RNA viruses induce heterologous immune protection from atopy and asthma

Research areas: Molecular Virology, Immunology, Allergy

We showed that a preceding influenza A H1N1 HH/05/2009 virus infection protects from experimental asthma in a murine model. The protective effect was dependent on cross-reactivity between virus- and allergen-derived epitopes at the level of CD44+ CD62L T effector memory cells (Tem). Virus-induced T1 immune responses to allergens conferred a long-lasting protection. We were the first to demonstrate influenza-induced heterologous immune responses against allergens and aimed to investigate whether such responses were broadly applicable for several other RNA viruses and allergens. We have established and applied a robust bioinformatics pipeline (collaboration with Z02) for the identification of potentially cross-reactive epitope pairs between Respiratory Syncytial Virus (RSV), Rhinovirus (RV), SARS-CoV-2 and influenza virus strains of the 2019/2020 quadrivalent influenza vaccine (QIV) vs >2500 food and inhalant allergen protein sequences. In silico results from our extensive systematic approach generated a priority list of peptides, which were subsequently screened for MHC binding in vitro. Potentially cross-reactive RSV A2- and allergen-derived peptides which showed strong MHC binding, induced T cell activation and IFNγ production upon ex vivo stimulation of RSV-polarized lymphocytes. Importantly, combinatorial pentamer staining revealed truly cross-reactive T cells in the lungs of animals previously infected with RSV A2. Moreover, we provided proof-of-principle evidence for RV-mediated attenuation of allergen-induced experimental asthma. The remaining ultimate question is the clinical relevance of our findings for people with atopic asthma. We hypothesize that virus peptide immunization induces allergen-specific protective immune responses via attenuation of T2 responses to cross-reactive peptides. We thus aim to investigate whether immunization with RV- or RSV-derived cross-reactive peptides protect from experimental asthma either directly or via transfer of Tem from immunized mice. Second, we shall decipher airway immune signatures by means of mass cytometry (CyTOF) among animals developing allergen-induced experimental asthma vs. those that have been previously infected with an RNA virus or immunized with virus peptides and thereby protected from asthma development. Furthermore, we will examine the impact of RNA virus (RSV, RV) infection and of virus peptide immunization on the pulmonary virome composition and diversity, and thus its contribution to RNA virus-induced heterologous immune protection from asthma. Vaccination with the seasonal QIV is currently recommended for asthmatics based on most national immunization guidelines. We shall thus vaccinate wild type and Class I HLA transgenic mice before subjecting to experimental asthma, induced by allergens cross-reactive to the vaccine. Cross-reactive T cells will be deeply phenotyped by means of mass cytometry, tetramer staining, and transcriptomics. Finally, we shall investigate T cell cross-reactivity in the human context, i.e. among healthy controls and atopic individuals previously vaccinated with the seasonal influenza vaccine. Frequencies of cross-reactive T cells will be correlated with natural infection- and immunization-history. Results from this line of experimentation are expected to advise public health policies in regards to influenza vaccination and pave the way for clinical trials involving peptide immunization of atopic asthmatic individuals.

Project-related publications of the investigator:

