scholarly journals Immunogenicity and Protection Efficacy of a Naked Self-Replicating mRNA-Based Zika Virus Vaccine

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 96 ◽  
Author(s):  
Zifu Zhong ◽  
João Paulo Portela Catani ◽  
Séan Mc Cafferty ◽  
Liesbeth Couck ◽  
Wim Van Den Broeck ◽  
...  
Keyword(s):  
Zika Virus ◽  
Emerging Infectious Diseases ◽  
Humoral Response ◽  
Type I ◽  
Messenger Rnas ◽  
Wild Type ◽  
Mice Model ◽  
Type I Ifns ◽  
Reporter Mice ◽  
Cellular Immune

To combat emerging infectious diseases like Zika virus (ZIKV), synthetic messenger RNAs (mRNAs) encoding viral antigens are very attractive as they allow a rapid, generic, and flexible production of vaccines. In this work, we engineered a self-replicating mRNA (sr-mRNA) vaccine encoding the pre-membrane and envelope (prM-E) glycoproteins of ZIKV. Intradermal electroporation of as few as 1 µg of this mRNA-based ZIKV vaccine induced potent humoral and cellular immune responses in BALB/c and especially IFNAR1-/- C57BL/6 mice, resulting in a complete protection of the latter mice against ZIKV infection. In wild-type C57BL/6 mice, the vaccine resulted in very low seroconversion rates and antibody titers. The potency of the vaccine was inversely related to the dose of mRNA used in wild-type BALB/c or C57BL/6 mice, as robust type I interferon (IFN) response was determined in a reporter mice model (IFN-β+/Δβ-luc). We further investigated the inability of the sr-prM-E-mRNA ZIKV vaccine to raise antibodies in wild-type C57BL/6 mice and found indications that type I IFNs elicited by this naked sr-mRNA vaccine might directly impede the induction of a robust humoral response. Therefore, we assume that the efficacy of sr-mRNA vaccines after intradermal electroporation might be increased by strategies that temper their inherent innate immunogenicity.

scholarly journals IFN-α Boosting of Mycobacterium bovis Bacillus Calmette Güerin-Vaccine Promoted Th1 Type Cellular Response and Protection against M. tuberculosis Infection

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
C. E. Rivas-Santiago ◽  
G. G. Guerrero
Keyword(s):  
Immune Response ◽  
Mycobacterium Bovis ◽  
Cellular Immune Response ◽  
Cellular Response ◽  
Bacterial Load ◽  
Bcg Vaccine ◽  
Type I ◽  
Bacillus Calmette Guerin ◽  
Type I Ifns ◽  
Cellular Immune

The role of type I IFNs in the pathogenesis and control of mycobacterial infection is still controversial. It has been reported that type I IFNs exacerbated M. tuberculosis infection through hampering Th1 type cellular immune response. However, under certain conditions they can act as natural immune adjuvants for commercial vaccines. At this point, we have reported recently that successive IFN-alpha boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccinated mice protected adult mice from intradermal M. lepraemurium infection and a difference in iNOS was observed. In the present work, we have found that intramuscular IFN-α boosting of Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccine, either in vitro (human cell line or macrophages derived from PBMC) or in vivo (aerosol mouse model of MTb infection), promoted mostly the development of specific anti-antimycobacterial Th1 type cytokines (IFN-γ; IL-12, TNF-alpha, and IL-17; IL1β) while bacterial load reduction (0.9 logs versus PBS or BCG vaccine) was observed. These findings indicate that, under the experimental settings reported here, interferon alpha can drive or affect the TH cellular immune response in favour of BCG-inducing immunity against M. tuberculosis infection.

scholarly journals Induction of USP25 by viral infection promotes innate antiviral responses by mediating the stabilization of TRAF3 and TRAF6

