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Immunity ; 54(12): 2772-2783.e5, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1517288


Humoral immunity is essential for protection against pathogens, emphasized by the prevention of 2-3 million deaths worldwide annually by childhood immunizations. Long-term protective immunity is dependent on the continual production of neutralizing antibodies by the subset of long-lived plasma cells (LLPCs). LLPCs are not intrinsically long-lived, but require interaction with LLPC niche stromal cells for survival. However, it remains unclear which and how these interactions sustain LLPC survival and long-term humoral immunity. We now have found that the immunosuppressive enzyme indoleamine 2,3- dioxygenase 1 (IDO1) is required to sustain antibody responses and LLPC survival. Activation of IDO1 occurs upon the engagement of CD80/CD86 on the niche dendritic cells by CD28 on LLPC. Kynurenine, the product of IDO1 catabolism, activates the aryl hydrocarbon receptor in LLPC, reinforcing CD28 expression and survival signaling. These findings expand the immune function of IDO1 and uncover a novel pathway for sustaining LLPC survival and humoral immunity.

Dendritic Cells/immunology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Plasma Cells/immunology , Animals , Antibodies, Neutralizing/metabolism , B7-1 Antigen/metabolism , CD28 Antigens/metabolism , Cell Self Renewal , Cell Survival , Cells, Cultured , Female , Immunity, Humoral , Immunologic Memory , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Mice , Mice, Knockout
Signal Transduct Target Ther ; 5(1): 192, 2020 09 07.
Article in English | MEDLINE | ID: covidwho-748172

Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Gene Expression Regulation/immunology , Lymphopenia/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Adult , Aged , Aged, 80 and over , Betacoronavirus/immunology , Biomarkers/blood , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/genetics , Coronavirus Infections/mortality , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/mortality , Disease Progression , Female , Hepatitis A Virus Cellular Receptor 2/blood , Hepatitis A Virus Cellular Receptor 2/genetics , Hepatitis A Virus Cellular Receptor 2/immunology , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/blood , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Lymphocyte Count , Lymphopenia/diagnosis , Lymphopenia/genetics , Lymphopenia/mortality , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/genetics , Pneumonia, Viral/mortality , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Survival Analysis , T-Lymphocytes/virology , Tumor Necrosis Factor Receptor Superfamily, Member 7/blood , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 9/blood , Tumor Necrosis Factor Receptor Superfamily, Member 9/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology
Restor Neurol Neurosci ; 38(4): 343-354, 2020.
Article in English | MEDLINE | ID: covidwho-621099


Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into cells, corona viruses (CoV) activate aryl hydrocarbon receptors (AhRs) by an indoleamine 2,3-dioxygenase (IDO1)-independent mechanism, bypassing the IDO1-kynurenine-AhR pathway. The IDO1-kynurenine-AhR signaling pathway is used by multiple viral, microbial and parasitic pathogens to activate AhRs and to establish infections. AhRs enhance their own activity through an IDO1-AhR-IDO1 positive feedback loop prolonging activation induced by pathogens. Direct activation of AhRs by CoV induces immediate and simultaneous up-regulation of diverse AhR-dependent downstream effectors, and this, in turn, results in a "Systemic AhR Activation Syndrome" (SAAS) consisting of inflammation, thromboembolism, and fibrosis, culminating in multiple organ injuries, and death. Activation of AhRs by CoV may lead to diverse sets of phenotypic disease pictures depending on time after infection, overall state of health, hormonal balance, age, gender, comorbidities, but also diet and environmental factors modulating AhRs. We hypothesize that elimination of factors known to up-regulate AhRs, or implementation of measures known to down-regulate AhRs, should decrease severity of infection. Although therapies selectively down-regulating both AhR and IDO1 are currently lacking, medications in clinical use such as dexamethasone may down-regulate both AhR and IDO1 genes, as calcitriol/vitamin D3 may down-regulate the AhR gene, and tocopherol/vitamin E may down-regulate the IDO1 gene. Supplementation of calcitriol should therefore be subjected to epidemiological studies and tested in prospective trials for prevention of CoV infections, as should tocopherol, whereas dexamethasone could be tried in interventional trials. Because lack of physical exercise activates AhRs via the IDO1-kynurenine-AhR signaling pathway increasing risk of infection, physical exercise should be encouraged during quarantines and stay-at-home orders during pandemic outbreaks. Understanding which factors affect gene expression of both AhR and IDO1 may help in designing therapies to prevent and treat humans suffering from Covid-19.

Betacoronavirus/physiology , Coronavirus Infections/physiopathology , Indoleamine-Pyrrole 2,3,-Dioxygenase/physiology , Pandemics , Pneumonia, Viral/physiopathology , Receptors, Aryl Hydrocarbon/physiology , Air Pollutants/adverse effects , COVID-19 , Calcitriol/therapeutic use , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Dexamethasone/therapeutic use , Exercise , Feedback, Physiological , Female , Fibrosis/etiology , Gene Expression Regulation/drug effects , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/biosynthesis , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Inflammation/etiology , Kynurenine/physiology , Male , Molecular Targeted Therapy , Multiple Organ Failure/etiology , Obstetric Labor, Premature/etiology , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pregnancy , Pregnancy Complications, Infectious/physiopathology , Receptors, Aryl Hydrocarbon/biosynthesis , Receptors, Aryl Hydrocarbon/genetics , SARS-CoV-2 , Sensation Disorders/etiology , Signal Transduction/drug effects , Signal Transduction/physiology , Thromboembolism/etiology , Tocopherols/therapeutic use , COVID-19 Drug Treatment
J Virol ; 94(3)2020 01 17.
Article in English | MEDLINE | ID: covidwho-124739


The aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor/transcription factor that modulates several cellular and immunological processes following activation by pathogen-associated stimuli, though its role during virus infection is largely unknown. Here, we show that AhR is activated in cells infected with mouse hepatitis virus (MHV), a coronavirus (CoV), and contributes to the upregulation of downstream effector TCDD-inducible poly(ADP-ribose) polymerase (TiPARP) during infection. Knockdown of TiPARP reduced viral replication and increased interferon expression, suggesting that TiPARP functions in a proviral manner during MHV infection. We also show that MHV replication induced the expression of other genes known to be downstream of AhR in macrophages and dendritic cells and in livers of infected mice. Further, we found that chemically inhibiting or activating AhR reciprocally modulated the expression levels of cytokines induced by infection, specifically, interleukin 1ß (IL-1ß), IL-10, and tumor necrosis factor alpha (TNF-α), consistent with a role for AhR activation in the host response to MHV infection. Furthermore, while indoleamine 2,3-dioxygenase (IDO1) drives AhR activation in other settings, MHV infection induced equal expression of downstream genes in wild-type (WT) and IDO1-/- macrophages, suggesting an alternative pathway of AhR activation. In summary, we show that coronaviruses elicit AhR activation by an IDO1-independent pathway, contributing to upregulation of downstream effectors, including the proviral factor TiPARP, and to modulation of cytokine gene expression, and we identify a previously unappreciated role for AhR signaling in CoV pathogenesis.IMPORTANCE Coronaviruses are a family of positive-sense RNA viruses with human and agricultural significance. Characterizing the mechanisms by which coronavirus infection dictates pathogenesis or counters the host immune response would provide targets for the development of therapeutics. Here, we show that the aryl hydrocarbon receptor (AhR) is activated in cells infected with a prototypic coronavirus, mouse hepatitis virus (MHV), resulting in the expression of several effector genes. AhR is important for modulation of the host immune response to MHV and plays a role in the expression of TiPARP, which we show is required for maximal viral replication. Taken together, our findings highlight a previously unidentified role for AhR in regulating coronavirus replication and the immune response to the virus.

Cytokines/metabolism , Gene Expression Regulation, Enzymologic , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Murine hepatitis virus/physiology , Poly(ADP-ribose) Polymerases/biosynthesis , Proviruses/physiology , Receptors, Aryl Hydrocarbon/metabolism , Virus Replication/physiology , Animals , Cytokines/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Mice , Mice, Knockout , Poly(ADP-ribose) Polymerases/genetics , Receptors, Aryl Hydrocarbon/genetics , Signal Transduction