scholarly journals Enterocytes, fibroblasts and myeloid cells synergize in anti-bacterial and anti-viral pathways with IL22 as the central cytokine

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jean Paul ten Klooster ◽  
Marianne Bol-Schoenmakers ◽  
Kitty van Summeren ◽  
Arno L. W. van Vliet ◽  
Cornelis A. M. de Haan ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Viral Entry ◽  
Defense Mechanisms ◽  
Viral Infections ◽  
Myeloid Cells ◽  
Viral Proteins ◽  
Intestinal Cells ◽  
Important Cytokine ◽  
Bacterial Products

AbstractIL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNβ1 and subsequently IL7. IFNβ1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.

scholarly journals Antioxidant Treatment Reduces Expansion and Contraction of Antigen-Specific CD8+ T Cells during Primary but Not Secondary Viral Infection

2004 ◽  
Vol 78 (20) ◽  
pp. 11246-11257 ◽  
Author(s):  
Nathan G. Laniewski ◽  
Jason M. Grayson
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Large Scale ◽  
Viral Infections ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Response ◽  
Oxygen Intermediates ◽  
Mimetic Compound

ABSTRACT During many viral infections, antigen-specific CD8+ T cells undergo large-scale expansion. After viral clearance, the vast majority of effector CD8+ T cells undergo apoptosis. Previous studies have implicated reactive oxygen intermediates (ROI) in lymphocyte apoptosis. The purpose of the experiments presented here was to determine the role of ROI in the expansion and contraction of CD8+ T cells in vivo during a physiological response such as viral infection. Mice were infected with lymphocytic choriomeningitis virus (LCMV) and treated with Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), a metalloporphyrin-mimetic compound with superoxide dismutase activity, from days 0 to 8 postinfection. At the peak of CD8+-T-cell response, on day 8 postinfection, the numbers of antigen-specific cells were 10-fold lower in MnTBAP-treated mice than in control mice. From days 8 to 30, a contraction phase ensued where the numbers of antigen-specific CD8+ T cells declined 25-fold in vehicle-treated mice compared to a 3.5-fold decrease in MnTBAP-treated mice. Differences in contraction appeared to be due to greater proliferation in drug-treated mice. By day 38, the numbers of antigen-specific CD8+ memory T cells were equivalent for the two groups. The administration of MnTBAP during secondary viral infection had no effect on the expansion of antigen-specific CD8+ secondary effector T cells. These data suggest that ROI production is critical for the massive expansion and contraction of antigen-specific CD8+ T cells during primary, but not secondary, viral infection.

scholarly journals Viral infection prevents diabetes by inducing regulatory T cells through NKT cell–plasmacytoid dendritic cell interplay

2011 ◽  
Vol 208 (4) ◽  
pp. 729-745 ◽  
Author(s):  
Julien Diana ◽  
Vedran Brezar ◽  
Lucie Beaudoin ◽  
Marc Dalod ◽  
Andrew Mellor ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Viral Infection ◽  
Pancreatic Islets ◽  
Viral Infections ◽  
Plasmacytoid Dendritic Cell ◽  
Inkt Cells ◽  
Pancreatic Lymph Nodes

Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell–mediated destruction of insulin-producing β cells, and viral infections can prevent the onset of disease. Invariant natural killer T cells (iNKT cells) exert a regulatory role in T1D by inhibiting autoimmune T cell responses. As iNKT cell–plasmacytoid dendritic cell (pDC) cooperation controls viral replication in the pancreatic islets, we investigated whether this cellular cross talk could interfere with T1D development during viral infection. Using both virus-induced and spontaneous mouse models of T1D, we show that upon viral infection, iNKT cells induce TGF-β–producing pDCs in the pancreatic lymph nodes (LNs). These tolerogenic pDCs convert naive anti-islet T cells into Foxp3+ CD4+ regulatory T cells (T reg cells) in pancreatic LNs. T reg cells are then recruited into the pancreatic islets where they produce TGF-β, which dampens the activity of viral- and islet-specific CD8+ T cells, thereby preventing T1D development in both T1D models. These findings reveal a crucial cooperation between iNKT cells, pDCs, and T reg cells for prevention of T1D by viral infection.

