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ABSTRACT: Influenza A H5N1 viruses remain a substantial threat to global public health. In particular, the expanding genetic diversity of H5N1 viruses and the associated risk for human adaptation underscore the importance of better understanding host immune responses that may protect against disease or infection. Although much emphasis has been placed on investigating early virus-host interactions and the induction of innate immune responses, little is known of the consequent adaptive immune response to H5N1 virus infection. In this review, we describe the H5N1 virus-specific and cross-reactive antibody and T cell responses in humans and animal models. Data from limited studies suggest that although initially robust, there is substantial waning of the serum antibody responses in survivors of H5N1 virus infection. Characterization of monoclonal antibodies generated from memory B cells of survivors of H5N1 virus infection has provided an understanding of the fine specificity of the human antibody response to H5N1 virus infection and identified strategies for immunotherapy. Human T cell responses induced by infection with seasonal influenza viruses are directed to relatively conserved internal proteins and cross-react with the H5N1 subtype. A role for T cell-based heterosubtypic immunity against H5N1 viruses is suggested in animal studies. Further studies on adaptive immune responses to H5N1 virus infection in both humans and animals are needed to inform the design of optimal immunological treatment and prevention modalities.
Virus Research 06/2013; · 2.94 Impact Factor
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Rogier Bodewes,
Danny Morick,
Gerrie de Mutsert,
Nynke Osinga,
Theo Bestebroer,
Stefan van der Vliet,
Saskia L Smits,
Thijs Kuiken, Guus F Rimmelzwaan,
Ron A M Fouchier,
Albert D M E Osterhaus
Emerging Infectious Diseases 03/2013; 19(3):511-2. · 6.79 Impact Factor
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ABSTRACT: Influenza A viruses (IAV) cause respiratory tract infections annually associated with excess mortality and morbidity. Nonspecific, innate immune mechanisms play a key role in protection against viral invasion at early stages of infection. A soluble protein present in mucosal secretions of the lung, surfactant protein D (SP-D), is an important component of this initial barrier that helps to prevent and limit IAV infections of the respiratory epithelium. This collagenous C-type lectin binds IAVs and thereby inhibits attachment and entry of the virus but also contributes to enhanced clearance of SP-D-opsonized virus via interactions with phagocytic cells. In addition, SP-D modulates the inflammatory response and helps to maintain a balance between effective neutralization/killing of IAV, and protection against alveolar damage resulting from IAV-induced excessive inflammatory responses. The mechanisms of interaction between SP-D and IAV not only depend on the structure and binding properties of SP-D but also on strain-specific features of IAV, and both issues will be discussed. SP-D from pigs exhibits distinct anti-IAV properties and is discussed in more detail. Finally, the potential of SP-D as a prophylactic and/or therapeutic antiviral agent to protect humans against infections by IAV is discussed.
Journal of Innate Immunity 02/2013; · 4.21 Impact Factor
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ABSTRACT: Dendritic cells express lectins receptors, like DC-SIGN, which allow these cells to sense glycans that are present on various bacterial and viral pathogens. Interaction of DC-SIGN with carbohydrate moieties induces maturation of dendritic cells and promotes endocytosis of pathogens which is an important property of these professional antigen presenting cells. Uptake of pathogens by dendritic cells may lead to cross-presentation of antigens or infection of these cells, which ultimately results in activation of virus-specific T cells in draining lymph nodes. Little is known about the interaction of DC-SIGN with influenza A viruses. Here we show that a virus with a non-functional receptor binding site in its hemagglutinin, can replicate in cells expressing DC-SIGN. Also in the absence of sialic acids, which is the receptor for influenza A viruses, these viruses replicate in DC-SIGN expressing cells including human dendritic cells. Furthermore, the efficiency of DC-SIGN mediated infection is dependent on the extent of glycosylation of the viral hemagglutinin.
