The role of human rhinovirus in immunology, COPD, and corresponding treatments

Abstract

The common cold is most often a result of human rhinovirus (HRV) infection. Common cold symptoms including rhinorrhea and nasal obstruction frequently occur during HRV infection of the upper respiratory tract. Conversely, HRV may also infect the epithelial cells of the lower respiratory tract. Symptom severity associated with HRV infection ranges from mild to potentially serious depending on a person’s susceptibility and pre-existing condition, such as chronic obstructive pulmonary disease. An over active host immune response is believed to be the primary contributor to HRV pathogenesis. Enhanced activity of various host cell cytokines and granulocytes mediate specific cellular pathways inducing many of the symptoms associated with HRV infection. There are over 100 serotypes of HRV which can be further categorized based on the specific characteristics of each type. The two main categories of HRV consist of the major and minor groups. The unique host cell receptor is the distinguishing factor between these two groups. Yet, these viruses may also differ in mechanism of infection and replication. Due to the high frequency of hospital and clinical visits and the corresponding economic burden, novel therapies are of interest. Several different treatment options varying from herbal remedies to anti-viral drugs have been studied. However, the vast number of HRV serotypes complicates the progress of developing a universal treatment for attenuating HRV infection.

Keywords

human rhinovirus / common cold / immunology / COPD

References

[1] Alper C M, Doyle W J, Skoner D P, Buchman C A, Cohen S, Gwaltney J M (1998). Prechallenge antibodies moderate disease expression in adults experimentally exposed to rhinovirus strain hanks. Clin Infect Dis, 27(1): 119–128

[2] Alper C M, Doyle W J, Skoner D P, Buchman C A, Seroky J T, Gwaltney J M, Cohen S A (1996). Prechallenge antibodies: moderators of infection rate, signs, and symptoms in adults experimentally challenged with rhinovirus type 39. Laryngoscope, 106(10): 1298–1305

[3] Andries K, Dewindt B, Snoeks J, Wouters L, Moereels H, Lewi P J, Janssen P A (1990). Two groups of rhinoviruses revealed by a panel of antiviral compounds present sequence divergence and differential pathogenicity. J Virol, 64(3): 1117–1123

[4] Arruda E, Pitkäranta A, Witek T J Jr, Doyle C A, Hayden F G (1997). Frequency and natural history of rhinovirus infections in adults during autumn. J Clin Microbiol, 35(11): 2864–2868

[5] Barral P M, Sarkar D, Fisher P B, Racaniello V R (2009). RIG-I is cleaved during picornavirus infection. Virology, 391(2): 171–176

[6] Bella J, Rossmann M G (2000). ICAM-1 receptors and cold viruses. Pharm Acta Helv, 74(2-3): 291–297

[7] Binford S L, Maldonado F, Brothers M A, Weady P T, Zalman L S, Meador J W 3rd, Matthews D A, Patick A K (2005). Conservation of amino acids in human rhinovirus 3C protease correlates with broad-spectrum antiviral activity of rupintrivir, a novel human rhinovirus 3C protease inhibitor. Antimicrob Agents Chemother, 49(2): 619–626

[8] Bochkov Y A, Palmenberg A C, Lee W M, Rathe J A, Amineva S P, Sun X, Pasic T R, Jarjour N N, Liggett S B, Gern J E (2011). Molecular modeling, organ culture and reverse genetics for a newly identified human rhinovirus C. Nat Med, 17(5): 627–632

[9] Brabec M, Schober D, Wagner E, Bayer N, Murphy R F, Blaas D, Fuchs R (2005). Opening of size-selective pores in endosomes during human rhinovirus serotype 2 in vivo uncoating monitored by single-organelle flow analysis. J Virol, 79(2): 1008–1016

[10] Brabec-Zaruba M, Pfanzagl B, Blaas D, Fuchs R (2009). Site of human rhinovirus RNA uncoating revealed by fluorescent in situ hybridization. J Virol, 83(8): 3770–3777

