scholarly journals Protective Memory Responses Are Modulated by Priming Events prior to Challenge

2009 ◽  
Vol 84 (2) ◽  
pp. 1047-1056 ◽  
Author(s):  
John A. Rutigliano ◽  
Melissa Y. Morris ◽  
Wen Yue ◽  
Rachael Keating ◽  
Richard J. Webby ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A ◽  
T Cell Response ◽  
H3n2 Virus ◽  
Cell Mediated Immunity ◽  
Influenza A Viruses ◽  
Differential Survival ◽  
Virus Challenge ◽  
Response Characteristics ◽  
H5n1 Influenza

ABSTRACT Human infections with highly pathogenic H5N1 avian influenza A viruses in the last decade have legitimized fears of a long-predicted pandemic. We thus investigated the response to secondary infections with an engineered, but still highly virulent, H5N1 influenza A virus in the C57BL/6 mouse model. Mice primed with the H1N1 A/Puerto Rico/8/34 (PR8) virus were partially protected from lethality following respiratory infection with the modified H5N1 virus A/Vietnam/1203/04 (ΔVn1203). In contrast, those that had been comparably exposed to the HKx31 (H3N2) virus succumbed to the ΔVn1203 challenge, despite similarities in viral replication, weight loss, and secondary CD8+-T-cell response characteristics. All three viruses share the internal genes of PR8 that are known to stimulate protective CD8+-T-cell-mediated immunity. This differential survival of PR8- and HKx31-primed mice was also apparent for antibody-deficient mice challenged with the ΔVn1203 virus. The relative protection afforded by PR8 priming was abrogated in tumor necrosis factor-deficient (TNF−/−) mice, although lung fluids from the B6 HKx31-primed mice contained more TNF early after challenge. These data demonstrate that the nature of the primary infection can influence pathological outcomes following virulent influenza virus challenge, although the effect is not clearly correlated with classical measures of CD8+-T-cell-mediated immunity.

scholarly journals Quantitative analysis of the CD8 + T–cell response to readily eliminated and persistent viruses

2000 ◽  
Vol 355 (1400) ◽  
pp. 1093-1101 ◽  
Author(s):  
P. C. Doherty ◽  
J. M. Riberdy ◽  
G. T. Belz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Flow Cytometric Analysis ◽  
T Cell Response ◽  
Basic Question ◽  
Cell Mediated Immunity ◽  
Specific Response ◽  
Turnover Rates

The recent development of techniques for the direct staining of peptide–specific CD8 + T cells has revolutionized the analysis of cell–mediated immunity (CMI) in virus infections. This approach has been used to quantify the acute and long–term consequences of infecting laboratory mice with the readily eliminated influenza A viruses (fluA) and a persistent γherpesvirus (γHV). It is now, for the first time, possible to work with real numbers in the analysis of CD8 + T CMI, and to define various characteristics of the responding lymphocytes both by direct flow cytometric analysis and by sorting for further in vitro manipulation. Relatively little has yet been done from the latter aspect, though we are rapidly accumulating a mass of numerical data. The acute, antigen–driven phases of the fluA and γHV–specific response look rather similar, but CD8 + T–cell numbers are maintained in the long term at a higher ‘set point’ in the persistent infection. Similarly, these ‘memory’ T cells continue to divide at a much greater rate in the γHV–infected mice. New insights have also been generated on the nature of the recall response following secondary challenge in both experimental systems, and the extent of protection conferred by large numbers of virus–specific CD8 + T cells has been determined. However, there are still many parameters that have received little attention, partly because they are difficult to measure. These include the rate of antigen–specific CD8 + T–cell loss, the extent of the lymphocyte ‘diaspora’ to other tissues, and the diversity of functional characteristics, turnover rates, clonal life spans and recirculation profiles. The basic question for immunologists remains how we reconcile the extraordinary plasticity of the immune system with the mechanisms that maintain a stable milieu interieur. This new capacity to quantify CD8 + T–cell responses in readily manipulated mouse models has obvious potential for illuminating homeostatic control, particularly if the experimental approaches to the problem are designed in the context of appropriate predictive models.