scholarly journals A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Torben Knuschke ◽  
Sebastian Kollenda ◽  
Christina Wenzek ◽  
Gennadiy Zelinskyy ◽  
Philine Steinbach ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
Viral Infection ◽  
Viral Infections ◽  
T Cell Immunity ◽  
Chronic Viral Infection ◽  
Therapeutic Vaccination ◽  
Chronic Viral Infections ◽  
Cell Immunity

ABSTRACT PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection. Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Prevention of inhibitory signals by blocking PD-L1 in combination with therapeutic vaccination with nanoparticles containing the microbial compound CpG and a CD8+ T cell Gag epitope peptide synergistically enhanced functional virus-specific CD8+ T cell responses and improved viral clearance. We characterized the CD8+ T cell populations that were affected by this combination therapy, demonstrating that new effector cells were generated and that exhausted CD8+ T cells were reactivated at the same time. While CD8+ T cells with high PD-1 (PD-1hi) expression turned into a large population of granzyme B-expressing CD8+ T cells after combination therapy, CXCR5-expressing follicular cytotoxic CD8+ T cells also expanded to a high degree. Thus, our study describes a very efficient approach to enhance virus control and may help us to understand the mechanisms of combination immunotherapy reactivating CD8+ T cell immunity. A better understanding of CD8+ T cell immunity during combination therapy will be important for developing efficient checkpoint therapies against chronic viral infections and cancer. IMPORTANCE Despite significant efforts, vaccines are not yet available for every infectious pathogen, and the search for a protective approach to prevent the establishment of chronic infections, i.e., with HIV, continues. Immune checkpoint therapies targeting inhibitory receptors, such as PD-1, have shown impressive results against solid tumors. However, immune checkpoint therapies have not yet been licensed to treat chronic viral infections, since a blockade of inhibitory receptors alone provides only limited benefit, as demonstrated in preclinical models of chronic viral infection. Thus, there is a high interest in the development of potent combination immunotherapies. Here, we tested whether the combination of a PD-L1 blockade and therapeutic vaccination with functionalized nanoparticles is a potent therapy during chronic Friend retrovirus infection. We demonstrate that the combination therapy induced a synergistic reinvigoration of the exhausted virus-specific CD8+ T cell immunity. Taken together, our results provide further information on how to improve PD-1-targeted therapies during chronic viral infection and cancer.

scholarly journals The iminosugars celgosivir, castanospermine and UV-4 inhibit SARS-CoV-2 replication

Glycobiology ◽  
2020 ◽  
Author(s):  
Elizabeth C Clarke ◽  
Robert A Nofchissey ◽  
Chunyan Ye ◽  
Steven B Bradfute
Keyword(s):  
Viral Replication ◽  
Viral Entry ◽  
Global Economy ◽  
Viral Infections ◽  
Active Form ◽  
Viral Proteins ◽  
Spike Protein ◽  
Dependent Manner ◽  
Protein Levels ◽  
A Cell

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an unprecedented challenge for health care and the global economy. Repurposing drugs that have shown promise in inhibiting other viral infections could allow for more rapid dispensation of urgently needed therapeutics. The Spike protein of SARS-CoV-2 is extensively glycosylated with 22 occupied N glycan sites and is required for viral entry. In other glycosylated viral proteins, glycosylation is required for interaction with calnexin and chaperone-mediated folding in the endoplasmic reticulum, and prevention of this interaction leads to unfolded viral proteins and thus inhibits viral replication. As such, we investigated two iminosugars, celgosivir, a prodrug of castanospermine, and UV-4, or N-(9-methoxynonyl)-1-deoxynojirimycin, a deoxynojirimycin derivative. Iminosugars are known inhibitors of the α-glucosidase I and II enzymes and were effective at inhibiting authentic SARS-CoV-2 viral replication in a cell culture system. Celgosivir prevented SARS-CoV-2-induced cell death and reduced viral replication and Spike protein levels in a dose-dependent manner in culture with Vero E6 cells. Castanospermine, the active form of celgosivir, was also able to inhibit SARS-CoV-2, confirming the canonical castanospermine mechanism of action of celgosivir. The monocyclic UV-4 also prevented SARS-CoV-2-induced death and reduced viral replication after 24 h of treatment, although the reduction in viral copies was lost after 48 h. Our findings suggest that iminosugars should be urgently investigated as potential SARS-CoV-2 inhibitors.

