Cell-mediated Immunity to Virus Causing Haemorrhagic Fever with Renal Syndrome: Generation of Cytotoxic T Lymphocytes

Asada, Hideo; Tamura, Manabu; Kondo, Kazuhiro; Dohi, Yoshitane; Yamanishi, Koichi

doi:10.1099/0022-1317-69-9-2179

Cited by 38 publications

(19 citation statements)

References 41 publications

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“…Asada et al generated CTL from mice infected with HTN and elucidated protective effects [3][4][5]. In addition, NP antigen was suggested as the target antigen for the CTL because of the cross protection by the CTLs against Hantaan and Puumala viruses which all of different serotypes.…”

Section: Discussionmentioning

confidence: 98%

“…Nakamura et al reported that the adoptive transfer of T cells obtained from the spleens of immunized mice, protected newborn mice from lethal HTN infection [21,22]. Furthermore, Asada et al generated CTLs and confirmed their protective activity by passive transfer to mice [3][4][5]. However, antigens relating to cellular immunity have not yet been determined since all studies were performed using immune cells prepared from mice infected with the HTN.…”

Section: In~oduefionmentioning

confidence: 93%

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Protective immunity of Hantaan virus nucleocapsid and envelope protein studied using baculovirus-expressed proteins

Yoshimatsu

Yoo

Yoshida

et al. 1993

Archives of Virology

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Recombinant Hantaan virus nucleocapsid protein (rNP) and recombinant envelope (rEnv) proteins were prepared using a baculovirus expression system to examine the role of Hantaan virus structural proteins in protective immunity. Passive transfer of spleen cells from mice immunized with rNP conferred partial protection or prolongation of time to death from fatal Hantaan virus infection in suckling mice which were challenged with Hantaan virus at 40 LD50 (survival rate: 43%) or 4 LD50 (survival rate: 43%). The T cell-enriched fraction protected one mouse from lethal infection but the B cell-enriched fraction had no such effect on fatal HTN infection. The protective effects of the antibody against HTN challenge were examined by passive immunization. The monoclonal antibody ECO 2 directed to NP also conferred partial survival and significant difference in time to death. Although rEnv antigen failed to induce neutralizing antibody, both immune spleen cells and immune serum to rEnv conferred partial protection upon suckling mice. These results indicate that both nucleocapsid and envelope proteins of Hantaan virus were responsible for induction of cell mediated protective immunity. Vero E 6 cells infected with Hantaan virus expressed envelope protein on the surface, as determined by flow cytometry. However, there was only negligible expression of nucleocapsid protein.

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Section: Discussionmentioning

confidence: 98%

Section: In~oduefionmentioning

confidence: 93%

Protective immunity of Hantaan virus nucleocapsid and envelope protein studied using baculovirus-expressed proteins

Yoshimatsu

Yoo

Yoshida

et al. 1993

Archives of Virology

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“…Rodent hantavirus models have, however, been proven most valuable for studies concerning humoral and cellular immune responses (4,8) and studies of reagents with potential therapeutic effects (29,41), as well as for vaccine candidate studies (15,23,29,30). In addition, rodent models may provide valuable information on the mechanisms underlying viral persistence, which leads to virus spread to humans.…”

Section: Fig 3 (A) Kinetics Of Igm and Igg Responses In Monkeys Infmentioning

confidence: 99%

Wild-Type Puumala Hantavirus Infection Induces Cytokines, C-Reactive Protein, Creatinine, and Nitric Oxide in Cynomolgus Macaques

