|
1
|
Krstanović F, Mihalić A, Rashidi AS, Sitnik KM, Ruzsics Z, Čičin-Šain L, Verjans GMGM, Jonjić S, Brizić I. Neuron-restricted cytomegalovirus latency in the central nervous system regulated by CD4 + T-cells and IFN-γ. J Neuroinflammation 2025; 22:95. [PMID: 40158177 PMCID: PMC11954325 DOI: 10.1186/s12974-025-03422-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 03/18/2025] [Indexed: 04/01/2025] Open
Abstract
All human herpesviruses establish latency following the resolution of the primary infection. Among these, α-herpesviruses HSV-1, HSV-2 and VZV establish latency in neurons, whereas neurons are not traditionally considered a site of latency for other herpesviruses. Using a combination of in vivo murine models and ex vivo human fetal tissues, we discovered that cytomegalovirus (CMV), a ubiquitous β-herpesvirus, can persist in neurons and that CD4+ T-cell-derived interferon-gamma is critical in restricting active viral replication in this cell type. Furthermore, we show that mouse CMV can establish latency in neurons and that CD4+ T-cells are essential in preventing viral reactivation. Our findings may have translational significance because human cytomegalovirus (HCMV) is the leading cause of congenital viral infections resulting in neurodevelopmental and neuroinflammatory lesions with long-term functional sequelae.
Collapse
Affiliation(s)
- Fran Krstanović
- Center for Proteomics, Faculty of Medicine, University of Rijeka, 51000, Rijeka, Croatia
| | - Andrea Mihalić
- Center for Proteomics, Faculty of Medicine, University of Rijeka, 51000, Rijeka, Croatia
| | - Ahmad Seyar Rashidi
- HerpeslabNL of the Department of Viroscience, Erasmus Medical Center, 3015 GD, Rotterdam, The Netherlands
| | - Katarzyna M Sitnik
- Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Viral Immunology, Helmholtz Centre for Infection Research, 38124, Braunschweig, Germany
| | - Zsolt Ruzsics
- Institute of Virology, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, 79104 , Freiburg, Germany
| | - Luka Čičin-Šain
- Department of Viral Immunology, Helmholtz Centre for Infection Research, 38124, Braunschweig, Germany
- Centre for Individualized Infection Medicine, Helmholtz Centre for Infection Research and the Hannover Medical School, 30625, Hannover, Germany
| | - Georges M G M Verjans
- HerpeslabNL of the Department of Viroscience, Erasmus Medical Center, 3015 GD, Rotterdam, The Netherlands
| | - Stipan Jonjić
- Center for Proteomics, Faculty of Medicine, University of Rijeka, 51000, Rijeka, Croatia
- Department of Biomedical Sciences, Croatian Academy of Sciences and Arts, 51000, Rijeka, Croatia
| | - Ilija Brizić
- Center for Proteomics, Faculty of Medicine, University of Rijeka, 51000, Rijeka, Croatia.
| |
Collapse
|
|
2
|
Cui X, Wang YT. Function of autophagy genes in innate immune defense against mucosal pathogens. Curr Opin Microbiol 2024; 79:102456. [PMID: 38554450 DOI: 10.1016/j.mib.2024.102456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/05/2024] [Accepted: 03/05/2024] [Indexed: 04/01/2024]
Abstract
Mucosal immunity is posed to constantly interact with commensal microbes and invading pathogens. As a fundamental cell biological pathway affecting immune response, autophagy regulates the interaction between mucosal immunity and microbes through multiple mechanisms, including direct elimination of microbes, control of inflammation, antigen presentation and lymphocyte homeostasis, and secretion of immune mediators. Some of these physiologically important functions do not involve canonical degradative autophagy but rely on certain autophagy genes and their 'autophagy gene-specific functions.' Here, we review the relationship between autophagy and important mucosal pathogens, including influenza virus, Mycobacterium tuberculosis, Salmonella enterica, Citrobacter rodentium, norovirus, and herpes simplex virus, with a particular focus on distinguishing the canonical versus gene-specific mechanisms of autophagy genes.
Collapse
Affiliation(s)
- Xiaoyan Cui
- Center for Infectious Disease Research, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China
| | - Ya-Ting Wang
- Center for Infectious Disease Research, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
| |
Collapse
|
|
3
|
Arnold KA, Peterson LF, Beck LA, Brewer MG. JAK Signaling Is Critically Important in Cytokine-Induced Viral Susceptibility of Keratinocytes. Int J Mol Sci 2023; 24:ijms24119243. [PMID: 37298195 DOI: 10.3390/ijms24119243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/20/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Little is known about whether type 1 (IFNγ), 2 (IL-4/IL-13), or 3 (IL-17A/IL-22) cytokines affect the susceptibility of keratinocytes (KC) to viruses. These immune pathways predominate in various skin diseases: lupus, atopic dermatitis (AD), and psoriasis, respectively. Janus kinase inhibitors (JAKi) are approved to treat both AD and psoriasis, and are in clinical development for lupus. We evaluated whether these cytokines alter viral susceptibility of KC and determined if this effect is modulated by treatment with JAKi. Viral susceptibility to vaccinia virus (VV) or herpes simplex virus-1 (HSV-1) ± JAKi was assessed in immortalized and primary human KC pretreated with cytokines. Exposure to type 2 (IL-4 + IL-13) or the type 3 (IL-22) cytokines significantly increased KC viral susceptibility. Specifically, there was a peak increase of 12.2 ± 3.1-fold (IL-4 + IL-13) or 7.7 ± 2.8-fold (IL-22) in VV infection as measured by plaque number. Conversely, IFNγ significantly reduced susceptibility to VV (63.1 ± 64.4-fold). The IL-4 + IL-13-induced viral susceptibility was reduced (44 ± 16%) by JAK1 inhibition, while the IL-22-enhanced viral susceptibility was diminished (76 ± 19%) by TYK2 inhibition. IFNγ-mediated resistance to viral infection was reversed by JAK2 inhibition (366 ± 294% increase in infection). Cytokines expressed in AD skin (IL-4, IL-13, IL-22) increase KC viral susceptibility while IFNγ is protective. JAKi that target JAK1 or TYK2 reversed cytokine-enhanced viral susceptibility, while JAK2 inhibition reduced the protective effects of IFNγ.
Collapse
Affiliation(s)
- Kimberly A Arnold
- Departments of Dermatology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Liam F Peterson
- Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Lisa A Beck
- Departments of Dermatology, University of Rochester Medical Center, Rochester, NY 14642, USA
- Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Matthew G Brewer
- Departments of Dermatology, University of Rochester Medical Center, Rochester, NY 14642, USA
| |
Collapse
|
|
4
|
Benzarti E, Murray KO, Ronca SE. Interleukins, Chemokines, and Tumor Necrosis Factor Superfamily Ligands in the Pathogenesis of West Nile Virus Infection. Viruses 2023; 15:v15030806. [PMID: 36992514 PMCID: PMC10053297 DOI: 10.3390/v15030806] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/31/2023] Open
Abstract
West Nile virus (WNV) is a mosquito-borne pathogen that can lead to encephalitis and death in susceptible hosts. Cytokines play a critical role in inflammation and immunity in response to WNV infection. Murine models provide evidence that some cytokines offer protection against acute WNV infection and assist with viral clearance, while others play a multifaceted role WNV neuropathogenesis and immune-mediated tissue damage. This article aims to provide an up-to-date review of cytokine expression patterns in human and experimental animal models of WNV infections. Here, we outline the interleukins, chemokines, and tumor necrosis factor superfamily ligands associated with WNV infection and pathogenesis and describe the complex roles they play in mediating both protection and pathology of the central nervous system during or after virus clearance. By understanding of the role of these cytokines during WNV neuroinvasive infection, we can develop treatment options aimed at modulating these immune molecules in order to reduce neuroinflammation and improve patient outcomes.
Collapse
Affiliation(s)
- Emna Benzarti
- Department of Pediatrics, Division of Tropical Medicine, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA
- William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA
| | - Kristy O Murray
- Department of Pediatrics, Division of Tropical Medicine, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA
- William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA
- National School of Tropical Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Immunology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Shannon E Ronca
- Department of Pediatrics, Division of Tropical Medicine, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA
- William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA
- National School of Tropical Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Immunology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
| |
Collapse
|
|
5
|
Visser I, Koenraadt CJ, Koopmans MP, Rockx B. The significance of mosquito saliva in arbovirus transmission and pathogenesis in the vertebrate host. One Health 2023. [DOI: 10.1016/j.onehlt.2023.100506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023] Open
|
|
6
|
Slonchak A, Wang X, Aguado J, Sng JDJ, Chaggar H, Freney ME, Yan K, Torres FJ, Amarilla AA, Balea R, Setoh YX, Peng N, Watterson D, Wolvetang E, Suhrbier A, Khromykh AA. Zika virus noncoding RNA cooperates with the viral protein NS5 to inhibit STAT1 phosphorylation and facilitate viral pathogenesis. SCIENCE ADVANCES 2022; 8:eadd8095. [PMID: 36449607 PMCID: PMC9710884 DOI: 10.1126/sciadv.add8095] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/13/2022] [Indexed: 05/25/2023]
Abstract
All flaviviruses, including Zika virus, produce noncoding subgenomic flaviviral RNA (sfRNA), which plays an important role in viral pathogenesis. However, the exact mechanism of how sfRNA enables viral evasion of antiviral response is not well defined. Here, we show that sfRNA is required for transplacental virus dissemination in pregnant mice and subsequent fetal brain infection. We also show that sfRNA promotes apoptosis of neural progenitor cells in human brain organoids, leading to their disintegration. In infected human placental cells, sfRNA inhibits multiple antiviral pathways and promotes apoptosis, with signal transducer and activator of transcription 1 (STAT1) identified as a key shared factor. We further show that the production of sfRNA leads to reduced phosphorylation and nuclear translocation of STAT1 via a mechanism that involves sfRNA binding to and stabilizing viral protein NS5. Our results suggest the cooperation between viral noncoding RNA and a viral protein as a novel strategy for counteracting antiviral responses.
