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  • Avian influenza and sialic acid receptors: eyes

    The Lancet Infectious Diseases 2005; 5:184-188
    DOI:10.1016/S1473-3099(05)01311-3
    Avian influenza and sialic acid receptors: more than meets the eye? Sigvard Olofsson a, Urban Kumlin b, Ken Dimock c and Dr Niklas Arnberg b

    See Reflection and Reaction
    See Media Watch
    See Reportage

    Summary

    Given our recent discoveries that the ocular human pathogens adenovirus serotype 37 and enterovirus serotype 70 use sialic acid linked to galactose via α2,3 glycosidic bonds as a cellular receptor, we propose that the presence of this receptor in the eye also explains the ocular tropism exhibited by zoonotic avian influenza A viruses such as subtype H5N1 in Hong Kong in 1997, H7N7 in the Netherlands in 2003, H7N2 in the USA in 2003, and H7N3 in Canada in 2004. We also draw attention to the implications this hypothesis may have for epizootic and zoonotic influenza, and the initiation of future pandemics.
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    Influenza A viruses are highly (but not completely) species and receptor specific.1,2 Thus, avian influenza A viruses that use α2,3-linked sialic acid (SA) receptors do not easily infect human beings and conversely, human influenza A viruses that bind α2,6-linked SA receptors do not easily infect aquatic birds.3?5 Furthermore, during the avian H7N7 Dutch outbreak in 2003, an unusual organ specificity was recognised.6 The major manifestation of the infection in human beings was ocular rather than respiratory; H7N7 virus was detected by PCR or cell culture in more than 80 human cases of conjunctivitis and in seven cases with respiratory infection. Serological data indicated that at least 1000 people contracted H7N7 virus, most of them without symptoms.7,8 The virus was suggested to be transmitted from the primary cases to more than 50% of their household contacts. The mean viral load in conjunctival swabs was high in patients with avian H7N7 and very low in patients with human H3N2. Conversely, the mean viral load in nose/throat swabs was high in patients with human H3N2 and very low in patients with avian H7N7. Before this outbreak, only sporadic cases of zoonotic avian influenza A virus-mediated conjunctivitis had been reported.9?17
    The unusual organ specificity observed in the Dutch outbreak of H7N7 in 2003 raises the question of whether an ocular tropism may be a general feature of avian influenza viruses. Besides the H7 data, H5N1 infection involving conjunctivitis was also reported during the outbreak in Hong Kong 1997.15?17 However, it should be remembered that conjunctivitis in human beings has not yet been reported from the ongoing outbreak of avian H5N1 in east Asia.18,19 Thus, a different organ tropism may not solely be explained by a difference in SA receptor specificity. Other mechanisms, such as differences in haemagglutinin cleavability, neuraminidase, internal proteins, temperature dependence, and immune evasion may also be involved in determining organ tropism.
    α2,3-linked sialic acid is a cellular receptor for multiple ocular viruses

    Adenovirus serotype 37 and enterovirus serotype 70 almost exclusively cause ocular disease. Adenovirus 37 was isolated for the first time in 1976,20 and is one of the most frequent causative agents of epidemic keratoconjunctivitis.21?23 Adenovirus 37 is transmitted via direct or indirect contact,24 and has infrequently been associated with a sexually transmitted disease.25 Consequently, adenovirus 37 is more common in densely populated areas of the world. In Japan alone, between half a million and one million individuals have epidemic keratoconjunctivitis every year.26 α2,3-linked SA is a cellular receptor for adenovirus 37 as shown by us27,28 and confirmed by others29 using SA-deficient cells, lectins, sialidases, and various soluble SA-containing compounds.
    Enterovirus 70 infection results primarily in a highly contagious ocular infection referred to as acute haemorrhagic conjunctivitis, which has also been associated, though infrequently, with neurological sequelae.30,31 Since enterovirus 70-associated acute haemorrhagic conjunctivitis was first recognised in western Africa in 1969, it has been responsible for tens of millions of cases, and has spread throughout tropical and subtropical regions of the world during two pandemics, in 1969?197132 and in 1980?1982.33 Enterovirus 70 has also been associated with numerous sporadic outbreaks of acute haemorrhagic conjunctivitis, the most recent occurring in India,34,35 Japan,36 and Israel.37 Although the host range of the majority of human enteroviruses is restricted to cells of primate origin, in vitro, enterovirus 70 replicates with various efficiencies in cells derived from a wide variety of mammalian species.38 The sialylated molecule CD55 is the main binding molecule for enterovirus 70 on HeLa cells; however, a second sialylated molecule also serves as a receptor.39,40 Enterovirus 70 attachment to other human cell lines, including corneal cells, is CD55-independent, but requires SA.40?42 Through the use of linkage-specific sialidases, sialyltransferases, and lectins, it has been shown that enterovirus 70 exhibits a strong preference for binding to α2,3-linked SA.41
    Besides adenovirus 37, enterovirus 70, and avian influenza A viruses, there are other viruses that exhibit ocular tropism but have not been shown to use SA as cellular receptors. Examples of receptors used by other viruses with ocular tropism are heparan sulphate, herpes virus entry mediator, and nectin 1 and 2 (which are used by herpes simplex virus types 1 and 2),43 CD150 (measles virus),44 and CD46 (measles virus45 and species B adenoviruses;46,47 adenovirus 37 belongs to species D). Thus, use of SA as a cellular receptor is not a prerequisite for viruses with ocular tropism. However, it should be noted that the ocular tropism of the viruses listed above is not nearly as pronounced as it is for adenovirus 37, enterovirus 70, or H7N7.