[11] Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C, and the TRial of Inhaled STeroids ANd long-acting beta2 agonists study group (2003). Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet, 361(9356): 449–456

[12] Casaburi R, Mahler D A, Jones P W, Wanner A, San P G, ZuWallack R L, Menjoge S S, Serby C W, Witek T Jr (2002). A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J, 19(2): 217–224

[13] Colonno R J, Callahan P L, Long W J (1986). Isolation of a monoclonal antibody that blocks attachment of the major group of human rhinoviruses. J Virol, 57(1): 7–12

[14] De Palma A M, Vliegen I, De Clercq E, Neyts J (2008). Selective inhibitors of picornavirus replication. Med Res Rev, 28(6): 823–884

[15] Di Pierro F, Rapacioli G, Ferrara T, Togni S (2012). Use of a standardized extract from Echinacea angustifolia (Polinacea) for the prevention of respiratory tract infections. Altern Med Rev, 17(1): 36–41

[16] Donaldson G C, Seemungal T A, Bhowmik A, Wedzicha J A (2002). Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax, 57(10): 847–852

[17] Douglas R M, Hemilä H, Chalker E, Treacy B (2007). Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev, (3): CD000980

[18] Douglass J A, Dhami D, Gurr C E, Bulpitt M, Shute J K, Howarth P H, Lindley I J, Church M K, Holgate S T (1994). Influence of interleukin-8 challenge in the nasal mucosa in atopic and nonatopic subjects. Am J Respir Crit Care Med, 150(4): 1108–1113

[19] Drahos J, Racaniello V R (2009). Cleavage of IPS-1 in cells infected with human rhinovirus. J Virol, 83(22): 11581–11587

[20] Edwards M R, Hewson C A, Laza-Stanca V, Lau H T, Mukaida N, Hershenson M B, Johnston S L (2007). Protein kinase R, IkappaB kinase-beta and NF-kappaB are required for human rhinovirus induced pro-inflammatory cytokine production in bronchial epithelial cells. Mol Immunol, 44(7): 1587–1597

[21] Fashner J, Ericson K, Werner S (2012). Treatment of the common cold in children and adults. Am Fam Physician, 86(2): 153–159

[22] Fehniger T A, Caligiuri M A (2001). Interleukin 15: biology and relevance to human disease. Blood, 97(1): 14–32

[23] Fraenkel D J, Bardin P G, Sanderson G, Lampe F, Johnston S L, Holgate S T (1995). Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am J Respir Crit Care Med, 151(3 Pt 1): 879–886

[24] Fuchs R, Blaas D (2010). Uncoating of human rhinoviruses. Rev Med Virol, 20(5): 281–297

[25] Gavala M L, Bertics P J, Gern J E (2011). Rhinoviruses, allergic inflammation, and asthma. Immunol Rev, 242(1): 69–90

[26] Giranda V L, Heinz B A, Oliveira M A, Minor I, Kim K H, Kolatkar P R, Rossmann M G, Rueckert R R (1992). Acid-induced structural changes in human rhinovirus 14: possible role in uncoating. Proc Natl Acad Sci USA, 89(21): 10213–10217

[27] Gwaltney J M Jr, Hendley J O, Simon G, Jordan W S Jr (1967). Rhinovirus infections in an industrial population. II. Characteristics of illness and antibody response. JAMA, 202(6): 494–500

[28] Haghighat A, Svitkin Y, Novoa I, Kuechler E, Skern T, Sonenberg N (1996). The eIF4G-eIF4E complex is the target for direct cleavage by the rhinovirus 2A proteinase. J Virol, 70(12): 8444–8450

[29] Harris J M 2nd, Gwaltney J M Jr (1996). Incubation periods of experimental rhinovirus infection and illness. Clin Infect Dis, 23(6): 1287–1290

[30] Hayden F G, Gwaltney J M Jr, Colonno R J (1988). Modification of experimental rhinovirus colds by receptor blockade. Antiviral Res, 9(4): 233–247

[31] Hemilä H (1996). Vitamin C and common cold incidence: a review of studies with subjects under heavy physical stress. Int J Sports Med, 17(5): 379–383