Collapse
Affiliation(s)
- Andrii Slonchak
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Xiaohui Wang
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Julio Aguado
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Julian D. J. Sng
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Harman Chaggar
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Morgan E. Freney
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Kexin Yan
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Francisco J. Torres
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Alberto A. Amarilla
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Rickyle Balea
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Yin Xiang Setoh
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Nias Peng
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Daniel Watterson
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, Global Virus Network Center of Excellence, Brisbane, QLD, Australia
| | - Ernst Wolvetang
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
| | - Andreas Suhrbier
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, Global Virus Network Center of Excellence, Brisbane, QLD, Australia
| | - Alexander A. Khromykh
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, Global Virus Network Center of Excellence, Brisbane, QLD, Australia
| |
Collapse
|
|
7
|
Sylvester PA, Jondle CN, Schmalzriedt DL, Dittel BN, Tarakanova VL. T Cell-Specific STAT1 Expression Promotes Lytic Replication and Supports the Establishment of Gammaherpesvirus Latent Reservoir in Splenic B Cells. mBio 2022; 13:e0210722. [PMID: 35968944 PMCID: PMC9430880 DOI: 10.1128/mbio.02107-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 07/22/2022] [Indexed: 11/30/2022] Open
Abstract
Gammaherpesviruses establish lifelong infections in most vertebrate species, including humans and rodents, and are associated with cancers, including B cell lymphomas. While type I and II interferon (IFN) systems of the host are critical for the control of acute and chronic gammaherpesvirus infection, the cell type-specific role(s) of IFN signaling during infection is poorly understood and is often masked by the profoundly altered viral pathogenesis in the hosts with global IFN deficiencies. STAT1 is a critical effector of all classical IFN responses along with its involvement in other cytokine signaling pathways. In this study, we defined the effect of T cell-specific STAT1 deficiency on the viral and host parameters of infection with murine gammaherpesvirus 68 (MHV68). MHV68 is a natural rodent pathogen that, similar to human gammaherpesviruses, manipulates and usurps B cell differentiation to establish a lifelong latent reservoir in B cells. Specifically, germinal center B cells host the majority of latent MHV68 reservoir in the lymphoid organs, particularly at the peak of viral latency. Unexpectedly, T cell-specific STAT1 expression, while limiting the overall expansion of the germinal center B cell population during chronic infection, rendered these B cells more effective at hosting the latent virus reservoir. Further, T cell-specific STAT1 expression in a wild type host limited circulating levels of IFNγ, with corresponding increases in lytic MHV68 replication and viral reactivation. Thus, our study unveils an unexpected proviral role of T cell-specific STAT1 expression during gammaherpesvirus infection of a natural intact host. IMPORTANCE Interferons (IFNs) represent a major antiviral host network vital to the control of multiple infections, including acute and chronic gammaherpesvirus infections. Ubiquitously expressed STAT1 plays a critical effector role in all classical IFN responses. This study utilized a mouse model of T cell-specific STAT1 deficiency to define cell type-intrinsic role of STAT1 during natural gammaherpesvirus infection. Unexpectedly, T cell-specific loss of STAT1 led to better control of acute and persistent gammaherpesvirus replication and decreased establishment of latent viral reservoir in B cells, revealing a surprisingly diverse proviral role of T cell-intrinsic STAT1.
Collapse
Affiliation(s)
- P. A. Sylvester
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - C. N. Jondle
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - D. L. Schmalzriedt
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - B. N. Dittel
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Versiti Blood Research Institute, Milwaukee, Wisconsin, USA
| | - V. L. Tarakanova
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
- Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| |
Collapse
|
|
8
|
Sherman TJ, Petty D, Schountz T, Hodges N, Hawkinson AC. Increased Ifng and Il10 Expression Correlate with Disease in Rodent Models Experimentally Infected with Modoc Virus. Viruses 2022; 14:v14051026. [PMID: 35632766 PMCID: PMC9146023 DOI: 10.3390/v14051026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 11/28/2022] Open
Abstract
Flaviviruses present an ongoing threat to global public health, although the factors that contribute to the disease remain incompletely understood. We examined an acute Modoc virus (MODV) infection of two rodent models. Viral RNA was detected in the kidneys, spleen, liver, brain, urine, and sera of experimentally infected deer mice, a reservoir host of MODV, and Syrian hamsters, a known disease model. As expected, clinical outcomes differed between species, and the levels of viral RNA recovered from various tissues demonstrated signs of differential replication and tissue tropism. Multivariate analysis indicated significance in the profile of expressed genes between species when analyzed across tissues and over time (p = 0.02). Between-subject effects with corrected models revealed a significance specific to the expression of Ifng (p = 0.01). the expression of Ifng was elevated in hamsters as compared to deer mice in brain tissues at all timepoints. As the over-expression of Ifng has been shown to correlate with decreased vascular integrity, the findings presented here offer a potential mechanism for viral dissemination into the CNS. The expression of IL10 also differed significantly between species at certain timepoints in brain tissues; however, it is uncertain how increased expression of this cytokine may influence the outcome of MODV-induced pathology.
Collapse
Affiliation(s)
- Tyler J. Sherman
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA; (D.P.); (T.S.); (N.H.)
- Correspondence:
| | - Douglas Petty
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA; (D.P.); (T.S.); (N.H.)
| | - Tony Schountz
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA; (D.P.); (T.S.); (N.H.)
| | - Natasha Hodges
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA; (D.P.); (T.S.); (N.H.)
| | - Ann C. Hawkinson
- School of Biological Sciences, College of Natural and Health Sciences, University of Northern Colorado, Greeley, CO 80524, USA;
| |
Collapse
|
|
9
|
Conserved Gammaherpesvirus Protein Kinase Counters the Antiviral Effects of Myeloid Cell-Specific STAT1 Expression To Promote the Establishment of Splenic B Cell Latency. J Virol 2021; 95:e0085921. [PMID: 34132573 DOI: 10.1128/jvi.00859-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Gammaherpesviruses establish lifelong infections and are associated with B cell lymphomas. Murine gammaherpesvirus 68 (MHV68) infects epithelial and myeloid cells during acute infection, with subsequent passage of the virus to B cells, where physiological B cell differentiation is usurped to ensure the establishment of a chronic latent reservoir. Interferons (IFNs) represent a major antiviral defense system that engages the transcriptional factor STAT1 to attenuate diverse acute and chronic viral infections, including those of gammaherpesviruses. Correspondingly, global deficiency of type I or type II IFN signaling profoundly increases the pathogenesis of acute and chronic gammaherpesvirus infection, compromises host survival, and impedes mechanistic understanding of cell type-specific role of IFN signaling. Here, we demonstrate that myeloid-specific STAT1 expression attenuates acute and persistent MHV68 replication in the lungs and suppresses viral reactivation from peritoneal cells, without any effect on the establishment of viral latent reservoir in splenic B cells. All gammaherpesviruses encode a conserved protein kinase that antagonizes type I IFN signaling in vitro. Here, we show that myeloid-specific STAT1 deficiency rescues the attenuated splenic latent reservoir of the kinase-null MHV68 mutant. However, despite having gained access to splenic B cells, the protein kinase-null MHV68 mutant fails to drive B cell differentiation. Thus, while myeloid-intrinsic STAT1 expression must be counteracted by the gammaherpesvirus protein kinase to facilitate viral passage to splenic B cells, expression of the viral protein kinase continues to be required to promote optimal B cell differentiation and viral reactivation, highlighting the multifunctional nature of this conserved viral protein during chronic infection. IMPORTANCE IFN signaling is a major antiviral system of the host that suppresses replication of diverse viruses, including acute and chronic gammaherpesvirus infection. STAT1 is a critical member and the primary antiviral effector of IFN signaling pathways. Given the significantly compromised antiviral status of global type I or type II IFN deficiency, unabated gammaherpesvirus replication and pathogenesis hinders understanding of cell type-specific antiviral effects. In this study, a mouse model of myeloid-specific STAT1 deficiency unveiled site-specific antiviral effects of STAT1 in the lungs and peritoneal cavity, but not the spleen, of chronically infected hosts. Interestingly, expression of a conserved gammaherpesvirus protein kinase was required to counteract the antiviral effects of myeloid-specific STAT1 expression to facilitate latent infection of splenic B cells, revealing a cell type-specific virus-host antagonism during the establishment of chronic gammaherpesvirus infection.
Collapse
|
|
10
|
Aida V, Pliasas VC, Neasham PJ, North JF, McWhorter KL, Glover SR, Kyriakis CS. Novel Vaccine Technologies in Veterinary Medicine: A Herald to Human Medicine Vaccines. Front Vet Sci 2021; 8:654289. [PMID: 33937377 PMCID: PMC8083957 DOI: 10.3389/fvets.2021.654289] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/17/2021] [Indexed: 01/10/2023] Open
Abstract
The success of inactivated and live-attenuated vaccines has enhanced livestock productivity, promoted food security, and attenuated the morbidity and mortality of several human, animal, and zoonotic diseases. However, these traditional vaccine technologies are not without fault. The efficacy of inactivated vaccines can be suboptimal with particular pathogens and safety concerns arise with live-attenuated vaccines. Additionally, the rate of emerging infectious diseases continues to increase and with that the need to quickly deploy new vaccines. Unfortunately, first generation vaccines are not conducive to such urgencies. Within the last three decades, veterinary medicine has spearheaded the advancement in novel vaccine development to circumvent several of the flaws associated with classical vaccines. These third generation vaccines, including DNA, RNA and recombinant viral-vector vaccines, induce both humoral and cellular immune response, are economically manufactured, safe to use, and can be utilized to differentiate infected from vaccinated animals. The present article offers a review of commercially available novel vaccine technologies currently utilized in companion animal, food animal, and wildlife disease control.
Collapse
Affiliation(s)
- Virginia Aida
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
- Emory-University of Georgia (UGA) Center of Excellence for Influenza Research and Surveillance (CEIRS), Auburn, AL, United States
| | - Vasilis C. Pliasas
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
- Emory-University of Georgia (UGA) Center of Excellence for Influenza Research and Surveillance (CEIRS), Auburn, AL, United States
| | - Peter J. Neasham
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
- Emory-University of Georgia (UGA) Center of Excellence for Influenza Research and Surveillance (CEIRS), Auburn, AL, United States
| | - J. Fletcher North
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
- Emory-University of Georgia (UGA) Center of Excellence for Influenza Research and Surveillance (CEIRS), Auburn, AL, United States
| | - Kirklin L. McWhorter
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
- Department of Chemistry, Emory University, Atlanta, GA, United States
| | - Sheniqua R. Glover
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
- Emory-University of Georgia (UGA) Center of Excellence for Influenza Research and Surveillance (CEIRS), Auburn, AL, United States
| | - Constantinos S. Kyriakis
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
- Emory-University of Georgia (UGA) Center of Excellence for Influenza Research and Surveillance (CEIRS), Auburn, AL, United States
- Center for Vaccines and Immunology, University of Georgia, Athens, GA, United States
| |
Collapse
|
|
11
|
Saiz JC, Martín-Acebes MA, Blázquez AB, Escribano-Romero E, Poderoso T, Jiménez de Oya N. Pathogenicity and virulence of West Nile virus revisited eight decades after its first isolation. Virulence 2021; 12:1145-1173. [PMID: 33843445 PMCID: PMC8043182 DOI: 10.1080/21505594.2021.1908740] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
West Nile virus (WNV) is a flavivirus which transmission cycle is maintained between mosquitoes and birds, although it occasionally causes sporadic outbreaks in horses and humans that can result in serious diseases and even death. Since its first isolation in Africa in 1937, WNV had been considered a neglected pathogen until its recent spread throughout Europe and the colonization of America, regions where it continues to cause outbreaks with severe neurological consequences in humans and horses. Although our knowledge about the characteristics and consequences of the virus has increased enormously lately, many questions remain to be resolved. Here, we thoroughly update our knowledge of different aspects of the WNV life cycle: virology and molecular classification, host cell interactions, transmission dynamics, host range, epidemiology and surveillance, immune response, clinical presentations, pathogenesis, diagnosis, prophylaxis (antivirals and vaccines), and prevention, and we highlight those aspects that are still unknown and that undoubtedly require further investigation.