    Viral tropism as a consequence of interorgan and intraorgan differences in SA linkages

    Unlike adenovirus 37, enterovirus 70, and avian influenza A viruses, human influenza A viruses preferentially use α2,6-linked SA as a cellular receptor and primarily cause respiratory manifestations. The organ-specific expression of different SA receptors parallels the tropism of human and avian viruses; on non-ciliated epithelial cells in the human respiratory tract, including larynx and trachea, α2,6-linked SA is expressed far more abundantly than α2,3-linked SA, whereas α2,3-linked SA is present on ocular and lacrimal duct epithelial cells (to the best of our knowledge, α2,6-linked SA has not been found on corneal or conjunctival epithelial cells).4,48?54 Moreover, the secretions in these tissues contain SA with a configuration opposite to that of the epithelial cells.
    The major sialylated components of respiratory and ocular secretions are the mucins. In the respiratory tract the secreted mucins are the high molecular mass dimeric or oligomeric mucins MUC2, MUC5AC, and MUC5B, and the low molecular mass monomeric MUC7.55 In the human respiratory tract, these secretions are rich in α2,3-linked SA.49,50 In the eye, the major secreted, high molecular mass mucin is MUC5AC.56 The low molecular mass mucin MUC7 is also expressed. By contrast with the respiratory tract, ocular secretory mucins are rich in α2,6-linked SA.57,58 In both organs, a major function of the secretory mucins is to act as a microbe/debris removing multimeric network that harbours defence molecules and holds fluid in place. Although other factors may contribute to the tropisms exhibited by human and avian influenza A viruses, it seems likely that differences in SA linkage on cells and in secretions of the eye and respiratory tract have a major role in determining organ specificity in human beings.
    In human beings, a unique protective mechanism may be offered by the opposite configuration of SA on ocular cells (α2,3), as opposed to the surrounding secretions (α2,6), and by the reverse situation in the respiratory tract (figure 1). We suggest that one evolutionary reason for this, driven by SA-binding pathogens, is that it provides an organ-specific, SA-linkage dependent barrier to SA-binding pathogens, such as influenza. This hypothesis is supported by the finding that, since diverging from our last common ancestor with apes (including chimpanzees, bonobos, gorillas, and orangutans), human beings have undergone a bidirectional switch in SA expression between airway epithelial cell surfaces (from α2,3-linked to α2,6-linked SA) and secreted mucins (from α2,6-linked to α2,3-linked SA).50 This switching could explain why chimpanzees are relatively resistant to experimental respiratory exposure to human influenza viruses,50 as has been described.59,60


    Click to enlarge image


    Figure 1. Interactions of avian and human influenza viruses with cells and soluble mucins of the eye and the respiratory tract Each set of four cells represents uninfected cells (left) and virus-infected cells at different stages, from viral attachment (second cell from the left) to cells releasing progeny virus (far right).




    The human eye bridges the species barrier

    A hitherto prevailing concept regarding the generation of pandemic influenza has been that human and avian influenza A viruses reassort and/or adapt mainly in pigs,61 where both α2,3-linked and α2,6-linked SA receptors are expressed in the respiratory tract, resulting in novel pathogenic strains with specificity for α2,6-linked SA. Studies also suggest that certain species of birds may be reservoirs in which influenza virus reassortants that recognise α2,6-linked SA-containing receptors arise.62?65 On the surface of the human respiratory epithelium, there is a predominance of α2,6-linked SA, whereas ciliated cells?a substantial cellular subset of the respiratory epithelium?seem to express α2,3-linked SA.48 Thus, ciliated cells in the human respiratory epithelium may serve directly as target cells for avian influenza A viruses. However, this hypothesis is not the sole possible explanation for the infectivity of avian influenza in human beings. The data presented by Koopmans and associates66 showed that there was a higher detection rate of H7N7 in eye swabs compared with throat swabs collected on the second day of illness. Also, conjunctivitis appeared before influenza-like illness in a secondary case that involved both ocular and respiratory disease during the Dutch outbreak of H7N7 in 2003.66 Taken together, these findings lead us to suggest another possibility: the establishment of α2,3 linked SA-specific avian influenza A virus in human beings, with the eye exposed to contaminated water, droplets, or fomites as a portal of entry, may be a first critical event. The next step may be an α2,3→α2,6 switch requiring as little as one or a few point mutations in haemagglutinin.67?69
    Once an avian influenza A virus is transferred from the eye to the respiratory tract of an individual co-infected with a human virus, probably via the nasolacrimal duct, or via self-inoculation (without excluding the possibility of viraemia), there is an increased risk of reassortment and/or adaptation, leading to a new α2,6-linked SA-specific and respiratory tract-tropic virus with the potential to initiate a pandemic. Experimental transmission of pharyngoconjunctival adenoviruses in human beings showed that inoculation of the conjunctiva readily caused both conjunctivitis and pharyngitis, whereas inoculation of the oropharynx resulted in no conjunctivitis and less pharyngitis.70
    Transfer of enveloped RNA viruses from the eye to other sites, including the respiratory tract, has been shown experimentally in primates.71,72 Influenza A virus given by the ocular route generated virus replication in the lungs of mice.73 We believe that the lacrimal route, via drainage of tear fluid including mucins and microbes from puncta in upper and lower eyelid through canaliculi to the lacrimal sac, and further through the nasolacrimal duct to the nasal cavity (figure 2), would be the major pathway available for avian influenza. During replication in the ocular tract there will be continuous influx of virions to the nasal cavity, and a respiratory infection may be established. Since the eye is of ectodermal origin and thereby immunoprivileged, the possibility of subclinical and/or prolonged influenza replication in the eye, followed by continuous transfer to the respiratory tract cannot be excluded. Thus, the likelihood of ligand adaptation to α2,6-linked SA increases even in the absence of co-infection with influenza of human origin. Unfortunately there is little known regarding viral transmission through?and interaction with?the nasolacrimal system. This system is rich in immunocompetent cells and in secretory goblet cells, and probably has an important role in microbial defence.53,54


