Background Human rhinoviruses (HRV) are associated with upper and lower respiratory illnesses, including severe infections causing hospitalization in both children and adults. Although the clinical significance of HRV infections is now well established, no detailed investigation of the immune response against HRV has been performed. The purpose of this study was to assess the IgG1 antibody response to the three known HRV species, HRV-A, -B and -C in healthy subjects. Methods Recombinant polypeptides of viral capsid protein 1 (VP1) from two genotypes of HRV-A, -B and -C were expressed as glutathione S-transferase (GST) fusion proteins and purified by affinity and then size exclusion chromatography. The presence of secondary structures similar to the natural antigens was verified by circular dichroism analysis. Total and species-specific IgG1 measurements were quantitated by immunoassays and immunoabsorption using sera from 63 healthy adults. Results Most adult sera reacted with the HRV VP1 antigens, at high titres. As expected, strong cross-reactivity between HRV genotypes of the same species was found. A high degree of cross-reactivity between different HRV species was also evident, particularly between HRV-A and HRV-C. Immunoabsorption studies revealed HRV-C specific titres were markedly and significantly lower than the HRV-A and HRV-B specific titres (P<0.0001). A truncated construct of HRV-C VP1 showed greater specificity in detecting anti-HRV-C antibodies. Conclusions High titres of IgG1 antibody were bound by the VP1 capsid proteins of HRV-A, -B and -C, but for the majority of people, a large proportion of the antibody to HRV-C was cross-reactive, especially to HRV-A. The improved specificity found for the truncated HRV-C VP1 indicates species-specific and cross-reactive regions could be defined.
References
[1]
M？kel？ MJ, Puhakka T, Ruuskanen O, Leinonen M, Saikku P, et al. (1998) Viruses and bacteria in the etiology of the common cold. J Clin Virol 36: 539–542.
[2]
Lau SKP, Yip CCY, Tsoi H, Lee RA, So L, et al. (2007) Clinical Features and Complete Genome Characterization of a Distinct Human Rhinovirus (HRV) Genetic Cluster, Probably Representing a Previously Undetected HRV Species, HRV-C, Associated with Acute Respiratory Illness in Children. J Clin Microbiol 45: 3655–3664.
[3]
Fry AM, Lu X, Olsen SJ, Chittaganpitch M, Sawatwong P, et al. (2011) Human rhinovirus infections in rural Thailand: epidemiological evidence for rhinovirus as both pathogen and bystander. PLoS One 6: e17780.
[4]
Ferguson PE, Gilroy NM, Faux CE, Mackay IM, Sloots TP, et al. (2013) Human rhinovirus C in adult haematopoietic stem cell transplant recipients with respiratory illness. J Clin Virol 56: 339–343.
[5]
Bizzintino J, Lee W, Laing I, Vang F, Pappas T, et al. (2011) Association between human rhinovirus C and severity of acute asthma in children. Eur Respir J 37: 1037–1042.
[6]
Hao W, Bernard K, Patel N, Ulbrandt N, Feng H, et al. (2012) Infection and Propagation of Human Rhinovirus C in Human Airway Epithelial Cells. J Virol 86: 13524–13532.
[7]
Granados A, Luinstra K, Chong S, Goodall E, Banh L, et al. (2012) Use of an improved quantitative polymerase chain reaction assay to determine differences in human rhinovirus viral loads in different populations. Diagn Microbiol Infect Dis 74: 384–387.
[8]
Kistler AL, Webster DR, Rouskin S, Magrini V, Credle JJ, et al. (2007) Genome-wide diversity and selective pressure in the human rhinovirus. Virol J 4: 40.
[9]
Barclay WS, Al-Nakib W, Higgins PG, Tyrrell DAJ (1989) The time course of the humoral immune response to rhinovirus infection. Epidemiol Infect 103: 659–669.
[10]
Butler WT, Waldmann TA, Rossen RD, Douglas Jr RG, Couch RB (1970) Changes in IgA and IgG concentrations in nasal secretions prior to the appearance of antibody during viral respiratory infection in man. J Immunol 105: 584–591.