PLoS ONE 01/2013; 8(2):e56164. · 4.09 Impact Factor
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ABSTRACT: Highly pathogenic avian influenza H5N1 viruses have devastated the poultry industry in many countries of the eastern hemisphere. Occasionally H5N1 viruses cross the species barrier and infect humans, sometimes with a severe clinical outcome. When this happens, there is a chance of reassortment between H5N1 and human influenza viruses. To assess the potential of H5N1 viruses to reassort with contemporary human influenza viruses (H1N1, H3N2 and pandemic H1N1), we used an in vitro selection method to generate reassortant viruses, that contained the H5 hemagglutinin gene, and that have a replication advantage in vitro. We found that the neuraminidase and matrix gene segments of human influenza viruses were preferentially selected by H5 viruses. However, these H5 reassortant viruses did not show a marked increase in replication in MDCK cells and human bronchial epithelial cells. In ferrets, inoculation with a mixture of H5N1-pandemic H1N1 reassortant viruses resulted in outgrowth of reassortant H5 viruses that had incorporated the neuraminidase and matrix gene segment of pandemic 2009 H1N1. This virus was not transmitted via aerosols or respiratory droplets to naïve recipient ferrets. Altogether, these data emphasize the potential of avian H5N1 viruses to reassort with contemporary human influenza viruses. The neuraminidase and matrix gene segments of human influenza viruses showed the highest genetic compatibility with HPAI H5N1 virus.
PLoS ONE 01/2013; 8(3):e59889. · 4.09 Impact Factor
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ABSTRACT: Virus-specific CD8+ T cells contribute to protective immunity against influenza A virus infections. Since the majority of these cells are directed to conserved viral proteins, they may afford protection against influenza A viruses of various subtypes. In the present study, we assessed the cross-reactivity of human CD8+ T lymphocytes, induced by infection with seasonal A(H1N1) or A(H3N2) influenza viruses, with 2009 pandemic influenza A/H1N1 virus (A(H1N1)pdm09) and swine origin triple reassortant A(H3N2) (A(H3N2)v) viruses that currently cause an increasing number of human cases in the USA. We demonstrated that CD8+ T cells induced after seasonal influenza A virus infections exert lytic activity and produce IFN-γ upon in vitro restimulation with A(H1N1)pdm09 and A(H3N2)v influenza A viruses. Furthermore, CD8+ T cells directed to A(H1N1)pdm09 virus displayed a high degree of cross-reactivity with A(H3N2)v viruses. It was concluded that cross-reacting T cells have the potential to afford protective immunity against A(H1N1)pdm09 viruses during the pandemic and offer some degree of protection against infection with A(H3N2)v viruses.
Journal of General Virology 11/2012; · 3.36 Impact Factor
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ABSTRACT: The influenza A virus is one of the leading causes of respiratory tract infections in humans. Upon infection with an influenza A virus, both innate and adaptive immune responses are induced. Here we discuss various strategies used by influenza A viruses to evade innate immune responses and recognition by components of the humoral and cellular immune response, which consequently may result in reduced clearing of the virus and virus-infected cells. Finally, we discuss how the current knowledge about immune evasion can be used to improve influenza A vaccination strategies.
Viruses 09/2012; 4(9):1438-76. · 1.50 Impact Factor
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ABSTRACT: C-type lectins are important molecules of the innate immune system. These molecules, like surfactant protein D (SP-D) can recognize glycans on pathogens and neutralize these. Also influenza viruses are recognized by SP-D and their susceptibility to neutralization by SP-D is dependent on the number of N-linked glycosylation sites in the hemagglutinin in particular. Porcine SP-D displayed stronger neutralizing activity to human influenza A viruses than to swine influenza A viruses. Although viruses from these species differ with regard to the number of glycosylation sites in the hemagglutinin, the mechanism underlying the differential recognition by porcine SP-D is poorly understood. Here we investigated the molecular basis for the differential recognition of a seasonal H1N1 and a 2009 pandemic H1N1 virus by porcine SP-D. We demonstrated that the number and position of glycosylation sites determine viral susceptibility to the neutralizing activity of porcine SP-D. However, predicting the effect remains difficult as it was shown to be dependent on the strain and the position of the glycosylation sites.
Virus Research 08/2012; 169(1):301-5. · 2.94 Impact Factor
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Sander Herfst,
Eefje J A Schrauwen,
Martin Linster,
Salin Chutinimitkul,
Emmie de Wit,
Vincent J Munster,
Erin M Sorrell,
Theo M Bestebroer,
David F Burke,
Derek J Smith, Guus F Rimmelzwaan,
Albert D M E Osterhaus,
Ron A M Fouchier
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ABSTRACT: Highly pathogenic avian influenza A/H5N1 virus can cause morbidity and mortality in humans but thus far has not acquired the ability to be transmitted by aerosol or respiratory droplet ("airborne transmission") between humans. To address the concern that the virus could acquire this ability under natural conditions, we genetically modified A/H5N1 virus by site-directed mutagenesis and subsequent serial passage in ferrets. The genetically modified A/H5N1 virus acquired mutations during passage in ferrets, ultimately becoming airborne transmissible in ferrets. None of the recipient ferrets died after airborne infection with the mutant A/H5N1 viruses. Four amino acid substitutions in the host receptor-binding protein hemagglutinin, and one in the polymerase complex protein basic polymerase 2, were consistently present in airborne-transmitted viruses. The transmissible viruses were sensitive to the antiviral drug oseltamivir and reacted well with antisera raised against H5 influenza vaccine strains. Thus, avian A/H5N1 influenza viruses can acquire the capacity for airborne transmission between mammals without recombination in an intermediate host and therefore constitute a risk for human pandemic influenza.