scholarly journals Pathogenicity and Vaccine Efficacy of Different Clades of Asian H5N1 Avian Influenza A Viruses in Domestic Ducks

2008 ◽  
Vol 82 (22) ◽  
pp. 11374-11382 ◽  
Author(s):  
Jeong-Ki Kim ◽  
Patrick Seiler ◽  
Heather L. Forrest ◽  
Alexey M. Khalenkov ◽  
John Franks ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Influenza A ◽  
Preventive Strategy ◽  
Complete Protection ◽  
Influenza A Viruses ◽  
Symptomatic Infection ◽  
Domestic Ducks ◽  
Virus Challenge ◽  
H5n1 Influenza

ABSTRACT Waterfowl represent the natural reservoir of all subtypes of influenza A viruses, including H5N1. Ducks are especially considered major contributors to the spread of H5N1 influenza A viruses because they exhibit diversity in morbidity and mortality. Therefore, as a preventive strategy against endemic as well as pandemic influenza, it is important to reduce the spread of H5N1 influenza A viruses in duck populations. Here, we describe the pathogenicity of dominant clades (clades 1 and 2) of H5N1 influenza A viruses circulating in birds in Asia. Four representatives of dominant clades of the viruses cause symptomatic infection but lead to different profiles of lethality in domestic ducks. We also demonstrate the efficacy, cross-protectiveness, and immunogenicity of three different inactivated oil emulsion whole-virus H5 influenza vaccines (derived by implementing reverse genetics) to the viruses in domestic ducks. A single dose of the vaccines containing 1 μg of hemagglutinin protein provides complete protection against a lethal A/Duck/Laos/25/06 (H5N1) influenza virus challenge, with no evidence of morbidity, mortality, or shedding of the challenge virus. Moreover, two of the three vaccines achieved complete cross-clade or cross-subclade protection against the heterologous avian influenza virus challenge. Interestingly, the vaccines induce low or undetectable titers of hemagglutination inhibition (HI), cross-HI, and/or virus neutralization antibodies. The mechanism of complete protection in the absence of detectable antibody responses remains an open question.

scholarly journals Consequences of Immunodominant Epitope Deletion for Minor Influenza Virus-Specific CD8+-T-Cell Responses

2005 ◽  
Vol 79 (7) ◽  
pp. 4329-4339 ◽  
Author(s):  
Samita S. Andreansky ◽  
John Stambas ◽  
Paul G. Thomas ◽  
Weidong Xie ◽  
Richard J. Webby ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Reverse Genetics ◽  
H3n2 Virus ◽  
Influenza A Viruses ◽  
Cell Responses ◽  
Infected Cells ◽  
H3n2 Influenza

ABSTRACT The extent to which CD8+ T cells specific for other antigens expand to compensate for the mutational loss of the prominent DbNP366 and DbPA224 epitopes has been investigated using H1N1 and H3N2 influenza A viruses modified by reverse genetics. Significantly increased numbers of CD8+ KbPB1703 +, CD8+ KbNS2114 +, and CD8+ DbPB1-F262 + T cells were found in the spleen and in the inflammatory population recovered by bronchoalveolar lavage from mice that were first given the −NP−PA H1N1 virus intraperitoneally and then challenged intranasally with the homologous H3N2 virus. The effect was less consistent when this prime-boost protocol was reversed. Also, though the quality of the response measured by cytokine staining showed some evidence of modification when these minor CD8+-T-cell populations were forced to play a more prominent part, the effects were relatively small and no consistent pattern emerged. The magnitude of the enhanced clonal expansion following secondary challenge suggested that the prime-boost with the −NP−PA viruses gave a response overall that was little different in magnitude from that following comparable exposure to the unmanipulated viruses. This was indeed shown to be the case when the total response was measured by ELISPOT analysis with virus-infected cells as stimulators. More surprisingly, the same effect was seen following primary challenge, though individual analysis of the CD8+ KbPB1703 +, CD8+ KbNS2114 +, and CD8+ DbPB1-F262 + sets gave no indication of compensatory expansion. A possible explanation is that novel, as yet undetected epitopes emerge following primary exposure to the −NP−PA deletion viruses. These findings have implications for both natural infections and vaccines.

scholarly journals Protection against a Lethal Avian Influenza A Virus in a Mammalian System

