CpG Oligonucleotides Protect Mice From Alphavirus Encephalitis: Role of NK Cells, Interferons, and TNF

Manangeeswaran, Mohanraj; Lewkowicz, Aaron P.; Israely, Tomer; Ireland, Derek D.C.; Verthelyi, Daniela

doi:10.3389/fimmu.2020.00237

Cited by 9 publications

(8 citation statements)

References 64 publications

(75 reference statements)

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“…As mentioned above, CpG-ODN can activate and enhance NK cell function, a characteristic that some authors have associated with enhanced anti-viral properties. For instance, CpG-ODN has been shown to effectively fight alphavirus encephalitis in neonatal mice ( 162 ). Moreover, CpG-ODN has also been shown to be efficacious as an adjuvant in vaccines against viruses, for example, by generating a humoral protective response to the HBV surface antigen HBsAg ( 88 ), which subsequently lead to the development of an FDA-approved vaccine against HBV that was superior compared to an established aluminum hydroxide-based HBV vaccine ( 120 ).…”

Section: Cpg-odn – Safety Considerations and Other Applicationsmentioning

confidence: 99%

CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance

et al. 2021

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Prevalence and incidence of IgE-mediated allergic diseases have increased over the past years in developed and developing countries. Allergen-specific immunotherapy (AIT) is currently the only curative treatment available for allergic diseases that has long-term efficacy. Although AIT has been proven successful as an immunomodulatory therapy since its beginnings, it still faces several unmet needs and challenges today. For instance, some patients can experience severe side effects, others are non-responders, and prolonged treatment schedules can lead to lack of patient adherence and therapy discontinuation. A common strategy to improve AIT relies on the use of adjuvants and immune modulators to boost its effects and improve its safety. Among the adjuvants tested for their clinical efficacy, CpG oligodeoxynucleotide (CpG-ODN) was investigated with limited success and without reaching phase III trials for clinical allergy treatment. However, recently discovered immune tolerance-promoting properties of CpG-ODN place this adjuvant again in a prominent position as an immune modulator for the treatment of allergic diseases. Indeed, it has been shown that the CpG-ODN dose and concentration are crucial in promoting immune regulation through the recruitment of pDCs. While low doses induce an inflammatory response, high doses of CpG-ODN trigger a tolerogenic response that can reverse a pre-established allergic milieu. Consistently, CpG-ODN has also been found to stimulate IL-10 producing B cells, so-called B regulatory cells (Bregs). Accordingly, CpG-ODN has shown its capacity to prevent and revert allergic reactions in several animal models showing its potential as both preventive and active treatment for IgE-mediated allergy. In this review, we describe how CpG-ODN-based therapies for allergic diseases, despite having shown limited success in the past, can still be exploited further as an adjuvant or immune modulator in the context of AIT and deserves additional attention. Here, we discuss the past and current knowledge, which highlights CpG-ODN as a potential adjuvant to be reevaluated for the enhancement of AIT when used in appropriate conditions and formulations.

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Section: Cpg-odn – Safety Considerations and Other Applicationsmentioning

confidence: 99%

CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance

et al. 2021

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“…Altered NK cells underlie the severe ZIKV infection in LILRB4-deficient mice. Although the number of NK cells infiltrating the CNS was lower than that of T cells (Figure 2F), they can play a key role in viral clearance by killing infected cells through exocytosis of cytolytic granules containing perforin and granzyme, or by secreting proinflammatory cytokines, in particular IFN-γ, and are therefore considered the first line of defense against viral infection such as DENV and Sindbis virus (34)(35)(36). Using antibodies against NK1.1 to deplete NK cells in vivo, we confirmed that these cells play a critical role in protection against meningoencephalitis by ZIKV, as mice lacking NK cells had higher viral load in the brain and increased mortality (Supplemental Figure 8).…”

Section: Resultsmentioning

confidence: 99%

NK cells require immune checkpoint receptor LILRB4/gp49B to control neurotropic Zika virus infections in mice

Lee¹,

Manangeeswaran²,

Lewkowicz³

et al. 2022

JCI Insight

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Immune cells express an array of inhibitory checkpoint receptors that are upregulated upon activation and limit tissue damage associated with excessive response to pathogens or allergens. Mouse leukocyte immunoglobulin like receptor B4 (LILRB4), also known as glycoprotein 49B (gp49B), is an inhibitory checkpoint receptor constitutively expressed in myeloid cells and upregulated in B cells, T cells, and NK cells upon activation. Here, we report that expression of LILRB4, which binds Zika virus (ZIKV), was increased in microglia and myeloid cells infiltrating the brains of neonatal mice with ZIKV-associated meningoencephalitis. Importantly, while C57BL/6 mice developed transient neurological symptoms but survived infection, mice lacking LILRB4/gp49B (LILRB4 KO) exhibited more severe signs of neurological disease and succumbed to disease. Their brains showed increased cellular infiltration but reduced control of viral burden. The reduced viral clearance was associated with altered NK cell function in the absence of LILRB4/gp49B. In naive animals, this manifested as reduced granzyme B responses to stimulation, but in ZIKV-infected animals, NK cells showed phenotypic changes that suggested altered maturation, diminished glucose consumption, reduced IFN-γ and granzyme B production, and impaired cytotoxicity. Together, our data reveal LILRB4/gp49B as an important regulator of NK cell function during viral infections.

