Descriptive omics-based clinical research provides valuable early steps in understanding host immune responses to respiratory pathogens in our global efforts to mitigate the impacts of severe respiratory infections with rapidly evolving technologies https://bit.ly/4bjJsv

Evans, Scott E

Pantaleon Garcia, Jezreel

English

DigitalCommons@The Texas Medical Center

Omics-based profiles and biomarkers of respiratory infections:are we there yet?Jezreel Pantaleon Garcia and Scott E. EvansDepartment of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.Corresponding author: Jezreel Pantaleon Garcia ( jpantaleon@mdanderson.org)Shareable abstract (@ERSpublications)Descriptive omics-based clinical research provides valuable early steps in understanding hostimmune responses to respiratory pathogens in our global efforts to mitigate the impacts of severerespiratory infections with rapidly evolving technologies https://bit.ly/4bjJsvLCite this article as: Pantaleon Garcia J, Evans SE. Omics-based profiles and biomarkers of respiratoryinfections: are we there yet? Eur Respir J 2024; 63: 2400137 [DOI: 10.1183/13993003.00137-2024].From the influenza pandemic of 1918–1919 to the most recent COVID-19 pandemic, respiratory infectionsremain a leading cause of mortality worldwide [1, 2]. Concurrently, the development of high-throughputomics technologies has revolutionised research about host responses to known and emerging respiratorypathogens [3], accelerating our understanding of highly prevalent pulmonary diseases [4]. Notably, omicstechnology-based characterisation of pathogens and host pathophysiology have critically supporteddiagnostic and therapeutic global health efforts during both the influenza A H1N1 and SARS-CoV-2pandemics [5–7]. Nonetheless, elucidation of key immune response mechanisms and development ofhost-targeted therapeutics remain important unrealised research and clinical priorities in the global fightagainst lower respiratory tract infections (LTRIs) [8, 9].In a report published in this issue of the European Respiratory Journal, LONG et al. [10] characterised thebaseline and longitudinal proteomic profiles of neutrophils in patients hospitalised with SARS-CoV-2infection in a 29-day prospective observational study. Analysing circulating neutrophils from >200hospitalised COVID-19, non-COVID-19 LTRI and non-infected patients, the authors identified a coreCOVID-19 neutrophil proteomic signature at baseline (hospital day 1) comprised of 171 type I interferon(IFN) response-related molecules. These core signature proteins were differentially expressed acrossCOVID-19 severity classifications at baseline (World Health Organization (WHO) scale 3–6), then mostlynormalising by day 7. This early, transient core proteomic signature supports accumulating evidence thatpatients with SARS-CoV-2 infection generate an initial, robust type I IFN response, contrary to reportspublished at the beginning of the COVID-19 pandemic [11]. From this list of core signature proteins,CXCR2 was the only neutrophil receptor that remained downregulated in the longitudinal profile ofnon-recovered patients (hospital day 29). The downregulation of CXCR2 in this cohort was alsoaccompanied by dysregulations of multiple metabolic pathways in severe COVID-19 patients (WHO 5–6).Not surprisingly, recent evidence also reveals that systemic type I IFN dysregulations in COVID-19patients are linked to metabolic changes that lead to immune reprogramming of circulating immunecells [12]. Furthermore, CXCR2 was previously reported as an immunomodulatory receptor associatedwith programmed proteomic disarming of neutrophils in multiple patients with severe community-acquiredpneumonia [13].Given the cell-specific resolution of untargeted proteomics from isolated neutrophils, the authors describedhow the expression of regulatory receptors alter both baseline and longitudinal immune and metabolicproteome profiles of hospitalised COVID-19 patients (figure 1). At baseline, the type I IFN response ofcritically ill COVID-19 patients was accompanied by increased expression of immunomodulatorymolecules (arginase 1 (ARG1) and transforming growth factor beta 1 (TGFB1)) and receptors (Toll-likereceptor 2 (TLR2), Fc γ receptor Ia (CD64-FCGR1A), C-type lectin domain family 4 member E (CLEC4E)and V-domain Ig suppressor of T cell activation (VISTA)). Interestingly, these neutrophil proteins wereCopyright ©The authors 2024.This version is distributed underthe terms of the CreativeCommons Attribution Non-Commercial Licence 4.0. Forcommercial reproduction rightsand permissions contactpermissions@ersnet.orgReceived: 19 Jan 2024Accepted: 29 Jan 2024https://doi.org/10.1183/13993003.00137-2024 Eur Respir J 2024; 63: 2400137EUROPEAN RESPIRATORY JOURNALEDITORIALJ. PANTALEON GARCIA AND S.E. EVANSrepresentative markers of the initial type I IFN baseline profiles during early hospitalisation stages (up today 7) of severe patients along with changes in multiple metabolic regulators, which later predominated asrepresentative metabolic proteins in the later stages of the non-recovered patients (at day 29). Thenon-recovered COVID-19 patients exhibited downregulation of key glycolytic proteins (hexokinase 3(HK3) and glucose transporter 3 (SLC2A3)), though these normalised in recovered patients. Additionally,the longitudinal analysis revealed a sustained reduction in glycogen phosphorylases L (PYGL) and B(PYGB). These rate-limiting enzymes of glycogenolysis were downregulated at all