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      Aspects of T Cell-Mediated Immunity Induced in Mice by a DNA Vaccine Based on the Dengue-NS1 Antigen after Challenge by the Intracerebral Route

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          Abstract

          Dengue disease has emerged as a major public health issue across tropical and subtropical countries. Infections caused by dengue virus (DENV) can evolve to life-threatening forms, resulting in about 20,000 deaths every year worldwide. Several animal models have been described concerning pre-clinical stages in vaccine development against dengue, each of them presenting limitations and advantages. Among these models, a traditional approach is the inoculation of a mouse-brain adapted DENV variant in immunocompetent animals by the intracerebral (i.c.) route. Despite the historical usage and relevance of this model for vaccine testing, little is known about the mechanisms by which the protection is developed upon vaccination. To cover this topic, a DNA vaccine based on the DENV non-structural protein 1 (pcTPANS1) was considered and investigations were focused on the induced T cell-mediated immunity against i.c.-DENV infection. Immunophenotyping assays by flow cytometry revealed that immunization with pcTPANS1 promotes a sustained T cell activation in spleen of i.c.-infected mice. Moreover, we found that the downregulation of CD45RB on T cells, as an indicator of cell activation, correlated with absence of morbidity upon virus challenge. Adoptive transfer procedures supported by CFSE-labeled cell tracking showed that NS1-specific T cells induced by vaccination, proliferate and migrate to peripheral organs of infected mice, such as the liver. Additionally, in late stages of infection (from the 7 th day onwards), vaccinated mice also presented reduced levels of circulating IFN-γ and IL-12p70 in comparison to non-vaccinated animals. In conclusion, this work presented new aspects about the T cell-mediated immunity concerning DNA vaccination with pcTPANS1 and the i.c. infection model. These insights can be explored in further studies of anti-dengue vaccine efficacy.

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          Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice.

          Flona Powrie, Michael W. Leach, Smita Mauze … (1993)
          CD4+ T cells in the mouse can be subdivided into two fractions based on the level of expression of the CD45RB determinant. Previous studies have shown that these subsets are functionally distinct. We have further characterized the properties of these subpopulations in vivo by injecting them into C. B-17 scid mice. The animals restored with the CD45RBhighCD4+ T cell population developed a lethal wasting disease with severe mononuclear cell infiltrates into the colon and elevated levels of IFN-gamma mRNA. In contrast, animals restored with the reciprocal CD45RBlow subset or with unfractionated CD4+ T cells did not develop the wasting or colitis. Importantly, the co-transfer of the CD45RBlow population with the CD45RBhigh population prevented the wasting disease and colitis. These data indicate that important regulatory interactions occur between the CD45RBhigh and CD45RBlowCD4+ T cell subsets and that disruption of this mechanism has fatal consequences.
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            Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models.

            Yukio Takeshita, Richard M. Ransohoff (2012)
            The blood-brain barrier (BBB) is the brain-specific capillary barrier that is critical for preventing toxic substances from entering the central nervous system (CNS). In contrast to vessels of peripheral organs, the BBB limits the exchange of inflammatory cells and mediators under physiological and pathological conditions. Clarifying these limitations and the role of chemokines in regulating the BBB would provide new insights into neuroprotective strategies in neuroinflammatory diseases. Because there is a paucity of in vitro BBB models, however, some mechanistic aspects of transmigration across the BBB still remain largely unknown. In this review, we summarize current knowledge of BBB cellular components, the multistep process of inflammatory cells crossing the BBB, functions of CNS-derived chemokines, and in vitro BBB models for transmigration, with a particular focus on new and recent findings. © 2012 John Wiley & Sons A/S.
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              The Economic Burden of Dengue