Science 06/2012; 336(6088):1534-41. · 31.20 Impact Factor
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Kim B Westgeest,
Miranda de Graaf,
Mathieu Fourment,
Theo M Bestebroer,
Ruud van Beek,
Monique I J Spronken,
Jan C de Jong, Guus F Rimmelzwaan,
Colin A Russell,
Albert D M E Osterhaus,
Gavin J D Smith,
Derek J Smith,
Ron A M Fouchier
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ABSTRACT: Each year, influenza viruses cause epidemics by evading pre-existing humoral immunity through mutations in the major glycoproteins: the haemagglutinin (HA) and the neuraminidase (NA). In 2004, the antigenic evolution of HA of human influenza A (H3N2) viruses was mapped (Smith et al., Science 305, 371-376, 2004) from its introduction in humans in 1968 until 2003. The current study focused on the genetic evolution of NA and compared it with HA using the dataset of Smith and colleagues, updated to the epidemic of the 2009/2010 season. Phylogenetic trees and genetic maps were constructed to visualize the genetic evolution of NA and HA. The results revealed multiple reassortment events over the years. Overall rates of evolutionary change were lower for NA than for HA1 at the nucleotide level. Selection pressures were estimated, revealing an abundance of negatively selected sites and sparse positively selected sites. The differences found between the evolution of NA and HA1 warrant further analysis of the evolution of NA at the phenotypic level, as has been done previously for HA.
Journal of General Virology 06/2012; 93(Pt 9):1996-2007. · 3.36 Impact Factor
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ABSTRACT: Exchange of gene segments between mammalian and avian influenza A viruses may lead to the emergence of potential pandemic influenza viruses. Since co-infection of single cells with two viruses is a prerequisite for reassortment to take place, we assessed frequencies of double-infection in vitro using influenza A/H5N1 and A/H1N1 viruses expressing the reporter genes eGFP or mCherry. Double-infected A549 and Madin-Darby canine kidney cells were detected by confocal microscopy and flow cytometry.
Journal of General Virology 04/2012; 93(Pt 8):1645-8. · 3.36 Impact Factor
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Laurens P Kil,
Marjolein J W de Bruijn,
Menno van Nimwegen,
Odilia B J Corneth,
Jan Piet van Hamburg,
Gemma M Dingjan,
Friedrich Thaiss, Guus F Rimmelzwaan,
Dirk Elewaut,
Dianne Delsing,
Pieter Fokko van Loo,
Rudi W Hendriks
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ABSTRACT: On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)-like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca(2+) influx, nuclear factor (NF)-κB activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK.
Blood 03/2012; 119(16):3744-56. · 9.90 Impact Factor
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Eefje J A Schrauwen,
Sander Herfst,
Lonneke M Leijten,
Peter van Run,
Theo M Bestebroer,
Martin Linster,
Rogier Bodewes,
Joost H C M Kreijtz, Guus F Rimmelzwaan,
Albert D M E Osterhaus,
Ron A M Fouchier,
Thijs Kuiken,
Debby van Riel
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ABSTRACT: The route by which highly pathogenic avian influenza (HPAI) H5N1 virus spreads systemically, including the central nervous system (CNS), is largely unknown in mammals. Especially, the olfactory route, which could be a route of entry into the CNS, has not been studied in detail. Although the multibasic cleavage site (MBCS) in the hemagglutinin (HA) of HPAI H5N1 viruses is a major determinant of systemic spread in poultry, the association between the MBCS and systemic spread in mammals is less clear. Here we determined the virus distribution of HPAI H5N1 virus in ferrets in time and space-including along the olfactory route-and the role of the MBCS in systemic replication. Intranasal inoculation with wild-type H5N1 virus revealed extensive replication in the olfactory mucosa, from which it spread to the olfactory bulb and the rest of the CNS, including the cerebrospinal fluid (CSF). Virus spread to the heart, liver, pancreas, and colon was also detected, indicating hematogenous spread. Ferrets inoculated intranasally with H5N1 virus lacking an MBCS demonstrated respiratory tract infection only. In conclusion, HPAI H5N1 virus can spread systemically via two different routes, olfactory and hematogenous, in ferrets. This systemic spread was dependent on the presence of the MBCS in HA.