Collapse
Affiliation(s)
- Juan-Carlos Saiz
- Department of Biotechnology, National Institute for Agricultural and Food Research and Technology (INIA), Madrid, Spain
| | - Miguel A Martín-Acebes
- Department of Biotechnology, National Institute for Agricultural and Food Research and Technology (INIA), Madrid, Spain
| | - Ana B Blázquez
- Department of Biotechnology, National Institute for Agricultural and Food Research and Technology (INIA), Madrid, Spain
| | - Estela Escribano-Romero
- Department of Biotechnology, National Institute for Agricultural and Food Research and Technology (INIA), Madrid, Spain
| | - Teresa Poderoso
- Molecular Virology Group, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Nereida Jiménez de Oya
- Department of Biotechnology, National Institute for Agricultural and Food Research and Technology (INIA), Madrid, Spain
| |
Collapse
|
|
12
|
Alli A, Ortiz JF, Atoot A, Atoot A, Millhouse PW. Management of West Nile Encephalitis: An Uncommon Complication of West Nile Virus. Cureus 2021; 13:e13183. [PMID: 33717727 PMCID: PMC7939534 DOI: 10.7759/cureus.13183] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
West Nile virus disease (WNVD) is a mosquito-borne disease that affects the meninges and central nervous system, causing West Nile virus (WNV) encephalitis, a debilitating, life-threatening condition, especially in the elderly. While there is a lot of research discussing different aspects of the disease, the treatment is mainly unknown. We conducted a literature review to explore the wide variety of treatment options that consolidate the knowledge about the most recent management of WNV encephalitis. We did a combined advanced search and Medical Subject Headings (MeSH) search on PubMed. Inclusion criteria included papers written in the English language and human subjects research for the past 25 years. We initially gather 110 papers, and after applying the inclusion/exclusion criteria, we end up with 30 articles for the paper's discussion. This review aims to provide clinicians with an overview of the latest approach in treating and managing hospitalized WNVD patients. It discusses case reports and the outcome of different treatment regimens done in vitro and in vivo. The study discusses all the advancements in treatment and prophylaxis and compares their effectiveness. However, more research is warranted to gain further insight to develop a single guideline for the management of this disease. This review discusses the following treatment modalities: ribavirin, interferon-alpha, intravenous immunoglobulin (IVIG), and other less-used drugs. More studies about ribavirin are needed to know if the drug is useful for WNV encephalitis. Interferon-alpha has been shown to have both protective and disease limiting properties. At the moment, there are no guidelines for the treatment of WNV encephalitis, nor is there a single Food and Drug Administration (FDA)-approved drug. For the time being, IVIG offers the best results in treating WNV encephalitis
Collapse
Affiliation(s)
- Ammar Alli
- Internal Medicine, Hospital del Mar, Barcelona, ESP
| | - Juan Fernando Ortiz
- Neurology, Universidad San Francisco de Quito, Quito, ECU.,Neurology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Adam Atoot
- Internal Medicine, Palisades Medical Center, North Bergen, USA
| | - Ali Atoot
- Anesthesiology, Hackensack University Medical Center, Hackensack, USA
| | - Paul W Millhouse
- General Practice, Drexel University College of Medicine, Philadelphia, USA
| |
Collapse
|
|
13
|
Medina GN, de los Santos T, Diaz-San Segundo F. Use of IFN-Based Biotherapeutics to Harness the Host Against Foot-And-Mouth Disease. Front Vet Sci 2020; 7:465. [PMID: 32851039 PMCID: PMC7431487 DOI: 10.3389/fvets.2020.00465] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/24/2020] [Indexed: 12/12/2022] Open
Abstract
Foot-and-mouth disease (FMD) is a highly contagious vesicular disease of cloven-hoofed animals that severely constrains international trade of livestock and animal products. Currently, disease control measures include broad surveillance, enforcement of sanitary policy, and use of an inactivated vaccine. While use of these measures has contributed to eliminating foot-and-mouth disease virus (FMDV) from a vast area of the world, the disease remains endemic in three continents, and outbreaks occasionally appear in previously declared FMD-free zones, causing economic and social devastation. Among others, a very fast rate of viral replication and the need for 7 days to achieve vaccine-induced protection are the main limitations in controlling the disease. New fast-acting antiviral strategies targeted to boost the innate immunity of the host to block viral replication are needed. Here we review the knowledge on the multiple strategies FMDV has evolved to block the host innate immunity, with particularly focus on the past and current research toward the development of interferon (IFN)-based biotherapeutics in relevant livestock species.
Collapse
Affiliation(s)
- Gisselle N. Medina
- Plum Island Animal Disease Center (PIADC), ARS, USDA, Orient Point, NY, United States
- Kansas State University, College of Veterinary Medicine, Manhattan, KS, United States
| | - Teresa de los Santos
- Plum Island Animal Disease Center (PIADC), ARS, USDA, Orient Point, NY, United States
| | | |
Collapse
|
|
14
|
Long-term, West Nile virus-induced neurological changes: A comparison of patients and rodent models. Brain Behav Immun Health 2020; 7:100105. [PMID: 34589866 PMCID: PMC8474605 DOI: 10.1016/j.bbih.2020.100105] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 07/07/2020] [Accepted: 07/12/2020] [Indexed: 02/06/2023] Open
Abstract
West Nile virus (WNV) is a mosquito-borne virus that can cause severe neurological disease in those infected. Those surviving infection often present with long-lasting neurological changes that can severely impede their lives. The most common reported symptoms are depression, memory loss, and motor dysfunction. These sequelae can persist for the rest of the patients’ lives. The pathogenesis behind these changes is still being determined. Here, we summarize current findings in human cases and rodent models, and discuss how these findings indicate that WNV induces a state in the brain similar neurodegenerative diseases. Rodent models have shown that infection leads to persistent virus and inflammation. Initial infection in the hippocampus leads to neuronal dysfunction, synapse elimination, and astrocytosis, all of which contribute to memory loss, mimicking findings in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). WNV infection acts on pathways, such as ubiquitin-signaled protein degradation, and induces the production of molecules, including IL-1β, IFN-γ, and α-synuclein, that are associated with neurodegenerative diseases. These findings indicate that WNV induces neurological damage through similar mechanisms as neurodegenerative diseases, and that pursuing research into the similarities will help advance our understanding of the pathogenesis of WNV-induced neurological sequelae.
In patients with and without diagnosed WNND, there are long-lasting neurological sequelae that can mimic neurodegenerative diseases. Some rodent models of WNV reproduce some of these changes with mechanisms similar to neurodegenerative diseases. There is significant overlap between WNV and ND pathogenesis and this has been understudied. Further research needs to be done to determine accuracy of animal models compared to human patients.
Collapse
|
|
15
|
Evidence for Anti-Viral Effects of Complete Freund's Adjuvant in the Mouse Model of Enterovirus Infection. Vaccines (Basel) 2020; 8:vaccines8030364. [PMID: 32645845 PMCID: PMC7563290 DOI: 10.3390/vaccines8030364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/03/2020] [Accepted: 07/03/2020] [Indexed: 11/16/2022] Open
Abstract
Group B coxsackieviruses (CVBs) belonging to the genus, Enterovirus and contain six serotypes that induce various diseases, whose occurrence may involve the mediation of more than one serotype. We recently identified immunogenic epitopes within coxsackieviruses B3 (CVB3) viral protein 1 that induce anti-viral T cell responses in mouse models of CVB infections. In our investigations to determine the protective responses of the viral epitopes, we unexpectedly noted that animals immunized with complete Freund’s adjuvant (CFA) alone and later challenged with CVB3 were completely protected against myocarditis. Similarly, the pancreatitis-inducing ability of CVB3 was remarkably reduced to only 10% in the CFA group as opposed to 73.3% in the control group that received no CFA. Additionally, no mortalities were noted in the CFA group, whereas 40% of control animals died during the course of 21 days post-infection with CVB3. Taken together, our data suggest that the adjuvant effects of CFA may be sufficient for protection against CVB infections. These observations may provide new insights into our understanding of the occurrence of viral infections.
Collapse
|
|
16
|
Creisher PS, Chandwani MN, Kamte YS, Covvey JR, Ganesan P, O’Donnell LA. Type II interferon signaling in the brain during a viral infection with age-dependent pathogenesis. Dev Neurobiol 2020; 80:213-228. [PMID: 32866337 PMCID: PMC8513332 DOI: 10.1002/dneu.22778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 06/13/2020] [Accepted: 08/05/2020] [Indexed: 01/10/2023]
Abstract
Viral infections of the central nervous system (CNS) often cause disease in an age-dependent manner, with greater neuropathology during the fetal and neonatal periods. Transgenic CD46+ mice model these age-dependent outcomes through a measles virus infection of CNS neurons. Adult CD46+ mice control viral spread and survive the infection in an interferon gamma (IFNγ)-dependent manner, whereas neonatal CD46+ mice succumb despite similar IFNγ expression in the brain. Thus, we hypothesized that IFNγ signaling in the adult brain may be more robust, potentially due to greater basal expression of IFNγ signaling proteins. To test this hypothesis, we evaluated the expression of canonical IFNγ signaling proteins in the neonatal and adult brain, including the IFNγ receptor, Janus kinase (JAK) 1/2, and signal transducer and activator of transcription-1 (STAT1) in the absence of infection. We also analyzed the expression and activation of STAT1 and IFNγ-stimulated genes during MV infection. We found that neonatal brains have equivalent or greater JAK/STAT1 expression in the hippocampus and the cerebellum than adults. IFNγ receptor expression varied by cell type in the brain but was widely expressed on neuronal and glial cells. During MV infection, increased STAT1 expression and activation correlated with viral load in the hippocampus regardless of age, but not in the cerebellum where viral load was consistently undetectable in adults. These results suggest the neonatal brain is capable of initiating IFNγ signaling during a viral infection, but that downstream STAT1 activation is insufficient to limit viral spread.
Collapse
Affiliation(s)
- Patrick S. Creisher
- Duquesne University, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Pittsburgh, PA 15282
| | - Manisha N. Chandwani
- Duquesne University, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Pittsburgh, PA 15282
| | - Yashika S. Kamte
- Duquesne University, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Pittsburgh, PA 15282
| | - Jordan R. Covvey
- Duquesne University, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Pittsburgh, PA 15282
| | - Priya Ganesan
- Duquesne University, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Pittsburgh, PA 15282
| | - Lauren A. O’Donnell
- Duquesne University, School of Pharmacy and Graduate School of Pharmaceutical Sciences, Pittsburgh, PA 15282
| |
Collapse
|
|
17
|
Martin MF, Nisole S. West Nile Virus Restriction in Mosquito and Human Cells: A Virus under Confinement. Vaccines (Basel) 2020; 8:E256. [PMID: 32485916 PMCID: PMC7350012 DOI: 10.3390/vaccines8020256] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 05/25/2020] [Accepted: 05/27/2020] [Indexed: 02/08/2023] Open
Abstract
West Nile virus (WNV) is an emerging neurotropic flavivirus that naturally circulates between mosquitoes and birds. However, WNV has a broad host range and can be transmitted from mosquitoes to several mammalian species, including humans, through infected saliva during a blood meal. Although WNV infections are mostly asymptomatic, 20% to 30% of cases are symptomatic and can occasionally lead to severe symptoms, including fatal meningitis or encephalitis. Over the past decades, WNV-carrying mosquitoes have become increasingly widespread across new regions, including North America and Europe, which constitutes a public health concern. Nevertheless, mosquito and human innate immune defenses can detect WNV infection and induce the expression of antiviral effectors, so-called viral restriction factors, to control viral propagation. Conversely, WNV has developed countermeasures to escape these host defenses, thus establishing a constant arms race between the virus and its hosts. Our review intends to cover most of the current knowledge on viral restriction factors as well as WNV evasion strategies in mosquito and human cells in order to bring an updated overview on WNV-host interactions.