[32] Hemilä H (1997). Vitamin C intake and susceptibility to the common cold. Br J Nutr, 77(1): 59–72

[33] Hendley J O, Gwaltney J M Jr (1988). Mechanisms of transmission of rhinovirus infections. Epidemiol Rev, 10: 243–258

[34] Hewson C A, Jardine A, Edwards M R, Laza-Stanca V, Johnston S L (2005). Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells. J Virol, 79(19): 12273–12279

[35] Jakiela B, Brockman-Schneider R, Amineva S, Lee W M, Gern J E (2008). Basal cells of differentiated bronchial epithelium are more susceptible to rhinovirus infection. Am J Respir Cell Mol Biol, 38(5): 517–523

[36] Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O, Akira S (2005). Cell type-specific involvement of RIG-I in antiviral response. Immunity, 23(1): 19–28

[37] Kaul P, Biagioli M C, Singh I, Turner R B (2000). Rhinovirus-induced oxidative stress and interleukin-8 elaboration involves p47-phox but is independent of attachment to intercellular adhesion molecule-1 and viral replication. J Infect Dis, 181(6): 1885–1890

[38] Kelly J T, Busse W W (2008). Host immune responses to rhinovirus: Mechanisms in asthma. J Allergy Clin Immunol, 122: 671–682; quiz 683–674

[39] Kennedy J L, Turner R B, Braciale T, Heymann P W, Borish L (2012). Pathogenesis of rhinovirus infection. Curr Opin Virol, 2(3): 287–293

[40] Khan A G, Pichler J, Rosemann A, Blaas D (2007). Human rhinovirus type 54 infection via heparan sulfate is less efficient and strictly dependent on low endosomal pH. J Virol, 81(9): 4625–4632

[41] Kim J, Sanders S P, Siekierski E S, Casolaro V, Proud D (2000). Role of NF-kappa B in cytokine production induced from human airway epithelial cells by rhinovirus infection. J Immunol, 165(6): 3384–3392

[42] Kim W K, Gern J E (2012). Updates in the relationship between human rhinovirus and asthma. Allergy Asthma Immunol Res, 4(3): 116–121

[43] Ko F W, Ip M, Chan P K, Ng S S, Chau S S, Hui D S (2008). A one-year prospective study of infectious etiology in patients hospitalized with acute exacerbations of COPD and concomitant pneumonia. Respir Med, 102(8): 1109–1116

[44] Laine P, Blomqvist S, Savolainen C, Andries K, Hovi T (2006). Alignment of capsid protein VP1 sequences of all human rhinovirus prototype strains: conserved motifs and functional domains. J Gen Virol, 87(Pt 1): 129–138

[45] Levandowski R A, Ou D W, Jackson G G (1986). Acute-phase decrease of T lymphocyte subsets in rhinovirus infection. J Infect Dis, 153(4): 743–748

[46] Liebig H D, Ziegler E, Yan R, Hartmuth K, Klump H, Kowalski H, Blaas D, Sommergruber W, Frasel L, Lamphear B, (1993). Purification of two picornaviral 2A proteinases: interaction with eIF-4 gamma and influence on in vitro translation. Biochemistry, 32(29): 7581–7588

[47] Lopez-Souza N, Dolganov G, Dubin R, Sachs L A, Sassina L, Sporer H, Yagi S, Schnurr D, Boushey H A, Widdicombe J H (2004). Resistance of differentiated human airway epithelium to infection by rhinovirus. Am J Physiol Lung Cell Mol Physiol, 286(2): L373–L381

[48] Mallia P, Message S D, Gielen V, Contoli M, Gray K, Kebadze T, Aniscenko J, Laza-Stanca V, Edwards M R, Slater L, Papi A, Stanciu L A, Kon O M, Johnson M, Johnston S L (2011). Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am J Respir Crit Care Med, 183(6): 734–742

[49] Mallia P, Message S D, Kebadze T, Parker H L, Kon O M, Johnston S L (2006). An experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study. Respir Res, 7(1): 116