  • Fragkou PC, De Angelis G, Menchinelli G, Can F, Garcia F, Morfin-Sherpa F, Dimopoulou D, Mack E, de Salazar A, Grossi A, Lytras T, Skevaki C. 2022. ESCMID COVID-19 guidelines: diagnostic testing for SARS-CoV-2. Clin Microbiol Infect doi:10.1016/j.cmi.2022.02.011.
  • Feng A, Yang E, Moore A, Dhingra S, Chang S, Yin X, Pi R, Mack E, Volkel S, Gessner R, Gundisch M, Neubauer A, Renz H, Tsiodras S, Fragkou P, Asuni A, Levitt J, Wilson J, Leong M, Lumb J, Mao R, Pinedo K, Roque J, Richards C, Stabile M, Swaminathan G, Salagianni M, Triantafyllia V, Bertrams W, Blish C, Carette J, Frankovich J, Meffre E, Nadeau KC, Singh U, Wang T, Prak EL, Herold S, Andreakos E, Schmeck B, Skevaki C, Rogers A, Utz P. 2022. Autoantibodies targeting cytokines and connective tissue disease autoantigens are common in acute non-SARS-CoV-2 infections. Res Sq doi:10.21203/rs.3.rs-1233038/v1.
  • Skevaki C, Ngocho JS, Amour C, Schmid-Grendelmeier P, Mmbaga BT, Renz H. 2021. Epidemiology and management of asthma and atopic dermatitis in Sub-Saharan Africa. J Allergy Clin Immunol 148:1378-1386.
  • Skevaki C, Karsonova A, Karaulov A, Fomina D, Xie M, Chinthrajah S, Nadeau KC, Renz H. 2021. SARS-CoV-2 infection and COVID-19 in asthmatics: a complex relationship. Nat Rev Immunol 21:202-203.
  • Renz H, Skevaki C. 2021. Early life microbial exposures and allergy risks: opportunities for prevention. Nat Rev Immunol 21:177-191.
  • Chang SE, Feng A, Meng W, Apostolidis SA, Mack E, Artandi M, Barman L, Bennett K, Chakraborty S, Chang I, Cheung P, Chinthrajah S, Dhingra S, Do E, Finck A, Gaano A, Gessner R, Giannini HM, Gonzalez J, Greib S, Gundisch M, Hsu AR, Kuo A, Manohar M, Mao R, Neeli I, Neubauer A, Oniyide O, Powell AE, Puri R, Renz H, Schapiro J, Weidenbacher PA, Wittman R, Ahuja N, Chung HR, Jagannathan P, James JA, Kim PS, Meyer NJ, Nadeau KC, Radic M, Robinson WH, Singh U, Wang TT, Wherry EJ, Skevaki C, Luning Prak ET, Utz PJ. 2021. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun 12:5417.
  • Balz K, Kaushik A, Chen M, Cemic F, Heger V, Renz H, Nadeau K, Skevaki C. 2021. Homologies between SARS-CoV-2 and allergen proteins may direct T cell-mediated heterologous immune responses. Sci Rep 11:4792.
  • Balz K, Trassl L, Hartel V, Nelson PP, Skevaki C. 2020. Virus-Induced T Cell-Mediated Heterologous Immunity and Vaccine Development. Front Immunol 11:513.
  • Skevaki C, Hudemann C, Matrosovich M, Mobs C, Paul S, Wachtendorf A, Alashkar Alhamwe B, Potaczek DP, Hagner S, Gemsa D, Garn H, Sette A, Renz H. 2018. Influenza-derived peptides cross-react with allergens and provide asthma protection. J Allergy Clin Immunol 142:804-814.
  • Skevaki C, Van den Berg J, Jones N, Garssen J, Vuillermin P, Levin M, Landay A, Renz H, Calder PC, Thornton CA. 2016. Immune biomarkers in the spectrum of childhood noncommunicable diseases. J Allergy Clin Immunol 137:1302-16.
  • Skevaki CL, Psarras S, Volonaki E, Pratsinis H, Spyridaki IS, Gaga M, Georgiou V, Vittorakis S, Telcian AG, Maggina P, Kletsas D, Gourgiotis D, Johnston SL, Papadopoulos NG. 2012. Rhinovirus-induced basic fibroblast growth factor release mediates airway remodeling features. Clin Transl Allergy 2:14.
  • Skevaki CL, Christodoulou I, Spyridaki IS, Tiniakou I, Georgiou V, Xepapadaki P, Kafetzis DA, Papadopoulos NG. 2009. Budesonide and formoterol inhibit inflammatory mediator production by bronchial epithelial cells infected with rhinovirus. Clin Exp Allergy 39:1700-10.