Collapse
Affiliation(s)
| | - Sébastien Nisole
- Viral Trafficking, Restriction and Innate Signaling Team, Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS, 34090 Montpellier, France;
| |
Collapse
|
|
18
|
Wang T, Li P, Zhang Y, Liu Y, Tan Z, Sun J, Ke X, Miao Y, Luo D, Hu Q, Xu F, Wang H, Zheng Z. In vivo imaging of Zika virus reveals dynamics of viral invasion in immune-sheltered tissues and vertical propagation during pregnancy. Am J Cancer Res 2020; 10:6430-6447. [PMID: 32483462 PMCID: PMC7255039 DOI: 10.7150/thno.43177] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 05/01/2020] [Indexed: 12/11/2022] Open
Abstract
Rationale: Zika virus (ZIKV) is a pathogenic virus known to cause a wide range of congenital abnormalities, including microcephaly, Guillain-Barre syndrome, meningoencephalitis, and other neurological complications, in humans. This study investigated the noninvasive detection of ZIKV infection in vivo, which is necessary for elucidating the virus's mechanisms of viral replication and pathogenesis, as well as to accelerate the development of anti-ZIKV therapeutic strategies. Methods: In this study, a recombinant ZIKV harbouring Nluc gene (ZIKV-Nluc) was designed, recovered, and purified. The levels of bioluminescence were directly correlated with viral loads in vitro and in vivo. The dynamics of ZIKV infection in A129 (interferon (IFN)-α/β receptor deficient), AG6 (IFN-α/β and IFN-γ receptor deficient), and C57BL/6 mice were characterized. Pregnant dams were infected with ZIKV-Nluc at E10 via intra footpad injection. Then, the pooled immune sera (anti-ZIKV neutralizing antibodies) #22-1 in ZIKV-Nluc virus-infected mice were visualized. Results: ZIKV-Nluc showed a high genetic stability and replicated well in cells with similar properties to the wild-type ZIKV (ZIKVwt). Striking bioluminescence signals were consistently observed in animal organs, including spleen, intestine, testis, uterus/ovary, and kidney. The ileocecal junction was found to be the crucial visceral target. Infection of pregnant dams with ZIKV-Nluc showed that ZIKV was capable of crossing the maternal-fetal barrier to infect the fetuses via vertical transmission. Furthermore, it was visualized that treatment with the pooled immune sera was found to greatly restrict the spread of the ZIKV-Nluc virus in mice. Conclusions: This study is the first to report the real-time noninvasive tracking of the progression of ZIKV invading immune-sheltered tissues and propagating vertically during pregnancy. The results demonstrate that ZIKV-Nluc represents a powerful tool for the study of the replication, dissemination, pathogenesis, and treatment of ZIKV in vitro and in vivo.
Collapse
|
|
19
|
Har-Noy M, Or R. Allo-priming as a universal anti-viral vaccine: protecting elderly from current COVID-19 and any future unknown viral outbreak. J Transl Med 2020; 18:196. [PMID: 32398026 PMCID: PMC7215129 DOI: 10.1186/s12967-020-02363-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 05/04/2020] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND We present the rationale for a novel allo-priming approach to serve the elderly as a universal anti-virus vaccine, as well serving to remodel the aging immune system in order to reverse immunosenescence and inflammaging. This approach has the potential to protect the most vulnerable from disease and provide society an incalculable economic benefit. Allo-priming healthy elderly adults is proposed to provide universal protection from progression of any type of viral infection, including protection against progression of the current outbreak of COVID-19 infection, and any future variants of the causative SARS-CoV-2 virus or the next 'Disease X'. Allo-priming is an alternative approach for the COVID-19 pandemic that provides a back-up in case vaccination strategies to elicit neutralizing antibody protection fails or fails to protect the vulnerable elderly population. The allo-priming is performed using activated, intentionally mismatched, ex vivo differentiated and expanded living Th1-like cells (AlloStim®) derived from healthy donors currently in clinical use as an experimental cancer vaccine. Multiple intradermal injections of AlloStim® creates a dominate titer of allo-specific Th1/CTL memory cells in circulation, replacing the dominance of exhausted memory cells of the aged immune system. Upon viral encounter, by-stander activation of the allo-specific memory cells causes an immediate release of IFN-ϒ, leading to development of an "anti-viral state", by-stander activation of innate cellular effector cells and activation of cross-reactive allo-specific CTL. In this manner, the non-specific activation of allo-specific Th1/CTL initiates a cascade of spatial and temporal immune events which act to limit the early viral titer. The release of endogenous heat shock proteins (HSP) and DAMP from lysed viral-infected cells, in the context of IFN-ϒ, creates of conditions for in situ vaccination leading to viral-specific Th1/CTL immunity. These viral-specific Th1/CTL provide sterilizing immunity and memory for protection from disease recurrence, while increasing the pool of Th1/CTL in circulation capable of responding to the next viral encounter. CONCLUSION Allo-priming has potential to provide universal protection from viral disease and is a strategy to reverse immunosenescence and counter-regulate chronic inflammation (inflammaging). Allo-priming can be used as an adjuvant for anti-viral vaccines and as a counter-measure for unknown biological threats and bio-economic terrorism.
Collapse
Affiliation(s)
- Michael Har-Noy
- Cancer Immunotherapy and Immunobiology Center, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel. .,Immunovative Therapies, Ltd, Malcha Technology Park, B1/F1, 9695101, Jerusalem, Israel. .,Mirror Biologics, Inc., 4824 E Baseline Rd #113, Phoenix, AZ, USA.
| | - Reuven Or
- Cancer Immunotherapy and Immunobiology Center, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel
| |
Collapse
|
|
20
|
Comparative Pathology of West Nile Virus in Humans and Non-Human Animals. Pathogens 2020; 9:pathogens9010048. [PMID: 31935992 PMCID: PMC7168622 DOI: 10.3390/pathogens9010048] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/03/2020] [Accepted: 01/03/2020] [Indexed: 12/11/2022] Open
Abstract
West Nile virus (WNV) continues to be a major cause of human arboviral neuroinvasive disease. Susceptible non-human vertebrates are particularly diverse, ranging from commonly affected birds and horses to less commonly affected species such as alligators. This review summarizes the pathology caused by West Nile virus during natural infections of humans and non-human animals. While the most well-known findings in human infection involve the central nervous system, WNV can also cause significant lesions in the heart, kidneys and eyes. Time has also revealed chronic neurologic sequelae related to prior human WNV infection. Similarly, neurologic disease is a prominent manifestation of WNV infection in most non-human non-host animals. However, in some avian species, which serve as the vertebrate host for WNV maintenance in nature, severe systemic disease can occur, with neurologic, cardiac, intestinal and renal injury leading to death. The pathology seen in experimental animal models of West Nile virus infection and knowledge gains on viral pathogenesis derived from these animal models are also briefly discussed. A gap in the current literature exists regarding the relationship between the neurotropic nature of WNV in vertebrates, virus propagation and transmission in nature. This and other knowledge gaps, and future directions for research into WNV pathology, are addressed.
Collapse
|
|
21
|
Thackray LB, Handley SA, Gorman MJ, Poddar S, Bagadia P, Briseño CG, Theisen DJ, Tan Q, Hykes BL, Lin H, Lucas TM, Desai C, Gordon JI, Murphy KM, Virgin HW, Diamond MS. Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections. Cell Rep 2019; 22:3440-3453.e6. [PMID: 29590614 PMCID: PMC5908250 DOI: 10.1016/j.celrep.2018.03.001] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 02/15/2018] [Accepted: 02/28/2018] [Indexed: 12/22/2022] Open
Abstract
Although the outcome of flavivirus infection can vary from asymptomatic to lethal, environmental factors modulating disease severity are poorly defined. Here, we observed increased susceptibility of mice to severe West Nile (WNV), Dengue, and Zika virus infections after treatment with oral antibiotics (Abx) that depleted the gut microbiota. Abx treatment impaired the development of optimal T cell responses, with decreased levels of WNV-specific CD8+ T cells associated with increased infection and immunopathology. Abx treatments that resulted in enhanced WNV susceptibility generated changes in the overall structure of the gut bacterial community and in the abundance of specific bacterial taxa. As little as 3 days of treatment with ampicillin was sufficient to alter host immunity and WNV outcome. Our results identify oral Abx therapy as a potential environmental determinant of systemic viral disease, and they raise the possibility that perturbation of the gut microbiota may have deleterious consequences for subsequent flavivirus infections.
Collapse
Affiliation(s)
- Larissa B Thackray
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Scott A Handley
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Matthew J Gorman
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Subhajit Poddar
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Prachi Bagadia
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Carlos G Briseño
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Derek J Theisen
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Qing Tan
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Barry L Hykes
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Hueylie Lin
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Tiffany M Lucas
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Chandni Desai
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Jeffrey I Gordon
- Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Center for Gut Microbiome and Nutrition Research, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Kenneth M Murphy
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Howard Hughes Medical Institute, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Herbert W Virgin
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Michael S Diamond
- Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA.
| |
Collapse
|
|
22
|
Gao P, Fan L, Du H, Xiang B, Li Y, Sun M, Kang Y, Chen L, Xu C, Li Y, Ren T. Recombinant Duck Interferon Gamma Inhibits H5N1 Influenza Virus Replication In Vitro and In Vivo. J Interferon Cytokine Res 2019; 38:290-297. [PMID: 30016179 DOI: 10.1089/jir.2018.0034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The highly pathogenic H5N1 avian influenza virus (AIV) is widespread in waterfowl, causing enormous economic losses and posing a significant threat to public health. An increasing number of reagents have been identified to prevent the spread of influenza; however, there have been no reports on the anti-H5N1 effects of duck interferons, which exhibit antiviral activity against other viruses. Our aim was to investigate the antiviral effects of purified duck interferons. In this study, we successfully cloned and expressed duck interferon gamma (IFN-γ) in Escherichia coli. The antiviral effects of this recombinant duck IFN-γ (rDuIFN-γ) was assessed in vitro and in vivo. rDuIFN-γ displayed antiviral activity against vesicular stomatitis virus and AIV in duck embryo fibroblasts. Pretreating ducks with 3.4 × 104 U rDuIFN-γ also partially decreased mortality from 70% to 30% and delayed onset in 2-day-old Peking ducks. Virus titers in tissues and viral shedding decreased, and the expression of interferon-stimulated genes increased in brain and spleen in rDuIFN-γ-treated ducks. These results indicate that duck IFN-γ has the potential to inhibit viral replication in ducks.
