scholarly journals Regulation of innate immune responses in macrophages differentiated in the presence of vitamin D and infected with dengue virus 2

2021 ◽  
Vol 15 (10) ◽  
pp. e0009873
Author(s):  
Jorge Andrés Castillo ◽  
Diana M. Giraldo ◽  
Juan C. Hernandez ◽  
Jolanda M. Smit ◽  
Izabela A. Rodenhuis-Zybert ◽  
...  
Keyword(s):  
Vitamin D ◽  
Inflammatory Response ◽  
Immune Responses ◽  
Dengue Virus ◽  
Severe Disease ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Oligoadenylate Synthetase ◽  
Protein Kinase R ◽  
Cellular Targets

A dysregulated or exacerbated inflammatory response is thought to be the key driver of the pathogenesis of severe disease caused by the mosquito-borne dengue virus (DENV). Compounds that restrict virus replication and modulate the inflammatory response could thus serve as promising therapeutics mitigating the disease pathogenesis. We and others have previously shown that macrophages, which are important cellular targets for DENV replication, differentiated in the presence of bioactive vitamin D (VitD3) are less permissive to viral replication, and produce lower levels of pro-inflammatory cytokines. Therefore, we here evaluated the extent and kinetics of innate immune responses of DENV-2 infected monocytes differentiated into macrophages in the presence (D3-MDMs) or absence of VitD3 (MDMs). We found that D3-MDMs expressed lower levels of RIG I, Toll-like receptor (TLR)3, and TLR7, as well as higher levels of SOCS-1 in response to DENV-2 infection. D3-MDMs produced lower levels of reactive oxygen species, related to a lower expression of TLR9. Moreover, although VitD3 treatment did not modulate either the expression of IFN-α or IFN-β, higher expression of protein kinase R (PKR) and 2′-5′-oligoadenylate synthetase 1 (OAS1) mRNA were found in D3-MDMs. Importantly, the observed effects were independent of reduced infection, highlighting the intrinsic differences between D3-MDMs and MDMs. Taken together, our results suggest that differentiation of MDMs in the presence of VitD3 modulates innate immunity in responses to DENV-2 infection.

scholarly journals SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial derived cells and cardiomyocytes

2020 ◽  
Author(s):  
Yize Li ◽  
David M Renner ◽  
Courtney E Comar ◽  
Jillian N Whelan ◽  
Hanako M Reyes ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Immune Responses ◽  
Innate Immune ◽  
Alveolar Type ◽  
Rnase L ◽  
Innate Immune Responses ◽  
Oligoadenylate Synthetase ◽  
Protein Kinase R ◽  
Double Stranded Rna ◽  
Ribonuclease L

SummaryCoronaviruses are adept at evading host antiviral pathways induced by viral double-stranded RNA, including interferon (IFN) signaling, oligoadenylate synthetase–ribonuclease L (OAS-RNase L), and protein kinase R (PKR). While dysregulated or inadequate IFN responses have been associated with severe coronavirus infection, the extent to which the recently emerged SARS-CoV-2 activates or antagonizes these pathways is relatively unknown. We found that SARS-CoV-2 infects patient-derived nasal epithelial cells, present at the initial site of infection, induced pluripotent stem cell-derived alveolar type 2 cells (iAT2), the major cell type infected in the lung, and cardiomyocytes (iCM), consistent with cardiovascular consequences of COVID-19 disease. Robust activation of IFN or OAS-RNase L is not observed in these cell types, while PKR activation is evident in iAT2 and iCM. In SARS-CoV-2 infected Calu-3 and A549ACE2 lung-derived cell lines, IFN induction remains relatively weak; however activation of OAS-RNase L and PKR is observed. This is in contrast to MERS-CoV, which effectively inhibits IFN signaling as well as OAS-RNase L and PKR pathways, but similar to mutant MERS-CoV lacking innate immune antagonists. Remarkably, both OAS-RNase L and PKR are activated in MAVS knockout A549ACE2 cells, demonstrating that SARS-CoV-2 can induce these host antiviral pathways despite minimal IFN production. Moreover, increased replication and cytopathic effect in RNASEL knockout A549ACE2 cells implicates OAS-RNase L in restricting SARS-CoV-2. Finally, while SARS-CoV-2 fails to antagonize these host defense pathways, which contrasts with other coronaviruses, the IFN signaling response is generally weak. These host-virus interactions may contribute to the unique pathogenesis of SARS-CoV-2.SignificanceSARS-CoV-2 emergence in late 2019 led to the COVID-19 pandemic that has had devastating effects on human health and the economy. Early innate immune responses are essential for protection against virus invasion. While inadequate innate immune responses are associated with severe COVID-19 diseases, understanding of the interaction of SARS-CoV-2 with host antiviral pathways is minimal. We have characterized the innate immune response to SARS-CoV-2 infections in relevant respiratory tract derived cells and cardiomyocytes and found that SARS-CoV-2 activates two antiviral pathways, oligoadenylate synthetase–ribonuclease L (OAS-RNase L), and protein kinase R (PKR), while inducing minimal levels of interferon. This in contrast to MERS-CoV which inhibits all three pathways. Activation of these pathways may contribute to the distinctive pathogenesis of SARS-CoV-2.