2015 ◽  
Vol 112 (36) ◽  
pp. 11324-11329 ◽  
Author(s):  
Dandan Lin ◽  
Man Zhang ◽  
Meng-Xin Zhang ◽  
Yujie Ren ◽  
Jie Jin ◽  
...  
Keyword(s):  
Viral Infection ◽  
Proinflammatory Cytokines ◽  
Feedback Regulation ◽  
Type I Interferons ◽  
Type I ◽  
Wild Type ◽  
Dna Viruses ◽  
Type I Ifns ◽  
Specific Protease ◽  
Rna And Dna

Host pathogen-recognition receptors detect nucleic acid from invading viruses and initiate a series of signaling pathways that lead to the production of type I interferons (IFNs) and proinflammatory cytokines. Here, we found that a viral infection-induced deubiquitinase (DUB), ubiquitin-specific protease 25 (USP25) was required for host defense against RNA and DNA viruses. The activation of transcription factors IRF3 and NF-κB was impaired and the production of type I IFNs and proinflammatory cytokines was inhibited in Usp25−/− cells compared with the wild-type counterparts after RNA or DNA viruses infection. Consistently, USP25 deficient mice were more susceptible to H5N1 or HSV-1 infection compared with the wild-type mice. USP25 was associated with TRAF3 and TRAF6 after infection by RNA or DNA viruses and protected virus-induced proteasome-dependent or independent degradation of TRAF3 and TRAF6, respectively. Moreover, reconstitution of TRAF3 and TRAF6 into Usp25−/− MEFs restored virus-triggered production of type I IFNs and proinflammatory cytokines. Our findings thus reveal a previously uncovered positive feedback regulation of innate immune responses against RNA and DNA viruses by USP25.

scholarly journals Mice Lacking the Type I Interferon Receptor Are Resistant to Listeria monocytogenes

2004 ◽  
Vol 200 (4) ◽  
pp. 527-533 ◽  
Author(s):  
Victoria Auerbuch ◽  
Dirk G. Brockstedt ◽  
Nicole Meyer-Morse ◽  
Mary O'Riordan ◽  
Daniel A. Portnoy
Keyword(s):  
Listeria Monocytogenes ◽  
High Dose ◽  
Type I ◽  
Wild Type ◽  
Type I Ifns ◽  
Infection Resistance ◽  
Innate Antiviral Response ◽  
Factor Α

Listeria monocytogenes is a facultative intracellular pathogen that induces a cytosolic signaling cascade resulting in expression of interferon (IFN)-β. Although type I IFNs are critical in viral defense, their role in immunity to bacterial pathogens is much less clear. In this study, we addressed the role of type I IFNs by examining the infection of L. monocytogenes in BALB/c mice lacking the type I IFN receptor (IFN-α/βR−/−). During the first 24 h of infection in vivo, IFN-α/βR−/− and wild-type mice were similar in terms of L. monocytogenes survival. In addition, the intracellular fate of L. monocytogenes in macrophages cultured from IFN-α/βR−/− and wild-type mice was indistinguishable. However, by 72 h after inoculation in vivo, IFN-α/βR−/− mice were ∼1,000-fold more resistant to a high dose L. monocytogenes infection. Resistance was correlated with elevated levels of interleukin 12p70 in the blood and increased numbers of CD11b+ macrophages producing tumor necrosis factor α in the spleen of IFN-α/βR−/− mice. The results of this study suggest that L. monocytogenes might be exploiting an innate antiviral response to promote its pathogenesis.