[11]
Van Kempen M, Bachert C, Van Cauwenberge P (1999) An update on the pathophysiology of rhinovirus upper respiratory tract infections. Rhinology 37: 97–103.
[12]
Staneková Z, Vareckova E (2010) Conserved epitopes of influenza A virus inducing protective immunity and their prospects for universal vaccine development. Virol J 7: 351.
[13]
Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, et al. (2011) Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208: 181–193.
[14]
Weinfurter JT, Brunner K, Capuano SV, Li C, Broman KW, et al. (2011) Cross-reactive T cells are involved in rapid clearance of 2009 pandemic H1N1 influenza virus in nonhuman primates. PLoS Path 7: e1002381.
[15]
Kennedy JL, Turner RB, Braciale T, Heymann PW, Borish L (2012) Pathogenesis of rhinovirus infection. Curr Opin Virol 2: 287–293.
[16]
Laza-Stanca V, Stanciu LA, Message SD, Edwards MR, Gern JE, et al. (2006) Rhinovirus replication in human macrophages induces NF-kappaB-dependent tumor necrosis factor alpha production. J Virol 80: 8248–8258.
[17]
Gern JE, Brooks GD, Meyer P, Chang A, Shen K, et al. (2006) Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life. J Allergy Clin Immunol 117: 72–78.
[18]
Rossmann MG, Arnold E, Erickson JW, Frankenberger EA, Griffith JP, et al. (1985) Structure of a human common cold virus and functional relationship to other picornaviruses. Nature 317: 145–153.
[19]
Ledford RM, Patel NR, Demenczuk TM, Watanyar A, Herbertz T, et al. (2004) VP1 sequencing of all human rhinovirus serotypes: insights into genus phylogeny and susceptibility to antiviral capsid-binding compounds. J Virol 78: 3663–3674.
[20]
McErlean P, Shackelton LA, Lambert SB, Nissen MD, Sloots TP, et al. (2007) Characterisation of a newly identified human rhinovirus, HRV-QPM, discovered in infants with bronchiolitis. J Clin Virol 39: 67–75.
[21]
Hales BJ, Elliot CE, Chai LY, Pearce LJ, Tipayanon T, et al. (2013) Quantitation of IgE Binding to the Chitinase and Chitinase-Like House Dust Mite Allergens Der p 15 and Der p 18 Compared to the Major and Mid-Range Allergens. Int Arch Allergy Immunol 160: 233–240.
[22]
Whitmore L, Wallace BA (2008) Protein secondary structure analyses from circular dichroism spectroscopy: Methods and reference databases. Biopolymers 89: 392–400.
[23]
Lees JG, Miles AJ, Wien F, Wallace BA (2006) A reference database for circular dichroism spectroscopy covering fold and secondary structure space. Bioinformatics 22: 1955–1962.
[24]
Hales BJ, Chai LY, Elliot CE, Pearce LJ, Zhang G, et al. (2012) Antibacterial antibody responses associated with the development of asthma in house dust mite-sensitised and non-sensitised children. Thorax 67: 321–327.
[25]
Hales BJ, Bosco A, Mills KL, Hazell LA, Loh R, et al. (2004) Isoforms of the major peanut allergen Ara h 2: IgE binding in children with peanut allergy. Int Arch Allergy Immunol 135: 101–107.
[26]
Hales BJ, Pearce LJ, Kusel MMH, Holt PG, Sly PD, et al. (2008) Differences in the antibody response to a mucosal bacterial antigen between allergic and non-allergic subjects. Thorax 63: 221–227.
[27]
Ichikawa K, Vailes L, Pomes A, Chapman M (2001) Molecular cloning, expression and modelling of cat allergen, cystatin (Fel d 3), a cysteine protease inhibitor. Clinical & Experimental Allergy 31: 1279–1286.
[28]
Brockwell D, Yu L, Cooper S, Mccleland S, Cooper A, et al. (2001) Physicochemical consequences of the perdeuteriation of glutathione S-transferase from S. japonicum. Protein Sci 10: 572–580.
