Viral Infections, Allergy and Asthma, the Snot Thickens
Published on March 21, 2016
Viral Infections, Allergy and Asthma, the Snot Thickens
Efren Rael1, Arram Noshirvan2, and Andrew J. Long3
1Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, USA
2Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, USA
3California Pacific Medical Center/Stanford Lucille Packard Children’s Hospital Allergy and Asthma Clinic, Stanford University School of Medicine, USA
Corresponding author: Efren Rael, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, USA, E-mail: email@example.com
Citation: Rael E, Noshirvan A, Long AJ (2016) Viral Infections, Allergy and Asthma, the Snot Thickens. J Resp Dis 1(1): 102.
Allergic Associations with Viral Infections
Asthma exacerbations account for more than 1.5 million emergency room visits per year, more than half a million hospitalizations, and thousands of deaths annually in the United States . Viral infections in conjunction with allergy, increase asthma risk and are thought to account for an estimated 90% of pediatric, 75% of adult, acute clinical asthma events [1,2].
Rhinovirus (RV) is thought to account for 50-70% of virus associated asthma exacerbations [3,4]. Greater than 100 rhinovirus strains exist. Variable global infection rates and viral strains may account for population susceptibility differences. In a Brazilian cohort, rhinovirus was associated with 18.7% of pathogens identified in nasopharyngeal aspirates, implicating Rhinovirus-A vs Rhinovirus-C viral subtype in 23% vs. 5% respectively, p = 0.04, of asthma flares . In a Mexican cohort, Rhinovirus-C was associated with asthma, but not Rhinovirus-A or B serotypes .
Table 1: Known Infectious agents associated with asthma flares
Virus associated hospitalization rates, in children under five years, are similar for Humman metapnuemovirus (HMPV), influenza virus, the combination of parainfluenza virus types 1-3 at 1:1000 children and highest for RSV at 3:1000 children .
A clearer understanding of immune pathways responsible for synergistic viral and allergic responses might provide novel opportunities at interventions aimed at improving patient outcomes. Below, are recent papers that highlight cytokine networks bridging allergies, infections, and asthma.
Interleukin 25 (IL-25)
IL-25, along with other IL-17 family members, binds a heterodimeric receptor composed of IL-17RA and IL-17RB. In contrast to other IL-17 family members, IL-25 receptor activation uniquely induces allergic Th2 cytokine expression. Specifically, IL-25 promotes innate lymphoid type 2 (ILC2) cell stimulation and differentiation, and promotes production of allergy associated Th2 cytokines IL-5 and IL-13. In addition to ILC2 cells, IL-25 is also produced by eosinophils, mast cells, epithelial cells, and polarized Th2 cells, all allergy associated cells.
Comparing asthmatics non-asthmatic respiratory epithelium, asthmatics produce higher IL-25 levels in RV infection, leading to eosinophil and neutrophil recruitment and the association with more severe asthma . Blockade of IL-25 signaling via IL-17RB neutralization, abrogates RV associated asthma symptoms in mice .
Interleukin 33 (IL-33)
IL-33, primarily expressed in the epithelial cell nucleus and a member of the IL-1 family, is released from damaged cells and activates Th2 cells including mast cells, eosinophils, basophils and polarized Th2 cells via the IL-33 receptor, a heterodimer of ST2 and IL-1 receptor-like 1 (IL-1RAcP) . Multiple viruses associated with respiratory disease, activate IL-33, including RV, RSV, influenza, and parainfluenza [10-12].
RSV infection promotes IL-33 expression resulting in lung ILC2 and Th2 cell induction . However, compared to adults, the increase in IL-33 is much greater in neonates when the infection is severe . Influenza H3N1 induces expression of lung IL-33 by alveolar macrophages, independent of Th2 cell, NKT cell and adaptive immune mechanisms . Interestingly, H3N1, does not affect IL-33 expression from airway epithelial cells .
RV infection increases IL- 25 and IL-33 expression and can induce ILC2s and Th2 cells . IL-25 induction occurs in neonates when infections are severe. Patients who experience severe RSV or RV infections as an infant have a greater chance to develop asthma later in life [10,14].
Thymic Stromal Lymphopoietin (TSLP)
TSLP is expressed in skin, gut and lung epithelial cells and is responsible for TH2 promotion . Human airway epithelial cell infection with RSV or RV leads to increased expression of TSLP through activation of nuclear factor kappa B . TSLP is increased in infected epithelial cells from asthmatic children vs. non-asthmatic children in RV and in RSV infection . Human metapneumovirus also induces TSLP expression in human airway epithelial cells . Parainfluenza virus infection is not known to be associated with TSLP induction .
Variation in viral responses has yet to be elucidated. It is unclear if there are different cytokine networks activated in response to different viruses and within serotypes of viruses. Pathway activation appears to be age determinant. Moreover, infection can alter induction of tolerance to allergens.
RV respiratory epithelium infection can block aeroallergen tolerance via induction of IL-33, TSLP and OX40 ligand as well as predispose to asthma inflammation .
Anti-IL33, anti-TSLP and anti-17RA (IL-25 shared receptor) monoclonal antibodies are in, or are being evaluated for clinical trial.
Table 2: Monoclonal antibodies under clinical trial evaluation
- Custovic A, Johnston SL, Pavord I, Gaga M, Fabbri L, Bel EH, et al. EAACI position statement on asthma exacerbations and severe asthma. Allergy. 2013;68(12):1520-31. doi: 10.1111/all.12275.