Hematopoietic Cells from Ube1L-Deficient Mice Exhibit Impaired Short-Term Reconstitution Capacity Under the Stress of Bone Marrow Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 613-613
Author(s):  
Xiuli Cong ◽  
Ming Yan ◽  
Xiaoyan Yin
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Bone Marrow Cells ◽  
Type I ◽  
Wild Type ◽  
Short Term ◽  
Type I Ifns ◽  
Donor Cells ◽  
Transplantation Experiment

Abstract Following bone marrow transplantation, donor stem cells are recruited from their quiescent status to promote the rapid reconstitution of a depleted hematopoiesis system in recipients. This dynamic process is tightly regulated by a complex of internal and external signals. The proper proliferation and differentiation of hematopoietic stem cells (HSCs) are crucial for reconstitution of hematopoiesis in recipients with bone marrow ablation. Therefore, thoroughly understanding the complex regulation of HSCs during transplantation will be very helpful for future therapeutic applications. Type I interferons (IFNs) are induced in various types of cells by different stimuli. Protein modification by the ubiquitin like modifier ISG15 (ISGylation) is strongly induced by Type I IFNs. To understand whether Type I IFN signaling and protein ISGylation are important for the rapid reconstitution of the hematopoietic system upon depletion, we examined the expression levels of IFNs and protein ISGylation during transplantation. Our results showed a clear increase in Type I IFNs in the bone marrow cells of recipient mice at 4, 6, 8, and 10 days after transplantation, and obviously higher levels of protein ISGylation in different tissues at 2, 4, 6, and 8 days after transplantation. To further investigate the role of protein ISGylation in hematopoiesis, we examined the phenotypes of the Ube1L knockout mouse. Ube1L is a critical enzyme for protein ISG15 modification. Ube1L deficient cells do not have protein ISGylation upon IFN stimulation. Steady-state hematopoiesis was unperturbed in Ube1L −/− mice. In addition, Ube1L deficiency did not affect the colony-forming ability of progenitors in vitro. The in vivo colony-forming unit spleen (CFU-S) assay showed that the frequency of CFU-S12 was normal, however, the size of the colonies derived from Ube1L deficient cells were clearly reduced compared to wild-type cells. In transplant experiments, the homing capacity of Ube1L-deficient donor cells was not affected, however, at 3 weeks posttransplant, noncompetitive transplantation experiment revealed a 50% reduction in repopulation potential of Ube1L −/− bone marrow cells compared with Ube1L +/+ cells (p = 0.0015). A competitive transplantation experiment magnified and extended the Ube1L −/− phenotype showing that the Ube1L −/− cells had a significantly lower repopulating ability after 3 weeks (p = 0.0141), but less pronounced differences at 6 and 12 weeks. The lineage commitment of engrafted Ube1L-deficent cells was not affected. Further study showed that after transplantation in the multipotent progenitor (MPP) population, the absence of Ube1L resulted in fewer Ube1L −/− donor cells than Ube1L +/+ wild-type donor cells when compared to the competitors (p = 0.0367). These results indicate that in conditions that call for rapid proliferation, such as bone marrow transplantation, protein ISGylation appears to be critically involved in promoting and enhancing the proliferative response of short-term repopulation. This study will contribute to a thorough understanding of stem cell characteristics under transplantation, and may provide novel strategies to predict the potential risk factors related to ISGylation defects and enhance the success rate of HSC transplantation.

scholarly journals HIPK2 is necessary for type I interferon–mediated antiviral immunity

2019 ◽  
Vol 12 (573) ◽  
pp. eaau4604 ◽  
Author(s):  
Lili Cao ◽  
Guang Yang ◽  
Shandian Gao ◽  
Chunxia Jing ◽  
Ruth R. Montgomery ◽  
...  
Keyword(s):  
Rna Virus ◽  
Antiviral Immunity ◽  
Type I ◽  
Wild Type ◽  
Interacting Protein ◽  
Precise Control ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
Vesicular Stomatitis ◽  
Deficient Mice