[50] Marlin S D, Staunton D E, Springer T A, Stratowa C, Sommergruber W, Merluzzi V J (1990). A soluble form of intercellular adhesion molecule-1 inhibits rhinovirus infection. Nature, 344(6261): 70–72

[51] McManus T E, Marley A M, Baxter N, Christie S N, O’Neill H J, Elborn J S, Coyle P V, Kidney J C (2008). Respiratory viral infection in exacerbations of COPD. Respir Med, 102(11): 1575–1580

[52] Message S D, Johnston S L (2001). The immunology of virus infection in asthma. Eur Respir J, 18(6): 1013–1025

[53] Mukaida N, Okamoto S, Ishikawa Y, Matsushima K (1994). Molecular mechanism of interleukin-8 gene expression. J Leukoc Biol, 56(5): 554–558

[54] Müller-Jakic B, Breu W, Pröbstle A, Redl K, Greger H, Bauer R (1994). In vitro inhibition of cyclooxygenase and 5-lipoxygenase by alkamides from Echinacea and Achillea species. Planta Med, 60(1): 37–40

[55] Newcomb D C, Sajjan U, Nanua S, Jia Y, Goldsmith A M, Bentley J K, Hershenson M B (2005). Phosphatidylinositol 3-kinase is required for rhinovirus-induced airway epithelial cell interleukin-8 expression. J Biol Chem, 280(44): 36952–36961

[56] Niewoehner D E (2002). The role of systemic corticosteroids in acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Med, 1(4): 243–248

[57] Olson N H, Kolatkar P R, Oliveira M A, Cheng R H, Greve J M, McClelland A, Baker T S, Rossmann M G (1993). Structure of a human rhinovirus complexed with its receptor molecule. Proc Natl Acad Sci USA, 90(2): 507–511

[58] Papadopoulos N G, Bates P J, Bardin P G, Papi A, Leir S H, Fraenkel D J, Meyer J, Lackie P M, Sanderson G, Holgate S T, Johnston S L (2000). Rhinoviruses infect the lower airways. J Infect Dis, 181(6): 1875–1884

[59] Papi A, Bellettato C M, Braccioni F, Romagnoli M, Casolari P, Caramori G, Fabbri L M, Johnston S L (2006). Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med, 173(10): 1114–1121

[60] Papi A, Contoli M, Gasparini P, Bristot L, Edwards M R, Chicca M, Leis M, Ciaccia A, Caramori G, Johnston S L, Pinamonti S (2008). Role of xanthine oxidase activation and reduced glutathione depletion in rhinovirus induction of inflammation in respiratory epithelial cells. J Biol Chem, 283(42): 28595–28606

[61] Papi A, Papadopoulos N G, Stanciu L A, Bellettato C M, Pinamonti S, Degitz K, Holgate S T, Johnston S L (2002). Reducing agents inhibit rhinovirus-induced up-regulation of the rhinovirus receptor intercellular adhesion molecule-1 (ICAM-1) in respiratory epithelial cells. FASEB J, 16(14): 1934–1936

[62] Pappas D E, Hendley J O, Hayden F G, Winther B (2008). Symptom profile of common colds in school-aged children. Pediatr Infect Dis J, 27(1): 8–11

[63] Patick A K, Brothers M A, Maldonado F, Binford S, Maldonado O, Fuhrman S, Petersen A, Smith G J 3rd, Zalman L S, Burns-Naas L A, Tran J Q (2005).In vitro antiviral activity and single-dose pharmacokinetics in humans of a novel, orally bioavailable inhibitor of human rhinovirus 3C protease. Antimicrob Agents Chemother, 49(6): 2267–2275

[64] Potena A, Caramori G, Casolari P, Contoli M, Johnston S L, Papi A (2007). Pathophysiology of viral-induced exacerbations of COPD. Int J Chron Obstruct Pulmon Dis, 2(4): 477–483