              Duane J. Gubler (2012)
              Historically, dengue has been considered an unimportant public health problem because mortality rates were low and epidemics occurred only infrequently. In the years after World War II, great progress was made in controlling infectious diseases of all kinds, especially vector-borne diseases, and the war on infectious disease was declared won in the late 1960s.1 Coincident with this success in disease control was the economic recovery in some countries of Southeast Asia, and urban growth increased as people from rural areas migrated to the cities to find work. The lack of planning, inadequate housing, water, sewage, and waste management in these cities created ideal conditions for dengue viruses and their mosquito vector Aedes aegypti, both of which had been spread widely in the region during World War II, to thrive.2 The result was the emergence of epidemic dengue hemorrhagic fever. During the 1950s and 1960s, the disease was limited to a few countries in Southeast Asia, but as economic growth expanded, the cities and epidemic dengue also grew, because little effort was made to control the mosquito vector. In the 1970s and accelerating in the last two decades of the 20th century, epidemic dengue expanded regionally and globally. Epidemics increased in both frequency and magnitude, and the viruses became hyperendemic (cocirculation of multiple virus serotypes) in most major cities of the tropics. Despite this alarming emergence of a severe and fatal form of epidemic dengue, the disease was still considered a minor public health problem by policymakers. In 2012, dengue is the most important vector-borne viral disease of humans and likely more important than malaria globally in terms of morbidity and economic impact. The latest studies estimate 3.6 billion people living in areas of risk, over 230 million infections, millions of cases of dengue fever, over 2 million cases of the severe disease, and 21,000 deaths.3 In addition to the public health and economic costs, there is a major social impact in those countries where large epidemics occur, often disrupting primary care for hospitalized patients.4 Given the dramatic urban growth and lack of adequate surveillance for dengue in tropical developing countries in the past 50 years, it is likely that even these figures underestimate the true disease burden of dengue. Thus, ignored for many years, only recently has the potential magnitude of the dengue problem been acknowledged by policymakers and funding agencies. This acknowledgment has resulted in excellent progress in understanding dengue virus biology and development of dengue vaccines and antiviral drugs but not economic impact of the disease. As the pipeline of dengue vaccine candidates, a number of which are already in clinical trials, has grown, it has become apparent that vaccine access will require more and better studies on the actual cost of dengue to endemic communities. In recent years, many studies have been conducted in different Asian and American countries in attempts to measure the economic impact of dengue on a community. Although most have contributed valuable information on the subject, none has provided comprehensive data on the actual cost of dengue disease. The work by Halasa and others5 provides one of the best studies to date on that subject. Working in collaboration with the Puerto Rico Department of Health and the US Centers for Disease Control and Prevention Dengue Branch in Puerto Rico, the investigators conducted a comprehensive review of 100 laboratory-confirmed dengue patients who experienced the disease between July of 2008 and March of 2010. The study included both adults and children and hospitalized and ambulatory care patients. Records were reviewed for each patient, who was then subjected to a comprehensive interview about their illness and how it impacted their activities. The work by Halasa and others5 measured the cost, both direct and indirect, of dengue in six categories of cases and went to considerable effort to validate their data. The results, perhaps not surprisingly, show the economic burden of dengue in Puerto Rico to be very high. This study is the first study to show the societal distribution of the economic cost of dengue, with the individual household bearing the largest burden (48%) compared with only 24% by the government and 22% by insurance.5 The total annual cost of dengue between 2002 and 2010 was $46.45 million ($418 million during the 9-year period).5 Clearly, there is a need to conduct more comprehensive studies of this kind in other dengue-endemic countries of the world. These kinds of data are needed to allow policymakers and public health officials to make informed decisions on the cost efficacy of dengue control programs. The private sector also needs comprehensive economic analyses to guide decision-making in vaccines and antiviral drug development. Finally, international funding agencies require these kinds of data to establish priorities in public health funding. Studies of this kind will always have limitations, and this study was no exception. However, the work by Halasa and others5 clearly identified the most important limitations, such as recall bias and not being able to estimate the cost of tourism and deaths associated with dengue. The latter two limitations, however, would add to the overall cost of dengue, driving the cost even higher. The fact that the study was supported by a private vaccine manufacturer might raise questions about conflict of interest by some people. In my mind, however, this possibility is not an issue because of the detailed methodology used and the reputation of the Brandeis group as the leader in research on the economic impact of dengue.
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                Author and article information

                Contributors
                Philip J. Hogarth: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 15 September 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 9
                Electronic Location Identifier: e0163240
                Affiliations
                [1 ]Laboratory of Biotechnology and Physiology of Viral Infections, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
                [2 ]Laboratory of Clinical Immunology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
                Animal Health and Veterinary Laboratories Agency, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: ERAO AJSG ACMAN AMBA.

                • Data curation: ERAO.

                • Formal analysis: ERAO ACMAN AMBA.

                • Funding acquisition: AMBA.

                • Investigation: ERAO AJSG SMC ASA MMB ACMAN AMBA.

                • Methodology: ERAO AJSG SMC ASA MMB ACMAN AMBA.

                • Project administration: ACMAN AMBA.

                • Resources: AMBA.

                • Supervision: ACMAN AMBA.

                • Validation: ERAO AJSG SMC ASA MMB ACMAN AMBA.

                • Visualization: ERAO.

                • Writing – original draft: ERAO ACMAN AMBA.

                • Writing – review & editing: ERAO ACMAN AMBA.

                Author information
                http://orcid.org/0000-0002-5487-4032
                Article
                Publisher ID: PONE-D-16-19123
                DOI: 10.1371/journal.pone.0163240
                PMC ID: 5024998
                PubMed ID: 27631083
                SO-VID: 3297c6fa-7ead-4fd3-8207-5e1f0575835b
                Copyright © © 2016 Oliveira et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 11 May 2016
                Date accepted : 5 September 2016
                Page count
                Figures: 5, Tables: 0, Pages: 19
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: 44371/2014-0
                Award Recipient :
                ORCID: http://orcid.org/0000-0002-5487-4032
                Funded by: funder-id http://dx.doi.org/10.13039/501100004586, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro;
                Award ID: E26/110.271/2014
                Award Recipient :
                ORCID: http://orcid.org/0000-0002-5487-4032
                Funded by: Instituto Nacional de Ciência e Tecnologia de Vacinas (BR)
                Award ID: 573547/2008-4
                Award Recipient :
                ORCID: http://orcid.org/0000-0002-5487-4032
                Funded by: Programa de Desenvolvimento Tecnológico em Insumos para Saúde - FIOCRUZ (BR)
                Award ID: RVR11
                Award Recipient :
                ORCID: http://orcid.org/0000-0002-5487-4032
                This work was supported by the Conselho Nacional de Pesquisa e Desenvolvimento (CNPq) (grant number: 44371/2014-0) - http://www.cnpq.br/, Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) (grant number: E26/110.271/2014) - http://www.faperj.br/, Instituto Nacional de Ciência e Tecnologia de Vacinas (INCTV) (grant number: 573547/2008-4) - http://www.cpqrr.fiocruz.br/inctv/, Programa de Desenvolvimento Tecnológico e Inovação em Saúde da Fundação Oswaldo Cruz (PDTIS-FIOCRUZ) (grant number:RVR11) - http://www.castelo.fiocruz.br/vpplr/pdtis.php. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
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                Subject: Cell-Mediated Immunity
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                Subject: Cell-Mediated Immunity
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