Precise control of interferons (IFNs) is crucial to maintain immune homeostasis. Here, we demonstrated that homeodomain-interacting protein kinase 2 (HIPK2) was required for the production of type I IFNs in response to RNA virus infection. HIPK2 deficiency markedly impaired IFN production in macrophages after vesicular stomatitis virus (VSV) infection, and HIPK2-deficient mice were more susceptible to lethal VSV disease than were wild-type mice. After VSV infection, HIPK2 was cleaved by active caspases, which released a hyperactive, N-terminal fragment that translocated to the nucleus and further augmented antiviral responses. In part, HIPK2 interacted with ELF4 and promoted its phosphorylation at Ser369, which enabledIfn-b transcription. In addition, HIPK2 production was stimulated by type I IFNs to further enhance antiviral immunity. These data suggest that the kinase activity and nuclear localization of HIPK2 are essential for the production of type I IFNs.

scholarly journals cGAS–STING and MyD88 Pathways Synergize in Ly6Chi Monocyte to Promote Streptococcus pneumoniae-Induced Late-Stage Lung IFNγ Production

2021 ◽  
Vol 12 ◽  
Author(s):  
Seema Patel ◽  
Heidi R. Tucker ◽  
Himanshu Gogoi ◽  
Samira Mansouri ◽  
Lei Jin
Keyword(s):  
Streptococcus Pneumoniae ◽  
Late Stage ◽  
Early Stage ◽  
Intracellular Cytokine Staining ◽  
Pneumococcal Infection ◽  
Adoptive Cell Transfer ◽  
Type I ◽  
Type I Ifns ◽  
Reporter Mice ◽  
Sting Pathway

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway senses DNA and induces type I interferon (IFN) production. Whether and how the STING pathway crosstalk to other innate immune pathways during pathogen infection, however, remains unclear. Here, we showed that STING was needed for Streptococcus pneumoniae-induced late, not early, stage of lung IFNγ production. Using knockout mice, IFNγ reporter mice, intracellular cytokine staining, and adoptive cell transfer, we showed that cGAS–STING-dependent lung IFNγ production was independent of type I IFNs. Furthermore, STING expression in monocyte/monocyte-derived cells governed IFNγ production in the lung via the production of IL-12p70. Surprisingly, DNA stimulation alone could not induce IL-12p70 or IFNγ in Ly6Chi monocyte. The production of IFNγ required the activation by both DNA and heat-killed S. pneumococcus. Accordingly, MyD88−/− monocyte did not generate IL-12p70 or IFNγ. In summary, the cGAS–STING pathway synergizes with the MyD88 pathway in monocyte to promote late-stage lung IFNγ production during pulmonary pneumococcal infection.

scholarly journals A Live-attenuated Zika Virus Vaccine with High Production Capacity Confers Effective Protection in Neonatal Mice

2021 ◽  
Author(s):  
Xianmiao Ye ◽  
Xinglong Liu ◽  
Tao Shu ◽  
Weiqi Deng ◽  
Min Liao ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neurological Disorders ◽  
Protective Immunity ◽  
Vero Cells ◽  
Type I ◽  
Wild Type ◽  
Inhibitory Antibody ◽  
Effective Protection ◽  
Vectored Vaccine ◽  
Unique Amino Acid