Journal of Virology 01/2012; 86(7):3975-84. · 5.40 Impact Factor
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Josanne H Verhagen,
Vincent J Munster,
Frank Majoor,
Pascal Lexmond,
Oanh Vuong,
Job B G Stumpel, Guus F Rimmelzwaan,
Albert D M E Osterhaus,
Martin Schutten,
Roy Slaterus,
Ron A M Fouchier
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ABSTRACT: Avian influenza virus (AIV) surveillance studies in wild birds are usually conducted in rural areas and nature reserves. Less is known of avian influenza virus prevalence in wild birds located in densely populated urban areas, while these birds are more likely to be in close contact with humans. Influenza virus prevalence was investigated in 6059 wild birds sampled in cities in the Netherlands between 2006 and 2009, and compared with parallel AIV surveillance data from low urbanized areas in the Netherlands. Viral prevalence varied with the level of urbanization, with highest prevalence in low urbanized areas. Within cities virus was detected in 0.5% of birds, while seroprevalence exceeded 50%. Ring recoveries of urban wild birds sampled for virus detection demonstrated that most birds were sighted within the same city, while few were sighted in other cities or migrated up to 2659 km away from the sample location in the Netherlands. Here we show that urban birds were infected with AIVs and that urban birds were not separated completely from populations of long-distance migrants. The latter suggests that wild birds in cities may play a role in the introduction of AIVs into cities. Thus, urban bird populations should not be excluded as a human-animal interface for influenza viruses.
PLoS ONE 01/2012; 7(6):e38256. · 4.09 Impact Factor
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ABSTRACT: Influenza viruses continue to cause disease of varying severity among humans. People with underlying disease and the elderly are at increased risk of developing severe disease after infection with an influenza virus. As effective and safe vaccines are available, the WHO has recommended vaccinating these groups against influenza annually. In addition to this recommendation, public health authorities of a number of countries have recently recommended vaccinating all healthy children aged 6-59 months against influenza. Here, we review the currently available data concerning the burden of disease in children, the economical impact of implementing universal vaccination of children, the efficacy of currently available influenza virus vaccines, the theoretical concerns regarding preventing immunity otherwise induced by infections with seasonal influenza viruses, and finally, how to address these concerns.
Future Microbiology 10/2011; 6(10):1171-84. · 3.82 Impact Factor
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ABSTRACT: Infection with seasonal influenza A viruses induces immunity to potentially pandemic influenza A viruses of other subtypes (heterosubtypic immunity). We recently demonstrated that vaccination against seasonal influenza prevented the induction of heterosubtypic immunity against influenza A/H5N1 virus induced by infection with seasonal influenza in animal models, which correlated with the absence of virus-specific CD8(+) T cell responses. Annual vaccination of all healthy children against influenza has been recommended, but the impact of vaccination on the development of the virus-specific CD8(+) T cell immunity in children is currently unknown. Here we compared the virus-specific CD8(+) T cell immunity in children vaccinated annually with that in unvaccinated children. In the present study, we compared influenza A virus-specific cellular and humoral responses of unvaccinated healthy control children with those of children with cystic fibrosis (CF) who were vaccinated annually. Similar virus-specific CD4(+) T cell and antibody responses were observed, while an age-dependent increase of the virus-specific CD8(+) T cell response that was absent in vaccinated CF children was observed in unvaccinated healthy control children. Our results indicate that annual influenza vaccination is effective against seasonal influenza but hampers the development of virus-specific CD8(+) T cell responses. The consequences of these findings are discussed in the light of the development of protective immunity to seasonal and future pandemic influenza viruses.
Journal of Virology 08/2011; 85(22):11995-2000. · 5.40 Impact Factor
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ABSTRACT: To protect children against infection with seasonal influenza viruses, this age group is vaccinated annually in some countries. However, currently used inactivated seasonal influenza vaccines do not protect well against antigenically distinct pandemic influenza virus strains. Furthermore, annual vaccination may prevent infection with seasonal influenza viruses and subsequently the induction of heterosubtypic immunity. Therefore, the development of influenza vaccines that induce broad protective immunity should be considered a priority. In the absence of such vaccines children that are vaccinated annually against seasonal influenza should in a pandemic scenario also receive pandemic vaccines as soon as these become available. In order to protect young infant under six months of age for which no vaccines are registered at present, vaccination of pregnant women should be considered. This would afford protection through maternally derived antibodies. In addition, vaccination of close family members of young infants is recommended, to prevent transmission within the household.