scholarly journals N-dihydrogalactochitosan reduces mortality in a lethal mouse model of SARS-CoV-2

2021 ◽  
Author(s):  
Christopher M Weiss ◽  
Hongwei Liu ◽  
Erin E Ball ◽  
Samuel Lam ◽  
Tomas Hode ◽  
...  
Keyword(s):  
Immune Responses ◽  
Infectious Virus ◽  
Severe Disease ◽  
Upper Airway ◽  
Innate Immune ◽  
Morbidity And Mortality ◽  
Vaccine Hesitancy ◽  
Innate Immune Responses ◽  
Before And After ◽  
Rapid Emergence

The rapid emergence and global dissemination of SARS-CoV-2 that causes COVID-19 continues to cause an unprecedented global health burden resulting in more than 4 million deaths in the 20 months since the virus was discovered. While multiple vaccine countermeasures have been approved for emergency use, additional treatments are still needed due to sluggish vaccine rollout and vaccine hesitancy. Immunoadjuvant compounds delivered intranasally can guide non-specific innate immune responses during the critical early stages of viral replication, reducing morbidity and mortality. N-dihydrogalactochitosan (GC) is a novel mucoadhesive immunostimulatory polymer of β-0-4-linked N-acetylglucosamine that is solubilized by the conjugation of galactose glycans. We tested GC as a potential countermeasure for COVID-19. GC administered intranasally before and after SARS-CoV-2 exposure diminished morbidity and mortality in humanized ACE2 receptor expressing mice by up to 75% and reduced infectious virus levels in the upper airway and lungs. Our findings demonstrate a new application for soluble immunoadjuvants like GC for preventing severe disease associated with SARS-CoV-2.

scholarly journals Effect of Vitamin D Supplementation on Mycobacterium tuberculosis-Induced Innate Immune Responses in a Canadian Dené First Nations Cohort

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e40692 ◽  
Author(s):  
Linda Larcombe ◽  
Pamela Orr ◽  
Emily Turner-Brannen ◽  
Caroline R. Slivinski ◽  
Peter W. Nickerson ◽  
...  
Keyword(s):  
Vitamin D ◽  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
First Nations ◽  
Vitamin D Supplementation ◽  
Innate Immune ◽  
Innate Immune Responses

scholarly journals Vitamin D modulation of innate immune responses to respiratory viral infections

2016 ◽  
Vol 27 (1) ◽  
pp. e1909 ◽  
Author(s):  
Mihnea T. Zdrenghea ◽  
Heidi Makrinioti ◽  
Cristina Bagacean ◽  
Andy Bush ◽  
Sebastian L. Johnston ◽  
...  
Keyword(s):  
Vitamin D ◽  
Immune Responses ◽  
Viral Infections ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Respiratory Viral Infections

scholarly journals Cytosolic DNA sensor-initiated innate immune responses in mouse ovarian granulosa cells

Reproduction ◽  
2017 ◽  
Vol 153 (6) ◽  
pp. 821-834 ◽  
Author(s):  
Keqin Yan ◽  
Dingqing Feng ◽  
Jing Liang ◽  
Qing Wang ◽  
Lin Deng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Granulosa Cells ◽  
Innate Immune ◽  
Type I Interferons ◽  
Endocrine Function ◽  
Type I ◽  
Dna Sensor ◽  
Innate Immune Responses ◽  
Oligoadenylate Synthetase ◽  
Ovarian Granulosa Cells

Viral infections of the ovary may perturb ovarian functions. However, the mechanisms underlying innate immune responses in the ovary are poorly understood. The present study demonstrates that cytosolic viral DNA sensor signaling initiates the innate immune response in mouse ovarian granulosa cells and affects endocrine function. The cytosolic DNA sensors p204 and cGAS and their common signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in granulosa cells. Transfection with VACV70, a synthetic vaccinia virus (VACV) DNA analog, induced the expression of type I interferons (IFNA/B) and major inflammatory cytokines (TNFA and IL6) through IRF3 and NF-κB activation respectively. Moreover, several IFN-inducible antiviral proteins, including 2′,5′-oligoadenylate synthetase, IFN-stimulating gene 15 and Mx GTPase 1, were also induced by VACV70 transfection. The innate immune responses in granulosa cells were significantly reduced by the transfection of specific small-interfering RNAs targeting p204, cGas or Sting. Notably, the VACV70-triggered innate immune responses affected steroidogenesis in vivo and in vitro. The data presented in this study describe the mechanism underlying ovarian immune responses to viral infection.

scholarly journals Aedes aegypti Saliva Enhances Dengue Virus Infection of Human Keratinocytes by Suppressing Innate Immune Responses

2012 ◽  
Vol 132 (8) ◽  
pp. 2103-2105 ◽  
Author(s):  
Pornapat Surasombatpattana ◽  
Sirilaksana Patramool ◽  
Natthanej Luplertlop ◽  
Hans Yssel ◽  
Dorothée Missé
Keyword(s):  
Virus Infection ◽  
Aedes Aegypti ◽  
Immune Responses ◽  
Dengue Virus ◽  
Human Keratinocytes ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Dengue Virus Infection

scholarly journals Differential Modulation of Innate Immune Responses in Human Primary Cells by Influenza A Viruses Carrying Human or Avian Nonstructural Protein 1

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Paula L. Monteagudo ◽  
Raquel Muñoz-Moreno ◽  
Miguel Fribourg ◽  
Uma Potla ◽  
Ignacio Mena ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza A ◽  
Nonstructural Protein ◽  
Severe Disease ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Influenza A Viruses ◽  
Recombinant Viruses ◽  
Nonstructural Protein 1 ◽  
Human Primary Cells

ABSTRACT The influenza A virus (IAV) nonstructural protein 1 (NS1) contributes to disease pathogenesis through the inhibition of host innate immune responses. Dendritic cells (DCs) release interferons (IFNs) and proinflammatory cytokines and promote adaptive immunity upon viral infection. In order to characterize the strain-specific effects of IAV NS1 on human DC activation, we infected human DCs with a panel of recombinant viruses with the same backbone (A/Puerto Rico/08/1934) expressing different NS1 proteins from human and avian origin. We found that these viruses induced a clearly distinct phenotype in DCs. Specifically, viruses expressing NS1 from human IAV (either H1N1 or H3N2) induced higher levels of expression of type I (IFN-α and IFN-β) and type III (IFN-λ1 to IFNλ3) IFNs than viruses expressing avian IAV NS1 proteins (H5N1, H7N9, and H7N2), but the differences observed in the expression levels of proinflammatory cytokines like tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6) were not significant. In addition, using imaging flow cytometry, we found that human and avian NS1 proteins segregate based on their subcellular trafficking dynamics, which might be associated with the different innate immune profile induced in DCs by viruses expressing those NS1 proteins. Innate immune responses induced by our panel of IAV recombinant viruses were also characterized in normal human bronchial epithelial cells, and the results were consistent with those in DCs. Altogether, our results reveal an increased ability of NS1 from avian viruses to antagonize innate immune responses in human primary cells compared to the ability of NS1 from human viruses, which could contribute to the severe disease induced by avian IAV in humans. IMPORTANCE Influenza A viruses (IAVs) cause seasonal epidemics which result in an important health and economic burden. Wild aquatic birds are the natural host of IAV. However, IAV can infect diverse hosts, including humans, domestic poultry, pigs, and others. IAVs circulating in animals occasionally cross the species barrier, infecting humans, which results in mild to very severe disease. In some cases, these viruses can acquire the ability to be transmitted among humans and initiate a pandemic. The nonstructural 1 (NS1) protein of IAV is an important antagonist of the innate immune response. In this study, using recombinant viruses and primary human cells, we show that NS1 proteins from human and avian hosts show intrinsic differences in the modulation of the innate immunity in human dendritic cells and epithelial cells, as well as different cellular localization dynamics in infected cells.

scholarly journals Reverse Genetics System for Shuni Virus, an Emerging Orthobunyavirus with Zoonotic Potential

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 455
Author(s):  
Judith Oymans ◽  
Paul J. Wichgers Schreur ◽  
Sophie van Oort ◽  
Rianka Vloet ◽  
Marietjie Venter ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neurological Disease ◽  
Western Europe ◽  
Reverse Genetics ◽  
Molecular Mechanisms ◽  
Severe Disease ◽  
Innate Immune ◽  
Zoonotic Potential ◽  
Innate Immune Responses ◽  
North Western

The genus Orthobunyavirus (family Peribunyaviridae, order Bunyavirales) comprises over 170 named mosquito- and midge-borne viruses, several of which cause severe disease in animals or humans. Their three-segmented genomes enable reassortment with related viruses, which may result in novel viruses with altered host or tissue tropism and virulence. One such reassortant, Schmallenberg virus (SBV), emerged in north-western Europe in 2011. Shuni virus (SHUV) is an orthobunyavirus related to SBV that is associated with neurological disease in horses in southern Africa and recently caused an outbreak manifesting with neurological disease and birth defects among ruminants in Israel. The zoonotic potential of SHUV was recently underscored by its association with neurological disease in humans. We here report a reverse genetics system for SHUV and provide first evidence that the non-structural (NSs) protein of SHUV functions as an antagonist of host innate immune responses. We furthermore report the rescue of a reassortant containing the L and S segments of SBV and the M segment of SHUV. This novel reverse genetics system can now be used to study SHUV virulence and tropism, and to elucidate the molecular mechanisms that drive reassortment events.

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