Zika virus (ZIKV) infection during pregnancy has been linked to congenital abnormalities such as microcephaly in infants. An efficacious vaccine is still desirable for preventing the potential recurrence of ZIKV epidemic. Here, we report the generation of an attenuated ZIKV (rGZ02a) that has sharply decreased virulence in mice but grows to high titers in Vero cells, a widely approved cell line for manufacturing human vaccines. Compared to the wild-type ZIKV (GZ02) and a plasmid-launched rGZ02p, rGZ02a has 3 unique amino acid alterations in the envelope (E, S304F), non-structural protein 1 (NS1, R103K), and NS5 (W637R). rGZ02a is more sensitive to type I interferon than GZ02 and rGZ02p, and causes no severe neurological disorders in either wild-type neonatal C57BL/6 mice or type I interferon receptor knock-out (Ifnar1-/-) C57BL/6 mice. Immunization with rGZ02a elicits robust inhibitory antibody responses with a certain long-term durability. Neonates born to the immunized dams are effectively protected against ZIKV-caused neurological disorders and brain damage. rGZ02a as a booster vaccine greatly improves the protective immunity primed by Ad2-prME, an adenovirus vectored vaccine expressing ZIKV prM and E proteins. Our results illustrate that rGZ02a-induced maternal immunity can be transferred to the neonates and confer effective protection. Hence, rGZ02a may be developed as an alternative live-attenuated vaccine and warrants a further evaluation. IMPORTANCE Zika virus (ZIKV), a mosquito-borne flavivirus that has caused global outbreaks since 2013, is associated with severe neurological disorders such as Guillian-Barré syndrome in adults and microcephaly in infants. The ZIKV epidemic has gradually subsided, but a safe and effective vaccine is still desirable to prevent its potential recurrence, especially in endemic countries with competent mosquito vectors. Here, we describe a novel live-attenuated ZIKV, rGZ02a, that carries 3 unique amino acid alterations compared to the wild-type GZ02 and a plasmid-launched rGZ02p. The growth capacity of rGZ02a is comparable to GZ02 in Vero cells, but the pathogenicity is significantly attenuated in two mice models. Immunization with rGZ02a elicits robust inhibitory antibody responses in the dams and effectively protects their offspring against ZIKV disease. Importantly, in a heterologous prime-boost regimen, rGZ02a effectively boosts the protective immunity primed by an adenovirus vectored vaccine. Thus, rGZ02a is a promising candidate for live-attenuated ZIKV vaccine.

Two Different UGT1A1 Mutations causing Crigler–Najjar Syndrome types I and II in an Iranian Family

2015 ◽  
Vol 24 (4) ◽  
pp. 523-526 ◽  
Author(s):  
Yoshihiro Maruo ◽  
Mahdiyeh Behnam ◽  
Shinichi Ikushiro ◽  
Sayuri Nakahara ◽  
Narges Nouri ◽  
...  
Keyword(s):  
Serum Bilirubin ◽  
Total Serum Bilirubin ◽  
Total Serum ◽  
Compound Heterozygous ◽  
Type I ◽  
Syndrome Type ◽  
Type Ii ◽  
Wild Type ◽  
Iranian Family ◽  
Udp Glucuronosyltransferase

Background: Crigler–Najjar syndrome type I (CN-1) and type II (CN-2) are rare hereditary unconjugated hyperbilirubinemia disorders. However, there have been no reports regarding the co-existence of CN-1 and CN-2 in one family. We experienced a case of an Iranian family that included members with either CN-1 or CN-2. Genetic analysis revealed a mutation in the bilirubin UDP-glucuronosyltransferase (UGT1A1) gene that resulted in residual enzymatic activity.Case report: The female proband developed severe hyperbilirubinemia [total serum bilirubin concentration (TB) = 34.8 mg/dL] with bilirubin encephalopathy (kernicterus) and died after liver transplantation. Her family history included a cousin with kernicterus (TB = 30.0 mg/dL) diagnosed as CN-1. Her great grandfather (TB unknown) and uncle (TB = 23.0 mg/dL) developed jaundice, but without any treatment, they remained healthy as CN-2. Results: The affected cousin was homozygous for a novel frameshift mutation (c.381insGG, p.C127WfsX23). The affected uncle was compound heterozygous for p.C127WfsX23 and p.V225G linked with A(TA)7TAA. p.V225G-UGT1A1 reduced glucuronidation activity to 60% of wild-type. Thus, linkage of A(TA)7TAA and p.V225G might reduce UGT1A1 activity to 18%–36 % of the wild-type. Conclusion: Genetic and in vitro expression analyses are useful for accurate genetic counseling for a family with a history of both CN-1 and CN-2. Abbreviations: CN-1: Crigler–Najjar syndrome type I; CN-2: Crigler–Najjar syndrome type II; GS: Gilbert syndrome; UGT1A1: bilirubin UDP-glucuronosyltransferase; WT: Wild type; TB: total serum bilirubin.

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