Vaccine 08/2011; 29(43):7551-3. · 3.77 Impact Factor
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ABSTRACT: Most patients infected with highly pathogenic avian influenza A/H5N1 virus develop severe pneumonia resulting in acute respiratory distress syndrome, with extrarespiratory disease as an uncommon complication. Intranasal inoculation of ferrets with influenza A/H5N1 virus causes lesions in both the respiratory tract and extrarespiratory organs (primarily brain). However, the route of spread to extrarespiratory organs and the relative contribution of extrarespiratory disease to pathogenicity are largely unknown. In the present study, we characterized lesions in the respiratory tract and central nervous system (CNS) of ferrets (n = 8) inoculated intranasally with influenza virus A/Indonesia/5/2005 (H5N1). By 7 days after inoculation, only 3 of 8 ferrets had a mild or moderate bronchointerstitial pneumonia. In contrast, all 8 ferrets had moderate or severe CNS lesions, characterized by meningoencephalitis, choroiditis, and ependymitis, and centered on tissues adjoining the cerebrospinal fluid. These findings indicate that influenza A/H5N1 virus spread directly from nasal cavity to brain, and that CNS lesions contributed more than pulmonary lesions to the pathogenicity of influenza A/H5N1 virus infection in ferrets. In comparison, intratracheal inoculation of ferrets with the same virus reproducibly caused severe bronchointerstitial pneumonia. The method of virus inoculation requires careful consideration in the design of ferret experiments as a model for influenza A/H5N1 in humans.
American Journal Of Pathology 07/2011; 179(1):30-6. · 4.89 Impact Factor
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ABSTRACT: Influenza A (H1N1) viruses of swine origin were introduced into the human population in 2009 and caused a pandemic. The disease burden in the elderly was relatively low, which was attributed to the presence of cross-reacting serum antibodies in this age group, which were raised against seasonal influenza A (H1N1) viruses that circulated before 1957. It has also been described how infection with heterosubtypic influenza viruses can induce some degree of protection against infection by a novel strain of influenza virus. Here, we assess the extent of protective immunity against infection with the 2009 influenza A (H1N1) pandemic influenza virus that is afforded by infection with a seasonal influenza A (H3N2) virus in mice. Mice that experienced a primary A (H3N2) influenza virus infection displayed reduced weight loss after challenge infection and cleared the 2009 influenza A (H1N1) virus infection more rapidly. To elucidate the correlates of protection of this heterosubtypic immunity to pandemic H1N1 virus infection, adoptive transfer experiments were carried out by using selected post-infection lymphocyte populations. Virus-specific CD8(+) T-cells in concert with CD4(+) T-cells were responsible for the observed protection. These findings may not only provide an explanation for epidemiological differences in the incidence of severe pandemic H1N1 infections, they also indicate that the induction of cross-reactive virus-specific CD8(+) and CD4(+) T-cell responses may be a suitable approach for the development of universal influenza vaccines.
Journal of General Virology 06/2011; 92(Pt 10):2339-49. · 3.36 Impact Factor
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Judith M A van den Brand,
Joost H C M Kreijtz,
Rogier Bodewes,
Koert J Stittelaar,
Geert van Amerongen,
Thijs Kuiken,
James Simon,
Ron A M Fouchier,
Giuseppe Del Giudice,
Rino Rappuoli, Guus F Rimmelzwaan,
Albert D M E Osterhaus
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ABSTRACT: Serum antibodies induced by seasonal influenza or seasonal influenza vaccination exhibit limited or no cross-reactivity against the 2009 pandemic swine-origin influenza virus of the H1N1 subtype (pH1N1). Ferrets immunized once or twice with MF59-adjuvanted seasonal influenza vaccine exhibited significantly reduced lung virus titers but no substantial clinical protection against pH1N1-associated disease. However, priming with MF59-adjuvanted seasonal influenza vaccine significantly increased the efficacy of a pandemic MF59-adjuvanted influenza vaccine against pH1N1 challenge. Elucidating the mechanism involved in this priming principle will contribute to our understanding of vaccine- and infection-induced correlates of protection. Furthermore, a practical consequence of these findings is that during an emerging pandemic, the implementation of a priming strategy with an available adjuvanted seasonal vaccine to precede the eventual pandemic vaccination campaign may be useful and life-saving.
Journal of Virology 03/2011; 85(6):2851-8. · 5.40 Impact Factor
