (54.12%). Computed tomography and/or magnetic resonance imaging most often demonstrated ventriculomegaly (74.07%), periventricular calcifications (66.67%), and microcephaly (40%). Most mothers of congenitally infected infants were exposed to rodents during pregnancy, predominantly mice, with flu-like symptoms mainly occurring during the first two trimesters of gestation. Mortality in congenitally infected children was 16.47%. The diagnosis of congenital LCMV infection was confirmed serologically in most patients (86.67%).CONCLUSIONLCMV is still an insufficiently recognized fetal teratogen that often leads to long-term neurologic sequelae. Clinicians need to be familiar with LCMV and its potential teratogenic effect and as well as to effectively differentiate LCMV from other TORCH (T: Toxoplasma gondii, O: Other pathogens, R: Rubella virus, C: Cytomegalovirus, H: Herpes simplex virus) pathogens.

Large viral meningoencephalitis CSF serologic panel lacks utility in clinical decisions and outcomes

IntroductionAccurate diagnosis of viral meningoencephalitis (VMe) and identification of the etiologic agent has clinical importance and large serology panels are available to aid in the detection of several viral pathogens. However, such panels are often send-out testing, with prolonged time to results, thus impacting the actionability of test results. We hypothesized these panels may not contribute to patient care and lack clinical utility. MethodsA retrospective review of all VMe CSF serology panels ordered at one pediatric (n = 53; 2017–2019) and two adult (n = 200; 2019–2020) tertiary care hospitals was performed to assess test clinical utility. Panels included serology for: Adenovirus, coxsackie and echoviruses, influenza, measles, lymphocytic choriomeningitis virus, herpes simplex virus, mumps, varicella zoster, encephalitis viruses. Clinical data collected included diagnostic test results, symptoms, comorbidities, and interventions. ResultsIn 129/200 (64.5 %) of adult cases and 37/53 (69.8 %) of pediatric cases CSF had a WBC less than 5 cells/mm2. In total, 127 (63.5 %, 127/200) adult panels had at least one positive target with 49 panels having more than one positive (38.6 %, 49/127). In 99.5 % of adult and 100 % of pediatric cases there was no change to decisions regarding starting, discontinuing, continuing, or changing antimicrobial therapy based on panel results. In no cases were potentially immunosuppressive therapies like steroid or IVIG administration delayed while awaiting the results of the panel. ConclusionsWhile all patients presented with neurologic symptoms, poor pre-screening for CNS inflammation using CSF WBC analysis likely contributed to poor clinical utility of the VMe panels. Large CSF serologic panels for VMe did not contribute to or add value to clinical decision making in our cohort.

Loss of CD47 alters CD8+ T cell activation in vitro and immunodynamics in mice

ABSTRACT CD47 has established roles in the immune system for regulating macrophage phagocytosis and lymphocyte activation, with growing evidence of its cell-intrinsic regulatory roles in natural killer and CD8+ T cells. CD47 limits antigen-dependent cytotoxic activities of human and murine CD8+ T cells, but its role in T cell activation kinetics remains unclear. Using in vitro and in vivo models, we show here that CD47 differentially regulates CD8+ T cell responses to short- versus long-term activation. Although CD47 was not required for T cell development in mice and early activation in vitro, short-term stimuli elevated pathogen-reactive gene expression and enhanced proliferation and the effector phenotypes of Cd47-deficient relative to Cd47-sufficient CD8+ T cells. In contrast, persistent TCR stimulation limited the effector phenotypes of Cd47 −/− CD8+ T cells and enhanced their apoptosis signature. CD8+ T cell expansion and activation in vivo induced by acute lymphocytic choriomeningitis virus (LCMV) infection did not differ in the absence of CD47. However, the frequency and effector phenotypes of Cd47−/− CD8+ T cells were constrained in chronic LCMV-infected as well as in mice bearing B16 melanoma tumors. Therefore, CD47 regulates CD8+ T cell activation, proliferation, and fitness in a context-dependent manner.

Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses

Viral hemorrhagic fevers caused by members of the order Bunyavirales comprise endemic and emerging human infections that are significant public health concerns. Despite the disease severity, there are few therapeutic options available, and therefore effective antiviral drugs are urgently needed to reduce disease burdens. Bunyaviruses, like influenza viruses (IFVs), possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We screened compounds from our CEN inhibitor (CENi) library and identified specific structural compounds that are 100 to 1,000 times more active invitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. To investigate their inhibitory mechanism of action, drug-resistant viruses were selected in culture. Whole-genome sequencing revealed that amino acid substitutions in the CEN region of drug-resistant viruses were located in similar positions as those of the CEN α3-helix loop of IFVs derived under drug selection. Thus, our studies suggest that CENi compounds inhibit both bunyavirus and IFV replication in a mechanistically similar manner. Structural analysis revealed that the side chain of the carboxyl group at the seventh position of the main structure of the compound was essential for the high antiviral activity against bunyaviruses. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. These data suggest a potential broad-spectrum clinical utility of CENis for the treatment of both severe influenza and hemorrhagic diseases caused by bunyaviruses.

Single-cell immune repertoire sequencing of B and T cells in murine models of infection and autoimmunity

Adaptive immune repertoires are composed by the ensemble of B and T-cell receptors within an individual, reflecting both past and current immune responses. Recent advances in single-cell sequencing enable recovery of the complete adaptive immune receptor sequences in addition to transcriptional information. Here, we recovered transcriptome and immune repertoire information for polyclonal T follicular helper cells following lymphocytic choriomeningitis virus (LCMV) infection, CD8+ T cells with binding specificity restricted to two distinct LCMV peptides, and B and T cells isolated from the nervous system in the context of experimental autoimmune encephalomyelitis. We could relate clonal expansion, germline gene usage, and clonal convergence to cell phenotypes spanning activation, memory, naive, antibody secretion, T-cell inflation, and regulation. Together, this dataset provides a resource for immunologists that can be integrated with future single-cell immune repertoire and transcriptome sequencing datasets.

Optimal disturbances for periodic solutions of time-delay differential equations

Abstract A concept of optimal disturbances of periodic solutions for a system of time-delay differential equations is defined. An algorithm for computing the optimal disturbances is proposed and justified. This algorithm is tested on the known system of four nonlinear time-delay differential equations modelling the dynamics of the experimental infection caused by the lymphocytic choriomeningitis virus. The results of numerical experiments are discussed.

Human LAMP1 accelerates Lassa virus fusion and potently promotes fusion pore dilation upon forcing viral fusion with non-endosomal membrane.

Lassa virus (LASV) cell entry is mediated by the interaction of the virus glycoprotein complex (GPC) with alpha-dystroglycan at the cell surface followed by binding to LAMP1 in late endosomes. However, LAMP1 is not absolutely required for LASV fusion, as this virus can infect LAMP1-deficient cells. Here, we used LASV GPC pseudoviruses, LASV virus-like particles and recombinant lymphocytic choriomeningitis virus expressing LASV GPC to investigate the role of human LAMP1 (hLAMP1) in LASV fusion with human and avian cells expressing a LAMP1 ortholog that does not support LASV entry. We employed a combination of single virus imaging and virus population-based fusion and infectivity assays to dissect the hLAMP1 requirement for initiation and completion of LASV fusion that culminates in the release of viral ribonucleoprotein into the cytoplasm. Unexpectedly, ectopic expression of hLAMP1 accelerated the kinetics of small fusion pore formation, but only modestly increased productive LASV fusion and infection of human and avian cells. To assess the effects of hLAMP1 in the absence of requisite endosomal host factors, we forced LASV fusion with the plasma membrane by applying low pH. Unlike the conventional LASV entry pathway, ectopic hLAMP1 expression dramatically promoted the initial and full dilation of pores formed through forced fusion at the plasma membrane. We further show that, while the soluble hLAMP1 ectodomain accelerates the kinetics of nascent pore formation, it fails to promote efficient pore dilation, suggesting the hLAMP1 transmembrane domain is involved in this late stage of LASV fusion. These findings reveal a previously unappreciated role of hLAMP1 in promoting dilation of LASV fusion pores, which is difficult to ascertain for endosomal fusion where several co-factors, such as bis(monoacylglycero)phosphate, likely regulate LASV entry.