    Click to enlarge image


    Figure 2. Possible transmission routes for avian influenza A particles replicating in the conjunctiva Transmission from the eye to the respiratory tract via the nasolacrimal duct (not drawn to scale).




    Conclusions

    Cases of zoonotic influenza caused by direct spread of avian influenza A viruses to human beings clearly occur in spite of the presumed low abundance of a suitable receptor in the respiratory tract. However, by contrast with human influenza, where ocular complications have been described only rarely,74 several case reports of zoonotic influenza have involved conjunctivitis. This is consistent with our hypothesis that, as with adenovirus 37 and enterovirus 70, ocular tropism of avian influenza viruses may be explained by their use of α2,3-linked SA as a receptor. Considering that the seroprevalence for avian influenza virus subtypes H4 to H13 in parts of southern China75 can reach 38% among rural dwellers, it is remarkable that human beings are not more frequent hosts for influenza virus reassortment, adaptation, and selection of novel pandemic strains. Nevertheless, human exposure to avian influenza A virus and outbreaks of zoonotic influenza are increasing, mainly of virulent H5 and H7 subtypes. Why subtypes other than H5 and H7 have not been associated with conjunctivitis in human beings is unclear. One explanation may be that other subtypes have not (yet) caused outbreaks of fowl plague on the scale of those of H5 and H7 subtypes. Another explanation may be a low surveillance for influenza virus in ocular infections. If the ongoing H5N1 epizootic situation in east Asia becomes endemic,76 it is likely that the number of zoonotic cases will increase. Consequently, with the presence of an ocular receptor for avian influenza in mind, we strongly recommend first, increased surveillance for influenza virus in ocular infections. and second, the use of eye protection when handling avian and zoonotic influenza, to minimise bird-to-human and human-to-human transmission, and to reduce the risk of a future pandemic.
    Conflict of interests
    We declare that we have no conflict of interests.


    Acknowledgments
    Sigvard Olofsson and Urban Kumlin contributed equally to this work. Niklas Arnberg is appointed by the Swedish Research Council and the Swedish Society for Medical Research.


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    <!--end simple-tail-->Affiliations

    a. Department of Clinical Virology, University of G?teborg, G?teborg, Sweden
    b. Department of Virology, Institute of Clinical Microbiology, Ume? University, Ume?, Sweden
    c. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada

    Correspondence to: Dr Niklas Arnberg, Department of Virology, Institute of Clinical Microbiology, Ume? University, SE-90185 Ume?, Sweden. Tel +46 90 7858440; fax +46 90 129905

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    Figure 1

    <TABLE class=popupBandContainer cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD class=popupAreaBody width="100%"><TABLE class=popupAreaContainer cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD class=popupPaneBody>

    Figure 1. Interactions of avian and human influenza viruses with cells and soluble mucins of the eye and the respiratory tract
    Each set of four cells represents uninfected cells (left) and virus-infected cells at different stages, from viral attachment (second cell from the left) to cells releasing progeny virus (far right).
    </TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE>

    Comment


    • #3
      Figure 2

      <TABLE class=popupBandContainer cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD class=popupAreaBody width="100%"><TABLE class=popupAreaContainer cellSpacing=0 cellPadding=0 width="100%" border=0><TBODY><TR><TD class=popupPaneBody>

      Figure 2. Possible transmission routes for avian influenza A particles replicating in the conjunctiva
      Transmission from the eye to the respiratory tract via the nasolacrimal duct (not drawn to scale).
      </TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE>

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