[65] Prchla E, Plank C, Wagner E, Blaas D, Fuchs R (1995). Virus-mediated release of endosomal content in vitro: different behavior of adenovirus and rhinovirus serotype 2. J Cell Biol, 131(1): 111–123

[66] Rabin R L, Park M K, Liao F, Swofford R, Stephany D, Farber J M (1999). Chemokine receptor responses on T cells are achieved through regulation of both receptor expression and signaling. J Immunol, 162(7): 3840–3850

[67] Retamales I, Elliott W M, Meshi B, Coxson H O, Pare P D, Sciurba F C, Rogers R M, Hayashi S, Hogg J C (2001). Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med, 164(3): 469–473

[68] Rollinger J M, Schmidtke M (2011). The human rhinovirus: human-pathological impact, mechanisms of antirhinoviral agents, and strategies for their discovery. Med Res Rev, 31(1): 42–92

[69] Sajjan U S, Jia Y, Newcomb D C, Bentley J K, Lukacs N W, LiPuma J J, Hershenson M B (2006). H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression. FASEB J, 20(12): 2121–2123

[70] Sasazuki S, Sasaki S, Tsubono Y, Okubo S, Hayashi M, Tsugane S (2006). Effect of vitamin C on common cold: randomized controlled trial. Eur J Clin Nutr, 60(1): 9–17

[71] Savolainen-Kopra C, Korpela T, Simonen-Tikka M L, Amiryousefi A, Ziegler T, Roivainen M, Hovi T (2012). Single treatment with ethanol hand rub is ineffective against human rhinovirus—hand washing with soap and water removes the virus efficiently. J Med Virol, 84(3): 543–547

[72] Schneider W J, Nimpf J (2003). LDL receptor relatives at the crossroad of endocytosis and signaling. Cell Mol Life Sci, 60(5): 892–903

[73] Science M, Johnstone J, Roth D E, Guyatt G, Loeb M (2012). Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. CMAJ, 184(10): E551–E561

[74] Skern T, Torgersen H, Auer H, Kuechler E, Blaas D (1991). Human rhinovirus mutants resistant to low pH. Virology, 183(2): 757–763

[75] Slater L, Bartlett N W, Haas J J, Zhu J, Message S D, Walton R P, Sykes A, Dahdaleh S, Clarke D L, Belvisi M G, Kon O M, Fujita T, Jeffery P K, Johnston S L, Edwards M R (2010). Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium. PLoS Pathog, 6(11): e1001178

[76] Snyers L, Zwickl H, Blaas D (2003). Human rhinovirus type 2 is internalized by clathrin-mediated endocytosis. J Virol, 77(9): 5360–5369

[77] Sommergruber W, Ahorn H, Klump H, Seipelt J, Zoephel A, Fessl F, Krystek E, Blaas D, Kuechler E, Liebig H D, Skern T (1994). 2A proteinases of coxsackie- and rhinovirus cleave peptides derived from eIF-4 gamma via a common recognition motif. Virology, 198(2): 741–745

[78] Strickland D K, Gonias S L, Argraves W S (2002). Diverse roles for the LDL receptor family. Trends Endocrinol Metab, 13(2): 66–74

[79] Sullivan S D, Ramsey S D, Lee T A (2000). The economic burden of COPD. Chest, 117(2 Suppl): 5S–9S

[80] Triantafilou K, Vakakis E, Richer E A, Evans G L, Villiers J P, Triantafilou M (2011). Human rhinovirus recognition in non-immune cells is mediated by Toll-like receptors and MDA-5, which trigger a synergetic pro-inflammatory immune response. Virulence, 2(1): 22–29

[81] Turner R B (2001). The treatment of rhinovirus infections: progress and potential. Antiviral Res, 49(1): 1–14

[82] Turner R B, Hendley J O (2005). Virucidal hand treatments for prevention of rhinovirus infection. J Antimicrob Chemother, 56(5): 805–807

[83] Turner R B, Hendley J O, Gwaltney J M Jr (1982). Shedding of infected ciliated epithelial cells in rhinovirus colds. J Infect Dis, 145(6): 849–853