Insights into Virus-Induced Immune Mediated Liver Pathology

In the context of chronic viral infections, the hepatic microenvironment dictates the outcome of the disease by influencing propagation of virus and regulation of cytotoxic CD8+ T cell response. Nevertheless, such regulation could be beneficial as it resolves the disease or could be detrimental as it causes liver pathological consequences. Liver pathology is a hallmark of chronic viral infection in both human and murine models. Such models show viral infection of hepatocytes and subsequent direct hepatic damage. Other compelling studies showed that liver injury was a consequence of overshooting CD8+ T cells response in experimental mice, so-called immune-mediated liver pathology. This review highlights the viral-induced immune mediated aspects of liver pathology based on the lymphocytic choriomeningitis virus (LCMV) and Hepatitis virus settings.

Locally acquired lymphocytic choriomeningitis virus infections in South-East Queensland: an outbreak of a pathogen rarely described in Australia.

Lymphocytic choriomeningitis virus (LCMV) is a zoonotic virus that can cause clinically significant illnesses in humans. Although cases of LCMV infection are well described globally, and there is evidence that the virus is present in Australian rodent populations, there has been only one case of domestically acquired LCMV infection published previously. Here, we describe a cluster of LCMV infections in South-East Queensland identified in early 2021, and the diagnostic testing processes implemented. This identifies LCMV as an under-recognised human pathogen in Australia.

Lymphocytic Choriomeningitis Virus Infection, Australia.

During a mouse plague in early 2021, a farmer from New South Wales, Australia, sought treatment for aseptic meningitis and was subsequently diagnosed with locally acquired lymphocytic choriomeningitis virus infection. Whole-genome sequencing identified a divergent and geographically distinct lymphocytic choriomeningitis virus strain compared with other published sequences.

Adoptive B cell therapy for chronic viral infection.

T cell-based therapies have been widely explored for the treatment of cancer and chronic infection, but B cell-based therapies have remained largely unexplored. To study the effect of B cell therapy, we adoptively transferred virus-specific B cells into mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). Adoptive transfer of virus-specific B cells resulted in increase in antibody titers and reduction of viral loads. Importantly, the efficacy of B cell therapy was partly dependent on antibody effector functions, and was improved by co-transferring virus-specific CD4 T cells. These findings provide a proof-of-concept that adoptive B cell therapy can be effective for the treatment of chronic infections, but provision of virus-specific CD4 T cells may be critical for optimal virus neutralization.

Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression.

The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8+ T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA/1J and DBA/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA/2J presented with exhausted T cells and persistent infection, and DBA/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA/1J and DBA/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA’s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection.

Vogt-Koyanagi-Harada disease diagnosed in members of the same family

Vogt-Koyanagi-Harada syndrome (VKH syndrome) is a rare granulomatous inflammatory disease that affects melanocyte pigment-producing melanocytes and primarily affects pigmented structures such as the eyes, inner ear, skin, meninges, and hair. VKT is an autoimmune disease, which is primarily a CD4 + Th1 T lymphocyte-mediated aggression to melanocytes. Melanin usually gives color to the skin, hair and eyes. Melanin is also found in the retina, where it plays a role in normal vision. The absence of ocular trauma or previous intraocular surgery differentiates VKHD from sympathetic ophthalmia, its main differential diagnosis. The disease has an acute onset of bilateral blurred vision with hyperemia preceded by flu-like symptoms. The acute uveitic stage is characterized by diffuse choroiditis with serous retinal detachment and optic disc hyperemia and edema. Fluorescein angiography at this stage demonstrates multiple initial hyperfluorescent dots. After the acute uveitic stage, pigmentary changes in the ocular and integumentary system may appear. Ocular findings may be accompanied by lymphocytic meningitis, hearing loss and/or tinnitus in a variable proportion of patients. Prompt diagnosis followed by early, aggressive, and long-term treatment with high-dose corticosteroids is most often followed by good visual results. However, some patients may have chronic uveal inflammation with functional deterioration of the eye.