JAC Advance Access published online on November 19, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn468
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Letter to the Editor |
Influenza virus infection: don't forget the role of the mucociliary system!
Laboratoire de Bactériologie Médicale, Centre Hospitalier Universitaire de Dijon, 21070 Dijon Cedex, France
* Corresponding author. Tel: +33-380-293-523; Fax: +33-380-293-280; E-mail: jean-marie.duez{at}chu-dijon.fr
Key Words: sialic acid , sialidase , neuraminidase , mucus
In a recent issue, Zhang1 summarized the interest in animal models to study the relationship between the influenza virus and secondary pneumonias. We agree with the role of a preceding influenza infection in secondary pneumonia.2–4 Referring to studies by McCullers's group,5–7 Zhang speculated on the adherence of Streptococcus pneumoniae in the lungs after cleavage of sialic acid residues from the surface of host cells, exposing cryptic receptors to S. pneumoniae and allowing bacteria to adhere. However, he did not mention that McCullers stated in 2006, ‘the receptors that pneumococcus utilizes to adhere and invade in the lung are currently unknown’.8 As these receptors have been searched for, but not found, it is tempting to suggest that perhaps they do not exist. Thus, they cannot be a reason to predict risks in the case of the therapeutic use of a sialidase fusion protein.
In the same issue, Nicholls et al.9 supported the therapeutic use of sialidase fusion proteins. These authors made a clear distinction between the secondary S. pneumoniae infection in relation to a viral neuraminidase and the secondary effects of influenza virus infection in relation to airway epithelial damage, considering that, from a scientific point of view, only the latter was significant. In our opinion, this distinction is not appropriate because the disorders produced by viral neuraminidase are important components of the epithelial damage to the airway.
Both points of view are interesting but obviously incomplete:
- the physiological role of sialic acid receptors is to allow adherence of the mucus that protects the epithelial tissues from dehydration, microbial pathogens10–13 and reactive oxygen species produced by infectious bacteria and/or the oxidative burst of leucocytes;10,14
- the mucus line of defence comprises a viscoelastic gel that immobilizes bacteria and virus, which are then cleared by the ciliary movements;10,13
- mucoproteins are either secreted or membrane-tethered,10 and sialoglycoproteins mediate the cell adherence and the viscoelasticity of mucus, and serve as receptor sites for the binding of exogenous macromolecules;15
- viral sialidase (neuraminidase) seems to facilitate the spread of the virus by limiting their attachment to the cells and to mucus layers;12,16
- in the early stages of influenza infection, respiratory cells are modified: ciliary function decreases,8 viral neuraminidase is expressed at the surface of epithelial cells and the neuraminidase lowers the adhesion of mucus, leaving the cells unprotected and allowing bacteria to develop at their surface;
- statistically, in these circumstances, the first bacterium to invade airways is Haemophilus influenzae, probably as a consequence of adhesins expressed in non-typeable strains of H. influenzae,17,18 and as indicated by Pfeiffer's belief19 that it was the causative agent of influenza. However, other bacteria are very often encountered. These include S. pneumoniae, which was extensively studied because it was capsulated and more pathogenic,2–5,8,20 and occasionally, Staphylococcus aureus or streptococci.8,21
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1 . Zhang H. Concerns of using sialidase fusion protein as an experimental drug to combat seasonal and pandemic influenza. J Antimicrob Chemother (2008) 62:219–23.
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Van der Sluijs KF, van Elden LJ, Nijhuis M, et al. IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection. J Immunol (2004) 172:7603–9.
3 . LeVine AM, Koeningsknecht V, Stark JM. Decreased pulmonary clearance of S. pneumoniae following influenza A infection in mice. J Virol Methods (2001) 94:173–86.[CrossRef][Web of Science][Medline]
4 . Plotkowski MC, Puchelle E, Beck G, et al. Adherence of type I Streptococcus pneumoniae to tracheal epithelium of mice infected with influenza A/PR8 virus. Am Rev Respir Dis (1986) 134:1040–4.[Web of Science][Medline]
5 . McCullers JA, Bartmess KC. Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumoniae. J Infect Dis (2003) 187:1000–9.[CrossRef][Web of Science][Medline]
6 . McCullers JA. Effect of antiviral treatment on the outcome of secondary bacterial pneumonia after influenza. J Infect Dis (2004) 190:519–26.[CrossRef][Web of Science][Medline]
7 . Peltolla VT, McCullers JA. Respiratory viruses predisposing to viral infections: role of neuramidinase. Pediatr Infect Dis (2004) 23(Suppl_1):S87–97.
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McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev (2006) 19:571–82.
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Nicholls JM, Aschenbrenner LM, Paulson JC, et al. Comment on: Concerns of using sialidase fusion protein as an experimental drug to combat seasonal and pandemic influenza. J Antimicrob Chemother (2008) 62:426–30.
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Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev (2006) 86:245–78.
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12 . Schauer R. Victor Ginsburg's influence on my research of the role of sialic acids in biological recognition. Arch Biochem Biophys (2004) 426:132–41.[CrossRef][Medline]
13 . Slomiany BL, Murty VLN, Piotrowski J, et al. Salivary mucins in oral mucosal defense. Gen Pharmacol (1996) 27:761–71.[Medline]
14 . Ogasawara Y, Namai T, Yoshino F, et al. Sialic acid is an essential moiety of mucin as a hydroxyl radical scavenger. FEBS Lett (2007) 581:2473–7.[Medline]
15 . Yoon JH, Kim KS, Kim SS, et al. Sialoglycoproteins and penultimate sugar expression pattern in developing murine olfactory and respiratory mucosa. Yonsei Med J (1998) 39:20–6.[Medline]
16 . Bianco A, Melchioni C. Neuraminic acid—structure, chemistry, biological activity. Stud Nat Prod Chem (2002) 27:103–54.
17 . Giufre M, Carattoli A, Cardines R, et al. Variation in expression of HMW1 and HMW2 adhesins in invasive nontypeable Haemophilus influenzae isolates. BMC Microbiol (2008) 8:1–7.[Medline]
18 . Davies J, Carlstedt I, Nilsson AK, et al. Binding of Haemophilus influenzae to purified mucins from the human respiratory tract. Infect Immun (1995) 63:2485–92.[Abstract]
19 . Pfeiffer R. Aus dem Institut für Mittheilungen über die Erreger der Influenza [From the Institute for Infectious Diseases. II. Provisional communication on the cause of influenza]. Deutsche Medicinishche Wochenschrift (1892) 18:28.
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Peltola VT, Boyd KL, McAuley JL, et al. Bacterial sinusitis and otitis media following influenza virus infection in ferrets. Infect Immun (2006) 74:2562–7.
21 . Brundage JF, Shanks GD. Deaths from bacterial pneumonia during 1918–19 influenza pandemic. Emerg Infect Dis (2008) 14:1193–9.[Medline]
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