- Busse WW, Lemanske RF Jr, Gern JE. Role of viral respiratory infections in asthma and asthma exacerbations. Lancet. 2010;376(9743):826-34. doi: 10.1016/S0140-6736(10)61380-3.
- Kennedy JL, Shaker M, McMeen V, Gern J, Carper H, Murphy D, et al. Comparison of viral load in individuals with and without asthma during infections with rhinovirus. Am J RespirCrit Care Med. 2014;189(5):532-9. doi: 10.1164/rccm.201310-1767OC.
- Soto-Quiros M, Avila L, Platts-Mills TA, Hunt JF, Erdman DD, Carper H, et al. High titers of IgE antibody to dust mite allergen and risk for wheezing among asthmatic children infected with rhinovirus. J Allergy ClinImmunol. 2012;129(6):1499-1505.e5. doi: 10.1016/j.jaci.2012.03.040.
- Fawkner-Corbett DW, Khoo SK, Duarte CM, Bezerra PG, Bochkov YA, Gern JE4, et al. Rhinovirus-C detection in children presenting with acute respiratory infection to hospital in Brazil. J Med Virol. 2016;88(1):58-63. doi: 10.1002/jmv.24300.
- Moreno-Valencia Y, Hernandez-Hernandez VA, Romero-Espinoza JA, Coronel-Tellez RH, Castillejos-Lopez M, Hernandez A, et al. Detection and Characterization of respiratory viruses causing Acute Respiratory Illness and Asthma Exacerbation in children during Three Different Season (2011-2014) in Mexico City. Influenza Other Respir Viruses. 2015. doi: 10.1111/irv.12346.
- Edwards KM, Zhu Y, Griffin MR, Weinberg GA, Hall CB, Szilagyi PG, Staat MA, et al. Burden of human metapneumovirus infection in young children. N Engl J Med. 2013;368(7):633-43. doi: 10.1056/NEJMoa1204630.
- Beale J, Jayaraman A, Jackson DJ, Macintyre JD, Edwards MR, Walton RP, et al. Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation. SciTransl Med. 2014;6(256):256ra134. doi: 10.1126/scitranslmed.3009124.
- Nakae S, Morita H, Ohno T, Arae K, Matsumoto K, Saito H. Role of interleukin-33 in innate-type immune cells in allergy. Allergol Int. 2013;62(1):13-20. doi: 10.2332/allergolint.13-RAI-0538.
- Saravia J, You D, Shrestha B, Jaligama S, Siefker D, Lee GI, et al. Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33. PLoSPathog. 2015;11(10):e1005217. doi: 10.1371/journal.ppat.1005217.
- Chang YJ, Kim HY, Albacker LA, Baumgarth N, McKenzie AN, Smith DE, et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol. 2011;12(7):631-8. doi: 10.1038/ni.2045.
- Holtzman MJ, Byers DE, Brett JA, Patel AC, Agapov E, Jin X, et al. Linking acute infection to chronic lung disease. The role of IL-33-expressing epithelial progenitor cells. Ann Am Thorac Soc. 2014;11Suppl 5:S287-91. doi: 10.1513/AnnalsATS.201402-056AW.
- Jackson DJ, Makrinioti H, Rana BM, Shamji BW, Trujillo-Torralbo MB, Footitt J, et al. IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo. Am J RespirCrit Care Med. 2014;190(12):1373-82. doi: 10.1164/rccm.201406-1039OC.
- Hong JY, Bentley JK, Chung Y, Lei J, Steenrod JM, Chen Q, et al. Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells. J Allergy ClinImmunol. 2014;134(2):429-39. doi: 10.1016/j.jaci.2014.04.020.
- Lee HC, Headley MB, Loo YM, Berlin A, Gale M Jr, Debley JS, et al. Thymic stromal lymphopoietin is induced by respiratory syncytial virus-infected airway epithelial cells and promotes a type 2 response to infection. J Allergy ClinImmunol. 2012;130(5):1187-1196.e5. doi: 10.1016/j.jaci.2012.07.031.
- Lay MK, Céspedes PF, Palavecino CE, León MA, Díaz RA, Salazar FJ, et al. Human metapneumovirus infection activates the TSLP pathway that drives excessive pulmonary inflammation and viral replication in mice. Eur J Immunol. 2015;45(6):1680-95. doi: 10.1002/eji.201445021.
- Lewandowska-Polak A, Brauncajs M, Paradowska E, Jarz?bska M, Kurowski M, Moskwa S, et al. Human parainfluenza virus type 3 (HPIV3) induces production of IFNgamma and RANTES in human nasal epithelial cells (HNECs). J Inflamm (Lond). 2015;12:16. doi: 10.1186/s12950-015-0054-7.
- Mehta AK, Duan W, Doerner AM, Traves SL, Broide DH, Proud D, et al. Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33. J Allergy ClinImmunol. 2016;137(1):278-288.e6. doi: 10.1016/j.jaci.2015.05.007.
- Cheemarla NR, Guerrero-Plata A. Immune Response to Human Metapneumovirus Infection: What We Have Learned from the Mouse Model. Pathogens. 2015;4(3):682-96. doi: 10.3390/pathogens4030682.
Copyright: © 2015 Efren Rael, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.