Klingström

Plyusnin

Vaheri

et al. 2002

J Virol

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Hantaviruses cause two severe human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Approximately 200,000 cases are reported annually, and there is to date no specific treatment available. A major obstacle in studying the medical aspects of HFRS and HPS has been the lack of an adequate animal model. Here we show that infection of cynomolgus macaques by wild-type Puumala hantavirus resulted in typical signs of HFRS including lethargy, anorexia, proteinuria, and/or hematuria, in addition to cytokine (interleukin 6 [IL-6], IL-10, and tumor necrosis factor alpha), C-reactive protein, creatinine, and nitric oxide responses. Viral RNA was detected in plasma from days 3 to 7 postinoculation until days 24 to 28 postinoculation, infectious virus was recovered, and the virus-specific immune responses (immunoglobulin M [IgM], IgG, and neutralizing antibodies) mimicked those seen in humans. The results indicated that the monkey model will provide a valuable tool for studies of pathogenesis, candidate vaccines, and antivirals for hantavirus disease.Hantaviruses, members of the family Bunyaviridae, are known to cause two serious and often fatal human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The clinical symptoms of HFRS are characterized by fever, thrombocytopenia, renal failure, and, in severe cases, hemorrhage caused by capillary leak syndrome (13, 31). Puumala hantavirus (PUUV) causes a milder form of HFRS named nephropathia epidemica (NE), which occurs in northern and central Europe. The more severe forms of HFRS are caused by Hantaan (Asia) and Dobrava (Europe) viruses, while Seoul virus (worldwide) causes an intermediate form (3,17). Hantaviruses are carried by specific rodent hosts, and virus transmission to humans occurs via inhalation of aerosolized animal excreta (5, 32). The mortality of HFRS varies between Ͻ0.1 and 12%, depending on the causative virus (31, 32). Sin Nombre virus, Andes virus, and related hantaviruses cause HPS in the Americas, mainly characterized by acute respiratory dysfunction and with a mortality rate of approximately 40% (26, 27).In the rodent reservoirs, hantaviruses cause persistent and subclinical infections (31). Although successfully used, e.g., for studies of immune responses and for evaluation of vaccine candidates and/or therapeutic reagents, rodent models are of limited value for studying the pathogenesis of human hantavirus infections. Only two earlier studies of nonhuman primates have been reported, and both described models with certain limitations (9, 40). We have previously shown phenotypic and genetic changes of PUUV when propagated in cell culture, resulting in a decrease of infectivity for its natural host, the bank vole (Clethrionomys glareolus) (22). We therefore speculated that wild-type PUUV (strain Kazan-wt) might infect nonhuman primates in a way different from previously reported studies. Here we report the first successful experimental infection of cynomolgus macaque...

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“…As hantaviruses are a group of relatively closely related viruses, with several conserved regions within their N proteins, the characteristics of cross-reactive cellular immune responses are most interesting, but these have been investigated in only a small number of studies (1,2,11,38). In addition, a few groups have also reported on cross-protection after vaccination with the N and G1 or G2 proteins (7,13,19,41).…”

mentioning

confidence: 99%

Cross-Protection against Challenge with Puumala Virus after Immunization with Nucleocapsid Proteins from Different Hantaviruses

Nicacio

Valle

Padula

et al. 2002

J Virol

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Hantaviruses are rodent-borne agents that cause hemorrhagic fever with renal syndrome or hantavirus pulmonary syndrome in humans. The nucleocapsid protein (N) is relatively conserved among hantaviruses and highly immunogenic in both laboratory animals and humans, and it has been shown to induce efficient protective immunity in animal models. To investigate the ability of recombinant N (rN) from different hantaviruses to elicit cross-protection, we immunized bank voles with rN from Puumala (PUUV), Topografov (TOPV), Andes (ANDV), and Dobrava (DOBV) viruses and subsequently challenged them with PUUV. All animals immunized with PUUV and TOPV rN were completely protected. In the group immunized with DOBV rN, 7 of 10 animals were protected, while only 3 of 8 animals were protected in the group immunized with ANDV rN, which is more closely related to PUUV rN than DOBV rN. Humoral and cellular immune responses after rN immunization were also investigated. The highest cross-reactive humoral responses against PUUV antigen were detected in sera from ANDV rN-immunized animals, followed by those from TOPV rN-immunized animals, and only very low antibody cross-reactivity was observed in sera from DOBV rN-immunized animals. In proliferation assays, T lymphocytes from animals immunized with all heterologous rNs were as efficiently recalled in vitro by PUUV rN as were T lymphocytes from animals immunized with homologous protein. In summary, this study has shown that hantavirus N can elicit cross-protective immune responses against PUUV, and the results suggest a more important role for the cellular arm of the immune response than for the humoral arm in cross-protection elicited by rN.

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Cell-mediated Immunity to Virus Causing Haemorrhagic Fever with Renal Syndrome: Generation of Cytotoxic T Lymphocytes

Cited by 38 publications

References 41 publications

Protective immunity of Hantaan virus nucleocapsid and envelope protein studied using baculovirus-expressed proteins

Protective immunity of Hantaan virus nucleocapsid and envelope protein studied using baculovirus-expressed proteins

Wild-Type Puumala Hantavirus Infection Induces Cytokines, C-Reactive Protein, Creatinine, and Nitric Oxide in Cynomolgus Macaques

Cross-Protection against Challenge with Puumala Virus after Immunization with Nucleocapsid Proteins from Different Hantaviruses

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