1999 ◽  
Vol 73 (2) ◽  
pp. 1453-1459 ◽  
Author(s):  
Janice M. Riberdy ◽  
Kirsten J. Flynn ◽  
Juergen Stech ◽  
Robert G. Webster ◽  
John D. Altman ◽  
...  
Keyword(s):  
T Cell ◽  
Avian Influenza ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Immune Memory ◽  
H3n2 Virus ◽  
Influenza A Viruses ◽  
Cell Responses ◽  
Avian Influenza A Virus

ABSTRACT The question of how best to protect the human population against a potential influenza pandemic has been raised by the recent outbreak caused by an avian H5N1 virus in Hong Kong. The likely strategy would be to vaccinate with a less virulent, laboratory-adapted H5N1 strain isolated previously from birds. Little attention has been given, however, to dissecting the consequences of sequential exposure to serologically related influenza A viruses using contemporary immunology techniques. Such experiments with the H5N1 viruses are limited by the potential risk to humans. An extremely virulent H3N8 avian influenza A virus has been used to infect both immunoglobulin-expressing (Ig+/+) and Ig−/− mice primed previously with a laboratory-adapted H3N2 virus. The cross-reactive antibody response was very protective, while the recall of CD8+ T-cell memory in the Ig−/− mice provided some small measure of resistance to a low-dose H3N8 challenge. The H3N8 virus also replicated in the respiratory tracts of the H3N2-primed Ig+/+ mice, generating secondary CD8+ and CD4+ T-cell responses that may contribute to recovery. The results indicate that the various components of immune memory operate together to provide optimal protection, and they support the idea that related viruses of nonhuman origin can be used as vaccines.

scholarly journals Generation of both cross-reactive and virus-specific T-cell populations after immunization with serologically distinct influenza A viruses.

1977 ◽  
Vol 145 (3) ◽  
pp. 557-568 ◽  
Author(s):  
R B Effros ◽  
P C Doherty ◽  
W Gerhard ◽  
J Bennink
Keyword(s):  
T Cell ◽  
Influenza A ◽  
Competitive Inhibition ◽  
Influenza Viruses ◽  
Cytotoxic T Cell ◽  
Considerable Proportion ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Influenza A Viruses ◽  
Apparent Lack

Specificity of cytotoxic T-cell function was investigated for a range of different influenza viruses. T cells from mice immunized with A or B strain influenza viruses, or with vaccinia virus, showed reciprocal exclusion of cytotoxicity. Extensive cross-reactivity was, however, found for lymphocyte populations from mice infected with a variety of serologically distinct influenza A viruses, though serum antibodies did not cross-react when tested in a radioimmunoassay using comparable target cells as immunoadsorbents. This apparent lack of T-cell specificity was recognized for immune spleen cells generated after intraperitoneal inoculation of high titers of virus, and for mediastinal lymph node populations from mice with pneumonia due to infection with much less virus. The phenomenon could not be explained on the basis of exposure to the chicken host component, which is common to A and B strain viruses. However, not all of the virus-immune T-cell clones are cross-reactive. Competitive-inhibition experiments indicate that a considerable proportion of the lymphocyte response is restricted to the immunizing virus. Even so, the less specific component is significant. Also, exposure to one type A virus was found to prime for an enhanced cell-mediated immunity response after challenge with a second, serologically different A strain virus.

scholarly journals Hemagglutinin-specific complement-dependent antibody response to influenza infection

1978 ◽  
Vol 147 (1) ◽  
pp. 265-270 ◽  
Author(s):  
MW Verbonitz ◽  
FA Ennis ◽  
JT Hicks ◽  
P Albrecht
Keyword(s):  
T Cell ◽  
Antibody Response ◽  
Cell Response ◽  
Influenza A ◽  
Present Report ◽  
Influenza Infection ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Influenza A Viruses