Collapse
Affiliation(s)
- Pei Gao
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| | - Lei Fan
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| | - Haoyun Du
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| | - Bin Xiang
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| | - Yulian Li
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| | - Minhua Sun
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| | - Yinfeng Kang
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| | - Libin Chen
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| | - Chenggang Xu
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| | - Yaling Li
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China .,5 College of Animal Science and Technology, Shihezi University , Shihezi, Xinjiang, China
| | - Tao Ren
- 1 College of Veterinary Medicine, South China Agricultural University , Guangzhou, China .,2 National and Regional Joint Engineering Laboratory for Medicament of Zoonosis Prevention and Control , Guangzhou, China .,3 Key Laboratory of Animal Vaccine Development, Ministry of Agriculture , Guangzhou, China .,4 Key Laboratory of Zoonosis Prevention and Control of Guangdong Province , Guangzhou, China
| |
Collapse
|
|
23
|
Bai F, Thompson EA, Vig PJS, Leis AA. Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications. Pathogens 2019; 8:pathogens8040193. [PMID: 31623175 PMCID: PMC6963678 DOI: 10.3390/pathogens8040193] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/12/2019] [Accepted: 10/13/2019] [Indexed: 12/11/2022] Open
Abstract
West Nile virus (WNV) is the most common mosquito-borne virus in North America. WNV-associated neuroinvasive disease affects all ages, although elderly and immunocompromised individuals are particularly at risk. WNV neuroinvasive disease has killed over 2300 Americans since WNV entered into the United States in the New York City outbreak of 1999. Despite 20 years of intensive laboratory and clinical research, there are still no approved vaccines or antivirals available for human use. However, rapid progress has been made in both understanding the pathogenesis of WNV and treatment in clinical practices. This review summarizes our current understanding of WNV infection in terms of human clinical manifestations, host immune responses, neuroinvasion, and therapeutic interventions.
Collapse
Affiliation(s)
- Fengwei Bai
- Department of Cell and Molecular Biology, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
| | - E Ashley Thompson
- Department of Cell and Molecular Biology, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
| | - Parminder J S Vig
- Departments of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
| | - A Arturo Leis
- Methodist Rehabilitation Center, Jackson, MS 39216, USA.
| |
Collapse
|
|
24
|
Replication-Defective West Nile Virus with NS1 Deletion as a New Vaccine Platform for Flavivirus. J Virol 2019; 93:JVI.00720-19. [PMID: 31189715 DOI: 10.1128/jvi.00720-19] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 06/10/2019] [Indexed: 02/03/2023] Open
Abstract
We previously produced a replication-defective West Nile virus (WNV) lacking NS1 (WNV-ΔNS1) that could propagate at low levels (105 infectious units [IU]/ml) in a 293T cell line expressing wild-type (WT) NS1. This finding indicates the potential of developing WNV-ΔNS1 as a noninfectious vaccine. To explore this idea, we developed an NS1-expressing Vero cell line (VeroNS1) that significantly improved the yield of WNV-ΔNS1 (108 IU/ml). We evaluated the safety and efficacy of WNV-ΔNS1 in mice. WNV-ΔNS1 appeared to be safe, as no replicative virus was found in naive Vero cells after continuous culturing of WNV-ΔNS1 in VeroNS1 cells for 15 rounds. WNV-ΔNS1 was noninfectious in mice, even when IFNAR-/- mice were administered a high dose of WNV-ΔNS1. Vaccination with a single dose of WNV-ΔNS1 protected mice from a highly lethal challenge with WT WNV. The antibody response against WNV correlated well with the protection of vaccinated mice. Our study demonstrates the potential of the NS1 trans complementation system as a new platform for flavivirus vaccine development.IMPORTANCE Many flaviviruses are significant human pathogens that frequently cause outbreaks and epidemics around the world. Development of novel vaccine platforms against these pathogens is a public health priority. Using WNV as a model, we developed a new vaccine platform for flaviviruses. WNV containing a NS1 deletion (WNV-ΔNS1) could be efficiently trans complemented in Vero cells that constitutively expressed WT NS1 protein. A single-dose immunization with WNV-ΔNS1 elicited robust immune responses in mice. The immunized animals were fully protected against pathogenic WNV infection. No adverse effects related to the WNV-ΔNS1 vaccination were observed. The results have demonstrated the potential of the NS1 complementation system as an alternative platform for flavivirus vaccine development, especially for highly pathogenic flaviviruses.
Collapse
|
|
25
|
Pereiro P, Figueras A, Novoa B. Insights into teleost interferon-gamma biology: An update. FISH & SHELLFISH IMMUNOLOGY 2019; 90:150-164. [PMID: 31028897 DOI: 10.1016/j.fsi.2019.04.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 03/20/2019] [Accepted: 04/02/2019] [Indexed: 06/09/2023]
Abstract
Interferon-gamma (IFN-ϒ) is probably one of the most relevant cytokines orchestrating the immune response in vertebrates. Although the activities mediated by this molecule are well known in mammals, several aspects of the IFN-ϒ system in teleosts remain a riddle to scientists. Numerous studies support a potentially similar role of the fish IFN-ϒ signalling pathway in some well-described immunological processes induced by this cytokine in mammals. Nevertheless, the existence in some teleost species of duplicated ifng genes and an additional gene derived from ifng known as interferon-γ-related (ifngrel), among other things, raises new interesting questions about the mode of action of these various molecules in fish. Moreover, certain IFN-ϒ-mediated activities recently observed in mammals are still fully unknown in fish. Another attractive but mainly unexplored curious property of IFN-ϒ in vertebrates is its potential dual role depending on the type of pathogen. In addition, some aspects mediated by this molecule could favour the resolution of a bacterial infection but be harmful in the context of a viral disease, and vice versa. This review collects old and new aspects of IFN-ϒ research in teleosts and discusses new questions and pathways of investigation based on recent discoveries in mammals.
Collapse
Affiliation(s)
- Patricia Pereiro
- Instituto de Investigaciones Marinas (IIM), CSIC, Vigo, Spain; Laboratory of Biotechnology and Aquatic Genomics, Interdisciplinary Center for Aquaculture Research (INCAR), University of Concepción, Concepción, Chile
| | | | - Beatriz Novoa
- Instituto de Investigaciones Marinas (IIM), CSIC, Vigo, Spain.
| |
Collapse
|
|
26
|
Klein RS, Garber C, Funk KE, Salimi H, Soung A, Kanmogne M, Manivasagam S, Agner S, Cain M. Neuroinflammation During RNA Viral Infections. Annu Rev Immunol 2019; 37:73-95. [PMID: 31026414 PMCID: PMC6731125 DOI: 10.1146/annurev-immunol-042718-041417] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Neurotropic RNA viruses continue to emerge and are increasingly linked to diseases of the central nervous system (CNS) despite viral clearance. Indeed, the overall mortality of viral encephalitis in immunocompetent individuals is low, suggesting efficient mechanisms of virologic control within the CNS. Both immune and neural cells participate in this process, which requires extensive innate immune signaling between resident and infiltrating cells, including microglia and monocytes, that regulate the effector functions of antiviral T and B cells as they gain access to CNS compartments. While these interactions promote viral clearance via mainly neuroprotective mechanisms, they may also promote neuropathology and, in some cases, induce persistent alterations in CNS physiology and function that manifest as neurologic and psychiatric diseases. This review discusses mechanisms of RNA virus clearance and neurotoxicity during viral encephalitis with a focus on the cytokines essential for immune and neural cell inflammatory responses and interactions. Understanding neuroimmune communications in the setting of viral infections is essential for the development of treatments that augment neuroprotective processes while limiting ongoing immunopathological processes that cause ongoing CNS disease.
Collapse
Affiliation(s)
- Robyn S Klein
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri 63110, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | - Charise Garber
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| | - Kristen E Funk
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| | - Hamid Salimi
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| | - Allison Soung
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| | - Marlene Kanmogne
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| | - Sindhu Manivasagam
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| | - Shannon Agner
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | - Matthew Cain
- Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
| |
Collapse
|
|
27
|
Yee PTI, Tan SH, Ong KC, Tan KO, Wong KT, Hassan SS, Poh CL. Development of live attenuated Enterovirus 71 vaccine strains that confer protection against lethal challenge in mice. Sci Rep 2019; 9:4805. [PMID: 30886246 PMCID: PMC6423319 DOI: 10.1038/s41598-019-41285-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 02/27/2019] [Indexed: 12/12/2022] Open
Abstract
Besides causing mild hand, foot and mouth infections, Enterovirus A71 (EV-A71) is associated with neurological complications and fatality. With concerns about rising EV-A71 virulence, there is an urgency for more effective vaccines. The live attenuated vaccine (LAV) is a more valuable vaccine as it can elicit both humoral and cellular immune responses. A miRNA-based vaccine strain (pIY) carrying let-7a and miR-124a target genes in the EV-A71 genome which has a partial deletion in the 5′NTR (∆11 bp) and G64R mutation (3Dp°l) was designed. The viral RNA copy number and viral titers of the pIY strain were significantly lower in SHSY-5Y cells that expressed both let-7a and miR-124a. Inhibition of the cognate miRNAs expressed in RD and SHSY-5Y cells demonstrated de-repression of viral mRNA translation. A previously constructed multiply mutated strain, MMS and the pIY vaccine strain were assessed in their ability to protect 4-week old mice from hind limb paralysis. The MMS showed higher amounts of IFN-γ ex vivo than the pIY vaccine strain. There was absence of EV-A71 antigen in the skeletal muscles and spinal cord micrographs of mice vaccinated with the MMS and pIY strains. The MMS and pIY strains are promising LAV candidates developed against severe EV-A71 infections.
Collapse
Affiliation(s)
- Pinn Tsin Isabel Yee
- Centre for Virus and Vaccine Research, School of Science and Technology, Sunway University, Bandar Sunway, Selangor, 47500, Malaysia
| | - Soon Hao Tan
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Jalan University, 50603, Kuala Lumpur, Selangor, Malaysia
| | - Kien Chai Ong
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Jalan University, 50603, Kuala Lumpur, Selangor, Malaysia
| | - Kuan Onn Tan
- Department of Biological Sciences, School of Science and Technology, Sunway University, Kuala Lumpur, Selangor, 47500, Malaysia
| | - Kum Thong Wong
- Department of Pathology, Faculty of Medicine, University of Malaya, Jalan University, 50603, Kuala Lumpur, Selangor, Malaysia
| | - Sharifah Syed Hassan
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Jalan Lagoon Selatan, Bandar Sunway, 47500, Subang Jaya, Malaysia
| | - Chit Laa Poh
- Centre for Virus and Vaccine Research, School of Science and Technology, Sunway University, Bandar Sunway, Selangor, 47500, Malaysia.
| |
Collapse
|
|
28
|
Funk KE, Klein RS. CSF1R antagonism limits local restimulation of antiviral CD8 + T cells during viral encephalitis. J Neuroinflammation 2019; 16:22. [PMID: 30704498 PMCID: PMC6354430 DOI: 10.1186/s12974-019-1397-4] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 01/02/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Microglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling. Microglial depletion via CSF1R inactivation improves cognition in mouse models of neuroinflammation, but limits virologic control in the CNS of mouse models of neurotropic infections by unknown mechanisms. We hypothesize that CSF1R plays a critical role in myeloid cell responses that restrict viral replication and locally restimulate recruited antiviral T cells within the CNS. METHODS The impact of CSF1R signaling during West Nile virus infection was assessed in vivo using a mouse model of neurotropic infection. Pharmacological inactivation of CSF1R was achieved using PLX5622 prior to infection with virulent or attenuated strains of West Nile virus (WNV), an emerging neuropathogen. The subsequent effect of CSF1R antagonism on virologic control was assessed by measuring mortality and viral titers in the CNS and peripheral organs. Immune responses were assessed by flow cytometric-based phenotypic analyses of both peripheral and CNS immune cells. RESULTS Mice treated with CSF1R antagonist prior to infection exhibited higher susceptibility to lethal WNV infection and lack of virologic control in both the CNS and periphery. CSFR1 antagonism reduced B7 co-stimulatory signals on peripheral and CNS antigen-presenting cells (APCs) by depleting CNS cellular sources, which limited local reactivation of CNS-infiltrating virus-specific T cells and reduced viral clearance. CONCLUSIONS Our results demonstrate the impact of CSF1R antagonism on APC activation in the CNS and periphery and the importance of microglia in orchestrating the CNS immune response following neurotropic viral infection. These data will be an important consideration when assessing the benefit of CSF1R antagonism, which has been investigated as a therapeutic for neurodegenerative conditions, in which neuroinflammation is a contributing factor.