[29]
Kim S, Smith TJ, Chapman MS, Rossmann MG, Pevear DC, et al. (1989) Crystal structure of human rhinovirus serotype 1A (HRV1A). J Mol Biol 210: 91–111.
[30]
Zhang Y, Simpson AA, Ledford RM, Bator CM, Chakravarty S, et al. (2004) Structural and virological studies of the stages of virus replication that are affected by antirhinovirus compounds. J Virol 78: 11061–11069.
[31]
Aarntzen EH, de Vries IJM, G？ertz JH, Beldhuis-Valkis M, Brouwers HM, et al. (2012) Humoral anti-KLH responses in cancer patients treated with dendritic cell-based immunotherapy are dictated by different vaccination parameters. Cancer Immunol Immunother 61: 2003–2011.
[32]
Nabors GS, Braun PA, Herrmann DJ, Heise ML, Pyle DJ, et al. (2000) Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies to heterologous PspA molecules. Vaccine 18: 1743–1754.
[33]
Vance E, George S, Guinan E, Wheeler C, Antin J, et al. (1998) Comparison of multiple immunization schedules for Haemophilus influenzae type b-conjugate and tetanus toxoid vaccines following bone marrow transplantation. Bone Marrow Transplant 22: 735–741.
[34]
Semenova V, Steward-Clark E, Stamey K, Taylor T, Schmidt D, et al. (2004) Mass value assignment of total and subclass immunoglobulin G in a human standard anthrax reference serum. Clin Diagn Lab Immunol 11: 919–923.
[35]
McErlean P, Shackelton LA, Andrews E, Webster DR, Lambert SB, et al. (2008) Distinguishing molecular features and clinical characteristics of a putative new rhinovirus species, human rhinovirus C (HRV C). PLoS One 3: e1847.
[36]
Lau SKP, Yip CCY, Lin AWC, Lee RA, So LY, et al. (2009) Clinical and molecular epidemiology of human rhinovirus C in children and adults in Hong Kong reveals a possible distinct human rhinovirus C subgroup. J Infect Dis 200: 1096–1103.
[37]
Kim JH, Skountzou I, Compans R, Jacob J (2009) Original antigenic sin responses to influenza viruses. J Immunol 183: 3294–3301.
[38]
McIntyre CL, McWilliam Leitch EC, Savolainen-Kopra C, Hovi T, Simmonds P (2010) Analysis of genetic diversity and sites of recombination in human rhinovirus species C. J Virol. 84: 10297–10310.
[39]
Bochkov YA, Palmenberg AC, Lee WM, Rathe JA, Amineva SP, et al. (2011) Molecular modeling, organ culture and reverse genetics for a newly identified human rhinovirus C. Nat Med. 17: 627–632.
[40]
Ashraf S, Brockman-Schneider R, Bochkov YA, Pasic TR, Gern JE (2012) Biological characteristics and propagation of human rhinovirus-C in differentiated sinus epithelial cells. Virology 436: 143–149.
[41]
R？hm C, Zhou N, Süss J, Mackenzie J, Webster R (1996) Characterization of a novel influenza hemagglutinin, H15: criteria for determination of influenza A subtypes. Virology 217: 508–516.
[42]
Weghofer M, Dall’Antonia Y, Grote M, St？cklinger A, Kneidinger M, et al. (2008) Characterization of Der p 21, a new important allergen derived from the gut of house dust mites*. Allergy 63: 758–767.
[43]
Giranda VL, Heinz BA, Oliveira MA, Minor I, Kim KH, et al. (1992) Acid-induced structural changes in human rhinovirus 14: possible role in uncoating. Proc Natl Acad Sci U S A 89: 10213–10217.
[44]
Niespodziana K, Napora K, Cabauatan C, Focke-Tejkl M, Keller W, et al. (2012) Misdirected antibody responses against an N-terminal epitope on human rhinovirus VP1 as explanation for recurrent RV infections. FASEB J 26: 1001–1008.