The host defense response to influenza infection is complex. Specific humoral antibodies develop to the strain-specific surface antigens, the hemagglutinin and the neuraminidase, and to the internal antigens (matrix and nucleoprotein) which are common to all influenza A viruses (1). Antibodies to the hemagglutinin, which is the major surface antigen, neutralize viral infectivity (2). In addition to antibodies which have been detected against virion antigens, a cytotoxic T-cell response with specificity against the viral hemagglutinin on influenza-infected target cells (3-5) has been recently described. A more cross-reactive cytotoxic T-cell response has also been observed when a nonpermissively infected target cell is used in cytotoxicity assays (6,7). The present report describes the development during influenza infection and after vaccination of a cytolytic humoral antibody response which is directed against the hemagglutinin on infected target cells. This antibody-mediated lysis of infected cells in complement dependent, as has been reported with other virus infections (8-11).

scholarly journals Contemporary Analysis of MHC-Related Immunodominance Hierarchies in the CD8+T Cell Response to Influenza A Viruses

2000 ◽  
Vol 165 (5) ◽  
pp. 2404-2409 ◽  
Author(s):  
Gabrielle T. Belz ◽  
Philip G. Stevenson ◽  
Peter C. Doherty
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Influenza A ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Influenza A Viruses

scholarly journals CD4+T help promotes influenza virus-specific CD8+T cell memory by limiting metabolic dysfunction

2019 ◽  
Vol 116 (10) ◽  
pp. 4481-4488 ◽  
Author(s):  
Jolie G. Cullen ◽  
Hayley A. McQuilten ◽  
Kylie M. Quinn ◽  
Moshe Olshansky ◽  
Brendan E. Russ ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Response ◽  
T Cell Memory ◽  
Metabolic Dysfunction ◽  
Influenza A Viruses ◽  
Cell Memory ◽  
Cell Immunity ◽  
T Cell Help

There is continued interest in developing novel vaccine strategies that induce establish optimal CD8+cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4+T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4+T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8+T cell memory established in the presence or absence of a concurrent CD4+T cell response. We demonstrate that CD4+T cell help appears to be required at the initial priming phase of infection for the maintenance of IAV-specific CTL memory, with “unhelped” memory CTL exhibiting intrinsic dysfunction. High-throughput RNA-sequencing established that distinct transcriptional signatures characterize the helped vs. unhelped IAV-specific memory CTL phenotype, with the unhelped set showing a more “exhausted T cell” transcriptional profile. Moreover, we identify that unhelped memory CTLs exhibit defects in a variety of energetic pathways, leading to diminished spare respiratory capacity and diminished capacity to engage glycolysis upon reactivation. Hence, CD4+T help at the time of initial priming promotes molecular pathways that limit exhaustion by channeling metabolic processes essential for the rapid recall of memory CD8+T cells.

scholarly journals Characterization of a Human H5N1 Influenza A Virus Isolated in 2003

2005 ◽  
Vol 79 (15) ◽  
pp. 9926-9932 ◽  
Author(s):  
Kyoko Shinya ◽  
Masato Hatta ◽  
Shinya Yamada ◽  
Ayato Takada ◽  
Shinji Watanabe ◽  
...  
Keyword(s):  
Hong Kong ◽  
Avian Influenza ◽  
Influenza A Virus ◽  
Influenza A ◽  
Mainland China ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
H5n1 Avian Influenza Virus ◽  
H5n1 Influenza ◽  
Avian Influenza A Virus

ABSTRACT In 2003, H5N1 avian influenza virus infections were diagnosed in two Hong Kong residents who had visited the Fujian province in mainland China, affording us the opportunity to characterize one of the viral isolates, A/Hong Kong/213/03 (HK213; H5N1). In contrast to H5N1 viruses isolated from humans during the 1997 outbreak in Hong Kong, HK213 retained several features of aquatic bird viruses, including the lack of a deletion in the neuraminidase stalk and the absence of additional oligosaccharide chains at the globular head of the hemagglutinin molecule. It demonstrated weak pathogenicity in mice and ferrets but caused lethal infection in chickens. The original isolate failed to produce disease in ducks but became more pathogenic after five passages. Taken together, these findings portray the HK213 isolate as an aquatic avian influenza A virus without the molecular changes associated with the replication of H5N1 avian viruses in land-based poultry such as chickens. This case challenges the view that adaptation to land-based poultry is a prerequisite for the replication of aquatic avian influenza A viruses in humans.

Sign in / Sign up

Export Citation Format

Share Document