Collapse
Affiliation(s)
- Kristen E. Funk
- Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, MO 63110 USA
| | - Robyn S. Klein
- Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, MO 63110 USA
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110 USA
- Department of Neurosciences, Washington University School of Medicine, Saint Louis, MO 63110 USA
| |
Collapse
|
|
29
|
Chandwani MN, Creisher PS, O'Donnell LA. Understanding the Role of Antiviral Cytokines and Chemokines on Neural Stem/Progenitor Cell Activity and Survival. Viral Immunol 2018; 32:15-24. [PMID: 30307795 DOI: 10.1089/vim.2018.0091] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Viral infections of the central nervous system are accompanied by the expression of cytokines and chemokines that can be critical for the control of viral replication in the brain. The outcomes of cytokine/chemokine signaling in neural cells vary widely, with cell-specific effects on cellular activity, proliferation, and survival. Neural stem/progenitor cells (NSPCs) are often altered during viral infections, through direct infection by the virus or by the influence of immune cell activity or cytokine/chemokine signaling. However, it has been challenging to dissect the contribution of the virus and specific inflammatory mediators during an infection. In addition to initiating an antiviral program in infected NSPCs, cytokines/chemokines can induce multiple changes in NSPC behavior that can perturb NSPC numbers, differentiation into other neural cells, and migration to sites of injury, and ultimately brain development and repair. The focus of this review was to dissect the effects of common antiviral cytokines and chemokines on NSPC activity, and to consider the subsequent pathological consequences for the host from changes in NSPC function.
Collapse
Affiliation(s)
- Manisha N Chandwani
- Department of Pharmaceutical, Administrative, and Social Sciences, Graduate School of Pharmaceutical Sciences, Duquesne University School of Pharmacy , Pittsburgh, Pennsylvania
| | - Patrick S Creisher
- Department of Pharmaceutical, Administrative, and Social Sciences, Graduate School of Pharmaceutical Sciences, Duquesne University School of Pharmacy , Pittsburgh, Pennsylvania
| | - Lauren A O'Donnell
- Department of Pharmaceutical, Administrative, and Social Sciences, Graduate School of Pharmaceutical Sciences, Duquesne University School of Pharmacy , Pittsburgh, Pennsylvania
| |
Collapse
|
|
30
|
The Temporal Role of Cytokines in Flavivirus Protection and Pathogenesis. CURRENT CLINICAL MICROBIOLOGY REPORTS 2018. [DOI: 10.1007/s40588-018-0106-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
|
|
31
|
Manet C, Roth C, Tawfik A, Cantaert T, Sakuntabhai A, Montagutelli X. Host genetic control of mosquito-borne Flavivirus infections. Mamm Genome 2018; 29:384-407. [PMID: 30167843 PMCID: PMC7614898 DOI: 10.1007/s00335-018-9775-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 08/20/2018] [Indexed: 12/12/2022]
Abstract
Flaviviruses are arthropod-borne viruses, several of which represent emerging or re-emerging pathogens responsible for widespread infections with consequences ranging from asymptomatic seroconversion to severe clinical diseases and congenital developmental deficits. This variability is due to multiple factors including host genetic determinants, the role of which has been investigated in mouse models and human genetic studies. In this review, we provide an overview of the host genes and variants which modify susceptibility or resistance to major mosquito-borne flaviviruses infections in mice and humans.
Collapse
Affiliation(s)
- Caroline Manet
- Mouse Genetics Laboratory, Department of Genomes and Genetics, Institut Pasteur, Paris, France
| | - Claude Roth
- Functional Genetics of Infectious Diseases Unit, Department of Genomes and Genetics, Institut Pasteur, Paris, France
- CNRS, UMR 2000-Génomique Evolutive, Modélisation et Santé, Institut Pasteur, 75015, Paris, France
| | - Ahmed Tawfik
- Functional Genetics of Infectious Diseases Unit, Department of Genomes and Genetics, Institut Pasteur, Paris, France
- CNRS, UMR 2000-Génomique Evolutive, Modélisation et Santé, Institut Pasteur, 75015, Paris, France
| | - Tineke Cantaert
- Immunology Group, Institut Pasteur du Cambodge, International Network of Pasteur Institutes, Phnom Penh, 12201, Cambodia
| | - Anavaj Sakuntabhai
- Functional Genetics of Infectious Diseases Unit, Department of Genomes and Genetics, Institut Pasteur, Paris, France.
- CNRS, UMR 2000-Génomique Evolutive, Modélisation et Santé, Institut Pasteur, 75015, Paris, France.
| | - Xavier Montagutelli
- Mouse Genetics Laboratory, Department of Genomes and Genetics, Institut Pasteur, Paris, France.
| |
Collapse
|
|
32
|
Burgan SC, Gervasi SS, Martin LB. Parasite Tolerance and Host Competence in Avian Host Defense to West Nile Virus. ECOHEALTH 2018; 15:360-371. [PMID: 29569179 DOI: 10.1007/s10393-018-1332-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 02/15/2018] [Accepted: 03/07/2018] [Indexed: 06/08/2023]
Abstract
Competence, or the propensity of a host to transmit parasites, is partly underlain by host strategies to cope with infection (e.g., resistance and tolerance). Resistance represents the ability of hosts to prevent or clear infections, whereas tolerance captures the ability of individuals to cope with a given parasite burden. Here, we investigated (1) whether one easy-to-measure form of tolerance described well the dynamic relationships between host health and parasite burden, and (2) whether individual resistance and tolerance to West Nile virus (WNV) were predictable from single cytokine measures. We exposed house sparrows (HOSP) to WNV and measured subsequent changes in host performance, viral burden, and cytokine expression. We then used two novel approaches (one complex, one simpler) to estimate tolerance within-individual HOSP using four separate host performance traits. We lastly investigated changes in the expression of pro-inflammatory cytokine interferon-γ (IFN-γ) and anti-inflammatory cytokine interleukin-10 (IL-10). Both approaches to estimating tolerance were equivalent among WNV-infected HOSP; thus, an easy-to-measure tolerance estimation may be successfully applied in field studies. Constitutive expression of IFN-γ and IL-10 were predictive of resistance and tolerance to WNV, implicating these cytokines as viable biomarkers of host competence to WNV.
Collapse
Affiliation(s)
- Sarah C Burgan
- Department of Integrative Biology, University of South Florida, SCA 130, 12037 USF Beard Drive, Tampa, FL, 33620, USA
| | | | - Lynn B Martin
- Department of Integrative Biology, University of South Florida, SCA 130, 12037 USF Beard Drive, Tampa, FL, 33620, USA.
| |
Collapse
|
|
33
|
Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ. Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion. Front Immunol 2018; 9:847. [PMID: 29780381 PMCID: PMC5945880 DOI: 10.3389/fimmu.2018.00847] [Citation(s) in RCA: 855] [Impact Index Per Article: 122.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 04/05/2018] [Indexed: 12/15/2022] Open
Abstract
Interferon-gamma (IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-γ in tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limited success. In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However, the IFN-γ-mediated responses are still positively associated with patient's survival in several cancers. Consequently, major research efforts are required to understand the immune contexture in which IFN-γ induces its intricate and highly regulated effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways.
Collapse
Affiliation(s)
- Flávia Castro
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB – Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- ICBAS – Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Ana Patrícia Cardoso
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB – Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
| | - Raquel Madeira Gonçalves
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB – Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- ICBAS – Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Karine Serre
- IMM – Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Maria José Oliveira
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- INEB – Instituto de Engenharia Biomédica, Universidade do Porto, Porto, Portugal
- Departamento de Patologia e Oncologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| |
Collapse
|
|
34
|
Rotem E, Faingold O, Charni M, Klug YA, Harari D, Shmuel-Galia L, Nudelman A, Rotter V, Shai Y. The HTLV-1 gp21 fusion peptide inhibits antigen specific T-cell activation in-vitro and in mice. PLoS Pathog 2018; 14:e1007044. [PMID: 29727445 PMCID: PMC5955599 DOI: 10.1371/journal.ppat.1007044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 05/16/2018] [Accepted: 04/18/2018] [Indexed: 11/17/2022] Open
Abstract
The ability of the Lentivirus HIV-1 to inhibit T-cell activation by its gp41 fusion protein is well documented, yet limited data exists regarding other viral fusion proteins. HIV-1 utilizes membrane binding region of gp41 to inhibit T-cell receptor (TCR) complex activation. Here we examined whether this T-cell suppression strategy is unique to the HIV-1 gp41. We focused on T-cell modulation by the gp21 fusion peptide (FP) of the Human T-lymphotropic Virus 1 (HTLV-1), a Deltaretrovirus that like HIV infects CD4+ T-cells. Using mouse and human in-vitro T-cell models together with in-vivo T-cell hyper activation mouse model, we reveal that HTLV-1's FP inhibits T-cell activation and unlike the HIV FP, bypasses the TCR complex. HTLV FP inhibition induces a decrease in Th1 and an elevation in Th2 responses observed in mRNA, cytokine and transcription factor profiles. Administration of the HTLV FP in a T-cell hyper activation mouse model of multiple sclerosis alleviated symptoms and delayed disease onset. We further pinpointed the modulatory region within HTLV-1's FP to the same region previously identified as the HIV-1 FP active region, suggesting that through convergent evolution both viruses have obtained the ability to modulate T-cells using the same region of their fusion protein. Overall, our findings suggest that fusion protein based T-cell modulation may be a common viral trait.