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“…Neonatal mice have increased susceptibility to viruses and develop symptomatic infections when challenged with Alpha-, Arena- and Flavi-viruses, even when the adults of the same strain are resistant ( 18 , 19 , 23 , 33 – 35 ). As expected, neonatal hACE2 tg mice succumbed following a SARS-CoV-2 (10 2 -10 5 TCID 50 Washington 2020 isolate, IN) challenge in a dose-dependent manner ( Figures 1A–D and Supplementary Figure 2F ) and high titer virus were evident in the lungs and brain of mice challenged IN with 10 5 TCID 50 as determined by viral RNA levels and TCID 50 ( Figure 1E ).…”

Section: Resultsmentioning

confidence: 99%

“…This is different from challenges with the parental VSV or from rVSV expressing the Ebola Zaire glycoproteins as previously shown ( 18 ). The increased susceptibility of neonatal mice to viral infections is well established ( 18 , 23 , 34 , 35 , 45 , 46 ). This extends to coronaviruses where reports show the acquisition of virulence in young, but not aged, mice through serial passage of SARS-CoV Urbani strain ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

BSL2-compliant lethal mouse model of SARS-CoV-2 and variants of concern to evaluate therapeutics targeting the Spike protein

Manangeeswaran

Ireland²,

Thacker³

et al. 2022

Front. Immunol.

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Since first reported in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly acquiring mutations, particularly in the spike protein, that can modulate pathogenicity, transmission and antibody evasion leading to successive waves of COVID19 infections despite an unprecedented mass vaccination necessitating continuous adaptation of therapeutics. Small animal models can facilitate understanding host-pathogen interactions, target selection for therapeutic drugs, and vaccine development, but availability and cost of studies in BSL3 facilities hinder progress. To generate a BSL2-compatible in vivo system that specifically recapitulates spike protein mediated disease we used replication competent, GFP tagged, recombinant Vesicular Stomatitis Virus where the VSV glycoprotein was replaced by the SARS-CoV-2 spike protein (rVSV-SARS2-S). We show that infection requires hACE2 and challenge of neonatal but not adult, K18-hACE2 transgenic mice (hACE2tg) leads to productive infection of the lungs and brains. Although disease progression was faster in SARS-CoV-2 infected mice, infection with both viruses resulted in neuronal infection and encephalitis with increased expression of Interferon-stimulated Irf7, Bst2, Ifi294, as well as CxCL10, CCL5, CLC2, and LILRB4, and both models were uniformly lethal. Further, prophylactic treatment targeting the Spike protein (Receptor Binding Domain) with antibodies resulted in similar levels of protection from lethal infection against rVSV-SARS2-S and SARS-CoV-2 viruses. Strikingly, challenge of neonatal hACE2tg mice with SARS-CoV-2 Variants of Concern (SARS-CoV-2-α, -β, ϒ, or Δ) or the corresponding rVSV-SARS2-S viruses (rVSV-SARS2-Spike-α, rVSV-SARS2-Spike-β, rVSV-SARS2-Spike-ϒ or rVSV-SARS2-Spike-Δ) resulted in increased lethality, suggesting that the Spike protein plays a key role in determining the virulence of each variant. Thus, we propose that rVSV-SARS2-S virus can be used to understand the effect of changes to SARS-CoV-2 spike protein on infection and to evaluate existing or experimental therapeutics targeting spike protein of current or future VOC of SARS-CoV-2 under BSL-2 conditions.

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CpG Oligonucleotides Protect Mice From Alphavirus Encephalitis: Role of NK Cells, Interferons, and TNF

Cited by 9 publications

References 64 publications

CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance

CpG Adjuvant in Allergen-Specific Immunotherapy: Finding the Sweet Spot for the Induction of Immune Tolerance

NK cells require immune checkpoint receptor LILRB4/gp49B to control neurotropic Zika virus infections in mice

BSL2-compliant lethal mouse model of SARS-CoV-2 and variants of concern to evaluate therapeutics targeting the Spike protein

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