scholarly journals Viral Infection of Human Natural Killer Cells

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 243 ◽  
Author(s):  
Elisabeth van Erp ◽  
Mirjam van Kampen ◽  
Puck van Kasteren ◽  
Jelle de Wit
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Viral Entry ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Infection ◽  
Comprehensive Overview ◽  
Human Natural Killer Cells ◽  
Syncytial Virus

Natural killer (NK) cells are essential in the early immune response against viral infections, in particular through clearance of virus-infected cells. In return, viruses have evolved multiple mechanisms to evade NK cell-mediated viral clearance. Several unrelated viruses, including influenza virus, respiratory syncytial virus, and human immunodeficiency virus, can directly interfere with NK cell functioning through infection of these cells. Viral infection can lead to immune suppression, either by downregulation of the cytotoxic function or by triggering apoptosis, leading to depletion of NK cells. In contrast, some viruses induce proliferation or changes in the morphology of NK cells. In this review article, we provide a comprehensive overview of the viruses that have been reported to infect NK cells, we discuss their mechanisms of entry, and describe the interference with NK cell effector function and phenotype. Finally, we discuss the contribution of virus-infected NK cells to viral load. The development of specific therapeutics, such as viral entry inhibitors, could benefit from an enhanced understanding of viral infection of NK cells, opening up possibilities for the prevention of NK cell infection.

HLA class II upregulation during viral infection leads to HLA-DP–directed graft-versus-host disease after CD4+ donor lymphocyte infusion

Blood ◽  
2013 ◽  
Vol 122 (11) ◽  
pp. 1963-1973 ◽  
Author(s):  
Sanja Stevanović ◽  
Cornelis A. M. van Bergen ◽  
Simone A. P. van Luxemburg-Heijs ◽  
Boris van der Zouwen ◽  
Ekaterina S. Jordanova ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Graft Versus Host Disease ◽  
Cd4 T Cells ◽  
Viral Infections ◽  
Class Ii ◽  
Donor Lymphocyte Infusion ◽  
Hla Class Ii ◽  
Graft Versus Host ◽  
Key Points

Key Points GVHD after HLA-DPB1–mismatched CD4+ DLI after TCD-alloSCT is mediated by allo-reactive HLA-DPB1–directed CD4+ T cells. Viral infections after TCD-alloSCT can induce HLA class II on nonhematopoietic tissues, making them targets for CD4+ T cells in GVHD.

scholarly journals Abortive versus Productive Viral Infection of Dendritic Cells with a Paramyxovirus Results in Differential Upregulation of Select Costimulatory Molecules

2005 ◽  
Vol 79 (12) ◽  
pp. 7544-7557 ◽  
Author(s):  
Sharmila S. Pejawar ◽  
Griffith D. Parks ◽  
Martha A. Alexander-Miller
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Viral Infection ◽  
Viral Proteins ◽  
Simian Virus ◽  
Costimulatory Molecules ◽  
Productive Infection ◽  
Additional Signal ◽  
Antigen Presenting

ABSTRACT Dendritic cells are the most potent antigen-presenting cell for priming naive T cells. Optimal activation of T cells requires that dendritic cells undergo a process of maturation resulting in the increased expression of costimulatory molecules, such as CD40, CD86, and CD80, and the production of cytokines. In this study we analyzed the effect of infection of dendritic cells obtained from two strains of mice, BALB/c and C57BL/6, with the paramyxovirus simian virus 5 (SV5). Our results show that C57BL/6 bone marrow-derived dendritic cells (BMDC) are much more permissive to infection with SV5 at a multiplicity of infection (MOI) of 10 PFU/cell compared to BALB/c BMDC, as determined by the production of viral proteins and progeny. However, infection of BALB/c BMDC with a higher MOI of 50 PFU/cell resulted in a productive infection with the production of significant amounts of viral proteins and progeny. Regardless of the permissivity to infection, both BALB/c and C57BL/6 BMDC efficiently upregulated CD40 and CD86. However, CD80 upregulation correlated with the level of expression of viral proteins and the production of viral progeny. While secreted alpha/beta interferon was required for increased expression of all three molecules, optimal CD80 expression was dependent on an additional signal provided by a productive viral infection. These findings provide evidence that the signals controlling the expression of costimulatory molecules following viral infection are distinct. Further, they suggest that the amount of virus encountered and/or the permissivity of a dendritic cell to infection can alter the resulting maturation phenotype and functional capacity of the infected dendritic cell.