Collapse
Affiliation(s)
- Etai Rotem
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Omri Faingold
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Meital Charni
- Department of molecular cell biology, The Weizmann Institute of Science, Rehovot, Israel
| | - Yoel A Klug
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Daniel Harari
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Liraz Shmuel-Galia
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Alon Nudelman
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Varda Rotter
- Department of molecular cell biology, The Weizmann Institute of Science, Rehovot, Israel
| | - Yechiel Shai
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| |
Collapse
|
|
35
|
Gervasi SS, Burgan SC, Hofmeister E, Unnasch TR, Martin LB. Stress hormones predict a host superspreader phenotype in the West Nile virus system. Proc Biol Sci 2018; 284:rspb.2017.1090. [PMID: 28724737 DOI: 10.1098/rspb.2017.1090] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 06/14/2017] [Indexed: 12/20/2022] Open
Abstract
Glucocorticoid stress hormones, such as corticosterone (CORT), have profound effects on the behaviour and physiology of organisms, and thus have the potential to alter host competence and the contributions of individuals to population- and community-level pathogen dynamics. For example, CORT could alter the rate of contacts among hosts, pathogens and vectors through its widespread effects on host metabolism and activity levels. CORT could also affect the intensity and duration of pathogen shedding and risk of host mortality during infection. We experimentally manipulated songbird CORT, asking how CORT affected behavioural and physiological responses to a standardized West Nile virus (WNV) challenge. Although all birds became infected after exposure to the virus, only birds with elevated CORT had viral loads at or above the infectious threshold. Moreover, though the rate of mortality was faster in birds with elevated CORT compared with controls, most hosts with elevated CORT survived past the day of peak infectiousness. CORT concentrations just prior to inoculation with WNV and anti-inflammatory cytokine concentrations following viral exposure were predictive of individual duration of infectiousness and the ability to maintain physical performance during infection (i.e. tolerance), revealing putative biomarkers of competence. Collectively, our results suggest that glucocorticoid stress hormones could directly and indirectly mediate the spread of pathogens.
Collapse
Affiliation(s)
| | - Sarah C Burgan
- Department of Integrative Biology, University of South Florida, Tampa, FL 33620, USA
| | - Erik Hofmeister
- USGS National Wildlife Health Center, Madison, WI 53711, USA
| | - Thomas R Unnasch
- Department of Global Health, University of South Florida, Tampa, FL 33620, USA
| | - Lynn B Martin
- Department of Integrative Biology, University of South Florida, Tampa, FL 33620, USA
| |
Collapse
|
|
36
|
Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1. Nat Immunol 2018; 19:151-161. [PMID: 29292385 PMCID: PMC5786497 DOI: 10.1038/s41590-017-0021-y] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 11/27/2017] [Indexed: 02/08/2023]
Abstract
Memory impairment following West Nile virus neuroinvasive disease (WNND) is associated with loss of hippocampal synapses with lack of recovery. Adult neurogenesis and synaptogenesis are fundamental features of hippocampal repair, suggesting viruses impact these processes. Here, using an established model of WNND-induced cognitive dysfunction, transcriptional profiling revealed alterations in gene expression that limit adult neurogenesis, including interleukin (IL)-1. WNND-recovered animals exhibit decreased neuroblasts and increased astrogenesis, without recovery of hippocampal neurogenesis at thirty days. Analysis of cytokine production in ex vivo isolated microglia and astrocytes revealed the latter to be the predominant source of IL-1. IL-1R1-deficient, WNND-recovered mice exhibit normal neurogenesis, recovery of presynaptic termini, and resistance to spatial learning defects, the latter of which likewise occurred after treatment with IL-1R1 antagonist. Thus, preferential generation of proinflammatory astrocytes impairs neuronal progenitor cell homeostasis via expression of IL-1, which may underlie long-term cognitive consequences of WNND, but provides a therapeutic target.
Collapse
|
|
37
|
Abstract
The persistence of West Nile virus (WNV) infections throughout the USA since its inception in 1999 and its continuous spread throughout the globe calls for an urgent need of effective treatments and prevention measures. Although the licensing of several WNV vaccines for veterinary use provides a proof of concept, similar efforts on the development of an effective vaccine for humans remain still unsuccessful. Increased understanding of biology and pathogenesis of WNV together with recent technological advancements have raised hope that an effective WNV vaccine may be available in the near future. In addition, rapid progress in the structural and functional characterization of WNV and other flaviviral proteins have provided a solid base for the design and development of several classes of inhibitors as potential WNV therapeutics. Moreover, the therapeutic monoclonal antibodies demonstrate an excellent efficacy against WNV in animal models and represent a promising class of WNV therapeutics. However, there are some challenges as to the design and development of a safe and efficient WNV vaccine or therapeutic. In this chapter, we discuss the current approaches, progress, and challenges toward the development of WNV vaccines, therapeutic antibodies, and antiviral drugs.
Collapse
|
|
38
|
Jankowski MD, Moore ME, Hofmeister EK. An examination of the effect of aerosolized Permanone insecticide on zebra finch susceptibility to West Nile virus. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY 2017; 36:3376-3386. [PMID: 28722808 DOI: 10.1002/etc.3918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 01/23/2017] [Accepted: 07/15/2017] [Indexed: 06/07/2023]
Abstract
West Nile virus (WNV) is maintained cryptically primarily in avian (passerine) populations, where it is transmitted by Culex spp. mosquitoes. Mosquito-control measures currently include physical activities to reduce mosquito-breeding sites and the application of mosquito larvicides or aerosolized insecticides to kill adults (adulticides) when arboviral diseases such as WNV or Zika virus are detected in mosquito populations. Organochlorine, organophosphorus, carbamate, and pyrethroid insecticides are often used. Previous work suggests an effect of pyrethroids on the immune system in a variety of vertebrates. We examined the effects of exposure to aerosolized Permanone® 30:30 insecticide (permethrin and piperonyl butoxide in soy oil vehicle) at approximately 103 to 106 times potential environmental concentrations on the response of captive zebra finches (Taeniopygia guttata) to experimental challenge with WNV. Compared to vehicle control birds, WNV outcome was unchanged (65% of birds produced a viremia) in the "low" exposure (9.52 ± 3.13 mg/m3 standard deviation [SD] permethrin) group but reduced in the "high" exposure (mean 376.5 ± 27.9 mg/m3 SD permethrin) group (30% were viremic; p < 0.05). After clearing WNV infection, birds treated with Permanone regained less body mass than vehicle-treated birds (p < 0.001). The present study suggests that exposure to aerosolized Permanone insecticide at levels exceeding typical application rates has the potential to not change or to mildly enhance a bird's resistance to WNV. Environ Toxicol Chem 2017;36:3376-3386. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
Collapse
Affiliation(s)
- Mark D Jankowski
- Los Alamos National Laboratory, Los Alamos, New Mexico, USA
- US Environmental Protection Agency, Region 10, Seattle, Washington
| | - Murray E Moore
- Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - Erik K Hofmeister
- National Wildlife Health Center, US Geological Survey, Madison, Wisconsin
| |
Collapse
|
|
39
|
Minocycline Has Anti-inflammatory Effects and Reduces Cytotoxicity in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection. J Virol 2017; 91:JVI.00569-17. [PMID: 28878079 DOI: 10.1128/jvi.00569-17] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 08/27/2017] [Indexed: 12/13/2022] Open
Abstract
West Nile virus (WNV) is a neurotropic flavivirus that can cause significant neurological disease. Mouse models of WNV infection demonstrate that a proinflammatory environment is induced within the central nervous system (CNS) after WNV infection, leading to entry of activated peripheral immune cells. We utilized ex vivo spinal cord slice cultures (SCSC) to demonstrate that anti-inflammatory mechanisms may also play a role in WNV-induced pathology and/or recovery. Microglia are a type of macrophage that function as resident CNS immune cells. Similar to mouse models, infection of SCSC with WNV induces the upregulation of proinflammatory genes and proteins that are associated with microglial activation, including the microglial activation marker Iba1 and CC motif chemokines CCL2, CCL3, and CCL5. This suggests that microglia assume a proinflammatory phenotype in response to WNV infection similar to the proinflammatory (M1) activation that can be displayed by other macrophages. We now show that the WNV-induced expression of these and other proinflammatory genes was significantly decreased in the presence of minocycline, which has antineuroinflammatory properties, including the ability to inhibit proinflammatory microglial responses. Minocycline also caused a significant increase in the expression of anti-inflammatory genes associated with alternative anti-inflammatory (M2) macrophage activation, including interleukin 4 (IL-4), IL-13, and FIZZ1. Minocycline-dependent alterations to M1/M2 gene expression were associated with a significant increase in survival of neurons, microglia, and astrocytes in WNV-infected slices and markedly decreased levels of inducible nitric oxide synthase (iNOS). These results demonstrate that an anti-inflammatory environment induced by minocycline reduces viral cytotoxicity during WNV infection in ex vivo CNS tissue.IMPORTANCE West Nile virus (WNV) causes substantial morbidity and mortality, with no specific therapeutic treatments available. Antiviral inflammatory responses are a crucial component of WNV pathology, and understanding how they are regulated is important for tailoring effective treatments. Proinflammatory responses during WNV infection have been extensively studied, but anti-inflammatory responses (and their potential protective and reparative capabilities) following WNV infection have not been investigated. Minocycline induced the expression of genes associated with the anti-inflammatory (M2) activation of CNS macrophages (microglia) in WNV-infected SCSC while inhibiting the expression of genes associated with proinflammatory (M1) macrophage activation and was protective for multiple CNS cell types, indicating its potential use as a therapeutic reagent. This ex vivo culture system can uniquely address the ability of CNS parenchymal cells (neurons, astrocytes, and microglia) to respond to minocycline and to modulate the inflammatory environment and cytotoxicity in response to WNV infection without peripheral immune cell involvement.
Collapse
|
|
40
|
Li Q, Liu Q, Huang W, Wu J, Nie J, Wang M, Zhao C, Zhang L, Wang Y. An LASV GPC pseudotyped virus based reporter system enables evaluation of vaccines in mice under non-BSL-4 conditions. Vaccine 2017; 35:5172-5178. [PMID: 28797730 DOI: 10.1016/j.vaccine.2017.07.101] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 07/16/2017] [Accepted: 07/27/2017] [Indexed: 12/23/2022]
Abstract
Lassa virus (LASV) causes a severe hemorrhagic fever endemic throughout western Africa. Because of the ability to cause lethal disease in humans, limited treatment options, and potential as a bioweapon, the need for vaccines to prevent LASV epidemic is urgent. However, LASV vaccine development has been hindered by the lack of appropriate small animal models for efficacy evaluation independent of biosafety level four (BSL-4) facilities. Here we generated an LASV-glycoprotein precursor (GPC)-pseudotyped Human immunodeficiency virus containing firefly luciferase (Fluc) reporter gene as surrogate to develop a bioluminescent-imaging-based BALB/c mouse model for one-round infection under non-BSL-4 conditions, in which the bioluminescent intensity of Fluc was utilized as endpoint when evaluating vaccine efficacy. Electron microscopy analysis demonstrated that LASV GPC pseudotyped virus appeared structurally similar to native virion. Meanwhile, we constructed DNA vaccine (pSV1.0-LASVGPC) and pseudoparticle-based vaccine (LASVpp) that displayed conformational GPC protein of LASV strain Josiah to vaccinate BALB/c mice using intramuscular electroporation and by intraperitoneal routes, respectively. Vaccinated mice in LASVpp alone and DNA prime+LASVpp boost schedules were protected against 100 AID50 of LASV pseudovirus challenge, and it was found that in vivo efficiencies correlated with their anti-LASV neutralizing activities and MCP-1 cytokine levels in serum sampled before infection. The bioluminescence pseudovirus infection model can be useful tool for the preliminary evaluation of immunogenicity and efficacy of vaccine candidates against LASV outside of BSL-4 containments, and the results with pseudoparticle-based vaccine provided very helpful information for LASV vaccine design.