[84] Turner R B, Wecker M T, Pohl G, Witek T J, McNally E, St George R, Winther B, Hayden F G (1999). Efficacy of tremacamra, a soluble intercellular adhesion molecule 1, for experimental rhinovirus infection: a randomized clinical trial. JAMA, 281(19): 1797–1804

[85] Turner R B, Weingand K W, Yeh C H, Leedy D W (1998). Association between interleukin-8 concentration in nasal secretions and severity of symptoms of experimental rhinovirus colds. Clin Infect Dis, 26(4): 840–846

[86] Tyrrell D A, Cohen S, Schlarb J E (1993). Signs and symptoms in common colds. Epidemiol Infect, 111(1): 143–156

[87] Uncapher C R, DeWitt C M, Colonno R J (1991). The major and minor group receptor families contain all but one human rhinovirus serotype. Virology, 180(2): 814–817

[88] Vlasak M, Roivainen M, Reithmayer M, Goesler I, Laine P, Snyers L, Hovi T, Blaas D (2005). The minor receptor group of human rhinovirus (HRV) includes HRV23 and HRV25, but the presence of a lysine in the VP1 HI loop is not sufficient for receptor binding. J Virol, 79(12): 7389–7395

[89] Wang Q, Nagarkar D R, Bowman E R, Schneider D, Gosangi B, Lei J, Zhao Y, McHenry C L, Burgens R V, Miller D J, Sajjan U, Hershenson M B (2009). Role of double-stranded RNA pattern recognition receptors in rhinovirus-induced airway epithelial cell responses. J Immunol, 183(11): 6989–6997

[90] Wat D, Gelder C, Hibbitts S, Cafferty F, Bowler I, Pierrepoint M, Evans R, Doull I (2008). The role of respiratory viruses in cystic fibrosis. J Cyst Fibros, 7(4): 320–328

[91] Wilkinson T M, Hurst J R, Perera W R, Wilks M, Donaldson G C, Wedzicha J A (2006). Effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of COPD. Chest, 129(2): 317–324

[92] Winther B, Arruda E, Witek T J, Marlin S D, Tsianco M M, Innes D J, Hayden F G (2002). Expression of ICAM-1 in nasal epithelium and levels of soluble ICAM-1 in nasal lavage fluid during human experimental rhinovirus infection. Arch Otolaryngol Head Neck Surg, 128(2): 131–136

[93] Winther B, Greve J M, Gwaltney J M Jr, Innes D J, Eastham J R, McClelland A, Hendley J O (1997). Surface expression of intercellular adhesion molecule 1 on epithelial cells in the human adenoid. J Infect Dis, 176(2): 523–525

[94] Winther B, McCue K, Ashe K, Rubino J R, Hendley J O (2007). Environmental contamination with rhinovirus and transfer to fingers of healthy individuals by daily life activity. J Med Virol, 79(10): 1606–1610

[95] Xing L, Casasnovas J M, Cheng R H (2003). Structural analysis of human rhinovirus complexed with ICAM-1 reveals the dynamics of receptor-mediated virus uncoating. J Virol, 77(11): 6101–6107

[96] Xing L, Tjarnlund K, Lindqvist B, Kaplan G G, Feigelstock D, Cheng R H, Casasnovas J M (2000). Distinct cellular receptor interactions in poliovirus and rhinoviruses. EMBO J, 19(6): 1207–1216

[97] Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo Y M, Gale M Jr, Akira S, Yonehara S, Kato A, Fujita T (2005). Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol, 175(5): 2851–2858

[98] Zalman L S, Brothers M A, Dragovich P S, Zhou R, Prins T J, Worland S T, Patick A K (2000). Inhibition of human rhinovirus-induced cytokine production by AG7088, a human rhinovirus 3C protease inhibitor. Antimicrob Agents Chemother, 44(5): 1236–1241

Acknowledgements

This work is supported by grants of OU General Fund G110 and Research Excellence Fund of Biomedical Research and OSUMC Fund 013000. We thank the assistance of Yen Nguyen and Allison Hallman.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg