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

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.

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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Effects of changing milk replacer feedings from twice to once daily on Holstein calf innate immune responses before and after weaning

Journal of Dairy Science ◽

10.3168/jds.2010-3980 ◽

2011 ◽

Vol 94 (5) ◽

pp. 2557-2565 ◽

Cited By ~ 29

Author(s):

L.E. Hulbert ◽

C.J. Cobb ◽

J.A. Carroll ◽

M.A. Ballou

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Milk Replacer ◽

Innate Immune Responses ◽

Once Daily ◽

Before And After

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SARS-CoV-2 Impairs Dendritic Cells and Regulates DC-SIGN Gene Expression in Tissues

International Journal of Molecular Sciences ◽

10.3390/ijms22179228 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9228

Author(s):

Guoshuai Cai ◽

Mulong Du ◽

Yohan Bossé ◽

Helmut Albrecht ◽

Fei Qin ◽

...

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Immune Responses ◽

Single Cell ◽

Upper Airway ◽

Innate Immune ◽

Healthy Controls ◽

Innate Immune Responses ◽

Current Spreading ◽

Plasmacytoid Dcs

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22+ or ANXA1+ DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.

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

Journal of Virology ◽

10.1128/jvi.00999-19 ◽

2019 ◽

Vol 94 (1) ◽

Cited By ~ 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.

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

Viruses ◽

10.3390/v12040455 ◽

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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Widespread shortening of 3’ untranslated regions and increased exon inclusion are evolutionarily conserved features of innate immune responses to infection

10.1101/026831 ◽

2015 ◽

Cited By ~ 2

Author(s):

Athma A. Pai ◽

Golshid Baharian ◽

Ariane Pagé Sabourin ◽

Jessica F. Brinkworth ◽

Yohann Nédélec ◽

...

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Untranslated Regions ◽

Innate Immune Responses ◽

Dynamic Changes ◽

Evolutionarily Conserved ◽

Before And After ◽

Live Bacteria ◽

Quantify Gene Expression ◽

Processing Mechanisms

ABSTRACTThe contribution of pre-mRNA processing mechanisms to the regulation of immune responses remains poorly studied despite emerging examples of their role as regulators of immune defenses. Here, we used mRNA sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with two live bacteria. In response to both bacteria we identified thousands of genes that significantly change isoform usage in response to infection, and found global shifts towards (i) the inclusion of cassette exons and (ii) shorter 3’ UTRs. Using complementary data collected in non-human primates, we show that these features are evolutionarily conserved among primates. Finally, our results suggest that the pervasive usage of shorter 3’ UTRs is a mechanism for particular genes to evade repression by immune-activated miRNAs. Collectively, our results show that dynamic changes in RNA processing play a key role in the regulation of innate immune responses.

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Sex differences in innate anti-viral immune responses to respiratory viruses

10.1101/2020.09.18.20195784 ◽

2020 ◽

Author(s):

Eteri Regis ◽

Sara Fontanella ◽

Lijing Lin ◽

Rebecca Howard ◽

Sadia Haider ◽

...

Keyword(s):

Sex Differences ◽

Immune Responses ◽

Mononuclear Cells ◽

Respiratory Viruses ◽

Innate Immune ◽

Morbidity And Mortality ◽

High Morbidity ◽

Innate Immune Responses ◽

Peripheral Blood Mononuclear ◽

Syncytial Virus

Males have excess morbidity and mortality from respiratory viral infections and especially so in COVID-19. The mechanisms explaining this excess in disease burden in males are unknown. Innate immune responses are likely critical in protection against a novel virus like SARS-CoV-2. We hypothesised that innate immune responses may be deficient in males relative to females. To test this we stimulated peripheral blood mononuclear cells (PBMCs) from participants in a population-based birth cohort with three respiratory viruses (rhinoviruses-RV-A16 and RV-A1, and respiratory syncytial virus-RSV) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2). We measured interferon (IFN) and IFN-induced chemokine responses and investigated sex differences in virus-induced responses. IFN-α, IFN-β and IFN-γ responses to RV-A16 were deficient in males compared to females, fold-inductions being 1.92-fold (P<0.001), 2.04-fold (P<0.001) and 1.77-fold (P=0.003) lower in males than females, respectively. Similar significant deficiencies in innate immune responses were observed in males for eleven other cytokine-stimulus pairs. Responses in males were greater than those in females in only one of 35 cytokine-stimulus pairs investigated. Review of healthcare records revealed that 12.1% of males but only 6.6% of females were admitted to hospital with respiratory infections in the first year of life (P=0.017). Impaired innate anti-viral immunity in males likely results in high morbidity and mortality from respiratory viruses including COVID-19. Males may preferentially benefit from therapies that boost innate anti-viral immune responses.

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

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009873 ◽

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.

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The effective regulation of pro- and anti-inflammatory cytokines induced by combination of PA-MSHA and BPIFB1 in initiation of innate immune responses

Open Medicine ◽

10.1515/med-2017-0044 ◽

2017 ◽

Vol 12 (1) ◽

pp. 299-307 ◽

Cited By ~ 1

Author(s):

Weiqiang Zhou ◽

Zhiwen Duan ◽

Biao Yang ◽

Chunling Xiao

Keyword(s):

Inflammatory Response ◽

Immune Responses ◽

Inflammatory Cytokines ◽

Late Phase ◽

Upper Airway ◽

Innate Immune ◽

Antibody Array ◽

Innate Immune Responses ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

AbstractPA-MSHA and BPIFB1 play especially important roles in triggering innate immune responses by inducing production of pro- or anti-inflammatory cytokines in the oral cavity and upper airway. We found that PA-MSHA had a strong ability to activate pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. However, BPIFB1 alone did not express a directly inductive effect. With incubation of PA-MSHA and BPIFB1, the combination can activate the CD14/TLR4/MyD88 complex and induce secretion of subsequent downstream cytokines. We used a proteome profiler antibody array to evaluate the phosphokinases status with PA-MSHA and BPIFB1 treatment. The results showed that the activation of MAPK, STAT, and PI-3K pathways is involved in PA-MSHA-BPIFB1 treatment, and that the related pathways control the secretion of targeting cytokines in the downstream. When we assessed the content changes of cytokines, we found that PA-MSHA-BPIFB1 treatment increased the production of pro-inflammatory cytokines in the early phase of treatment and induced the increase of IL-4 in the late phase. Our observations suggest that PA-MSHA-BPIFB1 stimulates the release of pro-inflammatory cytokines, and thereby initiates the innate immune system against inflammation. Meanwhile, the gradual release of anti-inflammatory cytokine IL-4 by PA-MSHA-BPIFB1 can also regulate the degree of inflammatory response; thus the host can effectively resist the environmental risks, but also manipulate inflammatory response in an appropriate and adjustable manner.

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