Collapse
Affiliation(s)
- Qianqian Li
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Qiang Liu
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Weijin Huang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Jiajing Wu
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Jianhui Nie
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Meng Wang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Chenyan Zhao
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Li Zhang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Youchun Wang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing 100050, China.
| |
Collapse
|
|
41
|
Osteopontin Impacts West Nile virus Pathogenesis and Resistance by Regulating Inflammasome Components and Cell Death in the Central Nervous System at Early Time Points. Mediators Inflamm 2017; 2017:7582437. [PMID: 28811681 PMCID: PMC5547729 DOI: 10.1155/2017/7582437] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 04/17/2017] [Accepted: 05/22/2017] [Indexed: 11/23/2022] Open
Abstract
Osteopontin (OPN) is a molecule that is common in central nervous system (CNS) pathologies, which participates in the activation, migration, and survival of inflammatory cells. However, the mechanisms by which OPN modulates inflammatory pathways are not clear. To understand the role of OPN in CNS viral infections, we used a lethal mouse model of West Nile virus (WNV), characterized by the injection of high doses of the Eg101 strain of WNV, causing the increase of OPN levels in the brain since early time points. To measure the impact of OPN in neuropathogenesis and resistance, we compared C57BI/6 WT with mice lacking the OPN gene (OPN KO). OPN KO presented a significantly higher mortality compared to WT mice, detectable since day 5 pi. Our data suggests that OPN expression at early time points may provide protection against viral spread in the CNS by negatively controlling the type I IFN-sensitive, caspase 1-dependent inflammasome, while promoting an alternative caspase 8-associated pathway, to control the apoptosis of infected cells during WNV infection in the CNS. Overall, we conclude that the expression of OPN maintains a critical threshold in the innate immune response that controls apoptosis and lethal viral spread in early CNS infection.
Collapse
|
|
42
|
Shives KD, Tyler KL, Beckham JD. Molecular mechanisms of neuroinflammation and injury during acute viral encephalitis. J Neuroimmunol 2017; 308:102-111. [DOI: 10.1016/j.jneuroim.2017.03.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 02/23/2017] [Accepted: 03/06/2017] [Indexed: 01/25/2023]
|
|
43
|
Liu Q, Zhou S, Fan C, Huang W, Li Q, Liu S, Wu X, Li B, Wang Y. Biodistribution and residence time of adenovector serotype 5 in normal and immunodeficient mice and rats detected with bioluminescent imaging. Sci Rep 2017; 7:3597. [PMID: 28620164 PMCID: PMC5472566 DOI: 10.1038/s41598-017-03852-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 05/08/2017] [Indexed: 12/03/2022] Open
Abstract
As concerns increase about adenovirus type 5 (Ad5) being a safe gene transfer vector, it is important to evaluate its distribution, residence time, and possible toxicity in immunodeficient populations. To characterize the potential risk associated with different Ad5 vector delivery modes, we used immunocompetent and immunodeficient Rag2 -/- animals to establish mouse and rat models that could be monitored with bioluminescent imaging following intramuscular or intravascular infection with an engineered replication-incompetent Ad5 virus carrying the firefly luciferase gene (Ad5-Fluc). The Ad5 vector was less well-tolerated by Rag2 -/- animals than by wildtype ones, with delayed residence time, wider virus dissemination, less weight gain, and relatively severe pathological changes. In intravascularly Ad5-Fluc-infected Rag2 -/- mice, systemic virus dissemination extended from the abdomen to the limbs and head on day 9 post-infection. Additionally, significant increases in plasma TNF-α and IFN-γ, which may be important factors in the heightened immunopathology in the liver and brain, were detected in the Rag2 -/- mice 30 days after intravascular delivery. The Ad5 vector was better tolerated after intramuscular delivery than after intravascular delivery. Ad5-Fluc/Rag2 -/- mice and rats can be used as reliable models of an immunodeficient population in which to evaluate the safety of Ad5-vectored vaccines or gene therapy products.
Collapse
Affiliation(s)
- Qiang Liu
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Shuya Zhou
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Changfa Fan
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Weijin Huang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Qianqian Li
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Susu Liu
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Xi Wu
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Baowen Li
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Youchun Wang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, 100050, China.
| |
Collapse
|
|
44
|
Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis. J Virol 2017; 91:JVI.02409-16. [PMID: 28356527 DOI: 10.1128/jvi.02409-16] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 03/07/2017] [Indexed: 12/26/2022] Open
Abstract
West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain.IMPORTANCE In this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.
Collapse
|
|
45
|
|
|
46
|
Interleukin-17A Promotes CD8+ T Cell Cytotoxicity To Facilitate West Nile Virus Clearance. J Virol 2016; 91:JVI.01529-16. [PMID: 27795421 PMCID: PMC5165211 DOI: 10.1128/jvi.01529-16] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 10/06/2016] [Indexed: 01/05/2023] Open
Abstract
CD8+ T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8+ T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a-/-) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8+ T cells isolated from Il17a-/- mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 postinfection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A. In conclusion, we report a novel function of IL-17A in promoting CD8+ T cell cytotoxicity, which may have broad implications in other microbial infections and cancers. IMPORTANCE Interleukin-17A (IL-17A) and CD8+ T cells regulate diverse immune functions in microbial infections, malignancies, and autoimmune diseases. IL-17A is a proinflammatory cytokine produced by diverse cell types, while CD8+ T cells (known as cytotoxic T cells) are major cells that provide immunity against intracellular pathogens. Previous studies have demonstrated a crucial role of CD8+ T cells in recovery from West Nile virus (WNV) infection. However, the role of IL-17A during WNV infection remains unclear. Here, we demonstrate that IL-17A protects mice from lethal WNV infection by promoting CD8+ T cell-mediated clearance of WNV. In addition, treatment of WNV-infected mice with recombinant IL-17A reduces the viral burden and increases survival of mice, suggesting a potential therapeutic. This novel IL-17A-CD8+ T cell axis may also have broad implications for immunity to other microbial infections and cancers, where CD8+ T cell functions are crucial.
Collapse
|
|
47
|
Martin LB, Burgan SC, Adelman JS, Gervasi SS. Host Competence: An Organismal Trait to Integrate Immunology and Epidemiology. Integr Comp Biol 2016; 56:1225-1237. [DOI: 10.1093/icb/icw064] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
|
|
48
|
Salimi H, Cain MD, Klein RS. Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis. Neurotherapeutics 2016; 13:514-34. [PMID: 27220616 PMCID: PMC4965410 DOI: 10.1007/s13311-016-0443-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Arboviruses are arthropod-borne viruses that exhibit worldwide distribution, contributing to systemic and neurologic infections in a variety of geographical locations. Arboviruses are transmitted to vertebral hosts during blood feedings by mosquitoes, ticks, biting flies, mites, and nits. While the majority of arboviral infections do not lead to neuroinvasive forms of disease, they are among the most severe infectious risks to the health of the human central nervous system. The neurologic diseases caused by arboviruses include meningitis, encephalitis, myelitis, encephalomyelitis, neuritis, and myositis in which virus- and immune-mediated injury may lead to severe, persisting neurologic deficits or death. Here we will review the major families of emerging arboviruses that cause neurologic infections, their neuropathogenesis and host neuroimmunologic responses, and current strategies for treatment and prevention of neurologic infections they cause.
Collapse
Affiliation(s)
- Hamid Salimi
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Matthew D Cain
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Robyn S Klein
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA.
| |
Collapse
|
|
49
|
Uddin MJ, Suen WW, Bosco-Lauth A, Hartwig AE, Hall RA, Bowen RA, Bielefeldt-Ohmann H. Kinetics of the West Nile virus induced transcripts of selected cytokines and Toll-like receptors in equine peripheral blood mononuclear cells. Vet Res 2016; 47:61. [PMID: 27267361 PMCID: PMC4895877 DOI: 10.1186/s13567-016-0347-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 05/17/2016] [Indexed: 12/21/2022] Open
Abstract
West Nile virus (WNV) is one of the most common causes of epidemic viral encephalitis in horses worldwide. Peripheral blood mononuclear cells (PBMCs) are amongst the first to encounter the virus following a mosquito bite. This study aimed to elucidate the transcription kinetics of cytokine, Toll-like receptor (TLRs) and TLRs-associated genes following WNV challenge of equine PBMCs. PBMCs were challenged with an Australian strain of WNV (WNVNSW2011) and transcriptomes were quantified at 2, 6, 12 and 24 h post-infection (pi) using qRT-PCR. Type I and II interferons (IFNα, β and γ) mRNA transcription increased following WNV exposure, as did the transcripts for IL1α, IL1β, IL6, IL8, and IL22, but with slightly varying kinetics. TLR1, 3, 5, 7-9 transcripts were also upregulated in equine PBMCsin response to WNV challenge, as were those for MyD88, NF-κB, TRAF3, STAT1 and 2, IRF3 and 7, ISG15, as well as SOCS1 and 3 compared to the control cells. Expression of selected genes in the draining lymph node, spleen and brain (medulla oblongata) of experimentally infected horses was also assessed and transcription of most of these genes was also upregulated here. Although qRT-PCR detected higher viral RNA at 24 h pi compared to 6 h pi, the virus did not replicate productively in equine PBMCs. The up-regulation of gene-transcription for selected cytokines, IFNs, TLRs and TLRs-associated molecules suggests their involvement in virus recognition and control of WNV infection in the horse.
Collapse
Affiliation(s)
- Muhammad Jasim Uddin
- School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia
| | - Willy W Suen
- School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia
| | - Angela Bosco-Lauth
- Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, USA
| | - Airn-Elizabeth Hartwig
- Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, USA
| | - Roy A Hall
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia.,Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, QLD, Australia
| | - Richard A Bowen
- Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, USA
| | - Helle Bielefeldt-Ohmann
- School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia. .,School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia. .,Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, QLD, Australia.
| |
Collapse
|
|
50
|
Solomos AC, Rall GF. Get It through Your Thick Head: Emerging Principles in Neuroimmunology and Neurovirology Redefine Central Nervous System "Immune Privilege". ACS Chem Neurosci 2016; 7:435-41. [PMID: 26854733 DOI: 10.1021/acschemneuro.5b00336] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The central nervous system (CNS) coordinates all aspects of life, autonomic and sentient, though how it has evolved to contend with pathogenic infections remains, to a great degree, a mystery. The skull and cerebrospinal fluid (CSF) provide protection from blunt force contacts, and it was once thought that the blood-brain barrier (BBB) was a fortress that restricted pathogen entry and limited inflammation. Recent studies, however, have caused a revision of this viewpoint: the CNS is monitored by blood-borne lymphocytes, but can use alternative strategies to prevent or resolve many pathogenic challenges. In this Review, we discuss emerging principles that indicate how the CNS is immunologically unique from peripheral tissues. We focus on developments that include glymphatics, recently characterized brain lymphatic vessels, distinctions in innate and adaptive immune strategies, novel points of entry for neurotropic viruses, and, finally, how the periphery can influence CNS homeostasis and immune responses within the brain. Collectively, these attributes demand a re-evaluation of immunity in the brain: not privileged, but distinct.
Collapse
Affiliation(s)
- Andreas C. Solomos
- Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States
- Department
of Microbiology and Immunology, Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, Pennsylvania 19129, United States
| | - Glenn F. Rall
- Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, United States
| |
Collapse
|