scholarly journals Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells

2011 ◽  
Vol 208 (5) ◽  
pp. 987-999 ◽  
Author(s):  
Laura M. Fahey ◽  
Elizabeth B. Wilson ◽  
Heidi Elsaesser ◽  
Chris D. Fistonich ◽  
Dorian B. McGavern ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd4 T Cells ◽  
Viral Infections ◽  
Viral Persistence ◽  
Cd4 T Cell ◽  
T Follicular Helper Cells ◽  
Helper Cells ◽  
Follicular Helper

CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associated with control of acute viral infections. Considering that CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. We now demonstrate that CD4 T cell function is not extinguished as a result of viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively redirects CD4 T cell development away from the Th1 response induced during an acute infection toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral infection.

scholarly journals Regulation of Immune Response and Inflammatory Reactions against Viral Infection by VCAM-1

2008 ◽  
Vol 82 (6) ◽  
pp. 2952-2965 ◽  
Author(s):  
Rong Ou ◽  
Menghua Zhang ◽  
Lei Huang ◽  
Richard A. Flavell ◽  
Pandelakis A. Koni ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Infection ◽  
Viral Infections ◽  
Systemic Infection ◽  
Major Effect ◽  
Lymphocytic Choriomeningitis ◽  
Mutant Mice ◽  
Inflammatory Reactions ◽  
Circulating Lymphocytes

ABSTRACT The migration of activated antigen-specific immune cells to the target tissues of virus replication is controlled by the expression of adhesion molecules on the vascular endothelium that bind to ligands on circulating lymphocytes. Here, we demonstrate that the adhesion pathway mediated by vascular cell adhesion molecule 1 (VCAM-1) plays a role in regulating T-cell-mediated inflammation and pathology in nonlymphoid tissues, including the central nervous system (CNS) during viral infection. The ablation of VCAM-1 expression from endothelial and hematopoietic cells using a loxP-Cre recombination strategy had no major effect on the induction or overall tissue distribution of antigen-specific T cells during a systemic infection with lymphocytic choriomeningitis virus (LCMV), except in the case of lung tissue. However, enhanced resistance to lethal LCM and the significantly reduced magnitude and duration of footpad swelling observed in VCAM-1 mutant mice compared to B6 controls suggest a significant role for VCAM-1 in promoting successful local inflammatory reactions associated with efficient viral clearance and even life-threatening immunopathology under particular infection conditions. Interestingly, analysis of the infiltrating populations in the brains of intracerebrally infected mice revealed that VCAM-1 deletion significantly delayed migration into the CNS of antigen-presenting cells (macrophages and dendritic cells), which are critical for optimal stimulation of migrating virus-specific CD8+ T cells initiating a pathological cascade. We propose that the impaired migration of these accessory cells in the brain may explain the improved clinical outcome of infection in VCAM-1 mutant mice. Thus, these results underscore the potential role of VCAM-1 in regulating the immune response and inflammatory reactions against viral infections.

scholarly journals Exosomal miRNAs: novel players in viral infection

Epigenomics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 353-370 ◽  
Author(s):  
Javid Sadri Nahand ◽  
Maryam Mahjoubin-Tehran ◽  
Mohsen Moghoofei ◽  
Mohammad Hossein Pourhanifeh ◽  
Hamid Reza Mirzaei ◽  
...  
Keyword(s):  
Viral Infection ◽  
Host Response ◽  
Scientific Literature ◽  
Viral Infections ◽  
Viral Proteins ◽  
Google Scholar ◽  
Viral Diseases ◽  
Diagnostic Biomarkers ◽  
Exosomal Mirnas

Exosomes are secreted nanovesicles that are able to transfer their cargo (such as miRNAs) between cells. To determine to what extent exosomes and exosomal miRNAs are involved in the pathogenesis, progression and diagnosis of viral infections. The scientific literature (PubMed and Google Scholar) was searched from 1970 to 2019. The complex biogenesis of exosomes and miRNAs was reviewed. Exosomes contain both viral and host miRNAs that can be used as diagnostic biomarkers for viral diseases. Viral proteins can alter miRNAs, and conversely miRNAs can alter the host response to viral infections in a positive or negative manner. It is expected that exosomal miRNAs will be increasingly used for diagnosis, monitoring and even treatment of viral infections.

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