timepoints innon-recovered COVID-19 patients and were accompanied by dysfunctional neutrophil proteomes. Theseproteomes included reduction of integrins and migratory receptors (poor neutrophil migration), and granuleproteins and inhibitory receptors (high granule loss). Altogether, these findings support the recentdiscoveries of a neutrophil-specific proteomic disarming role of immunomodulatory receptors in respiratoryinfections [13] and exemplifies the immunosuppressive reprogramming of glycolytic and glycogenolyticmetabolic pathways involved in systemic immune responses after COVID-19 infection [12, 14].Bulk and single-cell omics-based research studies that aim to characterise systemic immune responses toSARS-CoV-2 infection have identified neutrophils as key players of local and systemic responses inCOVID-19 patients [15, 16]. There is extensive evidence supporting the importance of either sustained(hyperinflammation) or impaired type I IFN responses at the systemic level with a worse diseaseprogression in patients with SARS-CoV-2 infection [11, 17]. However, LONG et al. [10] further suggestconcurrent immunomodulatory receptor disturbances with temporally divergent metabolic reprogrammingof neutrophils. Their results expand the growing notion that circulating transcriptomic, metabolic andproteomic profiling can provide novel predictive biomarkers of acute and long-term outcomes ofCOVID-19 disease [14, 18–21]. In fact, several prospective studies in hospitalised infants with severeMass spectrometryNon-infectedNon-COVID-19COVID-19Baseline profilesIFN-I responseNeutrophil receptorsMetabolic regulatorsNeutrophil receptorsMetabolic regulatorsSYNE1, SYNE2,SUN2, LBRC5AR1,CXCR2PYGL, PYGB,GSK3A, GSK3BMX1,MX2TLR2, CLEC4D,VISTA, IL1R2FAO, ETC, CCA,GlycolysisNormalC3AR1,LTB4RSLC16A3Poor migration,granule lossC3AR1, S1PR4,LTB4R, CXCR2SLC16A3, SLC2A3,HK3, GB1, GYG1Recovery responseLongitudinal profilesRecovered Non-recoveredNeutrophils(Day 1, 7 and 29)Blood collectionLongitudinalProteome profiling of neutrophil responsesNeutrophil proteome profiles in SARS-CoV-2 infectionMttBaselineFIGURE 1 Proteomic profiling of neutrophil responses to SARS-CoV-2 from LONG et al. [10].https://doi.org/10.1183/13993003.00137-2024 2EUROPEAN RESPIRATORY JOURNAL EDITORIAL | J. PANTALEON GARCIA AND S.E. EVANSbronchiolitis have successfully identified omics-based epigenetic markers that link immune host responsemechanisms with current disease severity and future development of respiratory comorbidities [22, 23].One study reported a blood epigenomic DNA profile of 33 methylated CpG sites associated withbronchiolitis severity that is also differentially expressed in circulating immune cell responses ofneutrophils, cytotoxic T cells and helper T cells [22]. Another study found a nasal profile of 23 microRNAs (miRNAs) that targets messenger RNA (mRNA) of Toll-like receptor, Fc γ and Fc ε signallingpathways via direct miRNA–mRNA interactions and correlates with subsequent risk of asthmadevelopment [23]. These unanticipated and time-dependent changes in molecular profiles highlight theneed for longitudinal omics-based clinical discoveries when analysing immune host response landscapes ofrespiratory infections.Naturally, the associations presented by LONG et al. [10] are primarily descriptive, and the authors areappropriately cautious about asserting potential metabolic reprogramming mechanisms of neutrophils orpredictive biomarker functions of their proteome profiles. However, descriptive omics-based clinicalresearch are valuable early steps in understanding host immune responses to respiratory pathogens in ourglobal efforts to mitigate the impacts of severe respiratory infections with rapidly evolving technologies[20, 21, 24–27].Author contributions: J. Pantaleon Garcia and S.E. Evans contributed to the writing, editing and approval of thefinal article.Conflict of interest: J. Pantaleon Garcia has no competing conflicts of interest. S.E. Evans is an author on USpatent 8 883 174, “Stimulation of innate resistance of the lungs to infection with synthetic ligands” and owns stockin Pulmotect, Inc.Support statement: This work is funded by the US National Institutes of Health grant R35 HL144805 to S.E. Evans.Funding information for this article has been deposited with the Crossref Funder Registry.References1 Williams BA, Jones CH, Welch V, et al. Outlook of pandemic preparedness in a post-COVID-19 world. NPJVaccines 2023; 8: 178.2 Vos T, Lim SS, Abbafati C, et al. Global burden of 369 diseases and injuries in 204 countries and territories,1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020; 396: 1204–1222.3 Bos LDJ, de Jong MD, Sterk PJ, et al. How integration of global omics-data could help preparing forpandemics – a scent of influenza. Front Genet 2014; 5: 80.4 Kan M, Shumyatcher M, Himes BE. Using omics approaches to understand pulmonary diseases. Respir Res2017; 18: 149.5 Halabi S, Wilder R, Gostin LO, et al. Sharing pathogen genomic sequence data — toward effective pandemicprevention, preparedness, and response. N Engl J Med 2023; 388: 2401–2404.6 D’Adamo GL, Widdop JT, Giles EM. The future is now? Clinical and translational aspects of “Omics”technologies. Immunol Cell Biol 2021; 99: 168–176.7 Park JJH, Mogg R, Smith GE, et al. How COVID-19 has fundamentally changed clinical research in globalhealth. Lancet Glob Health 2021; 9: e711–e720.8 Dela Cruz CS, Wunderink RG, Christiani DC, et al. Future research directions in pneumonia. NHLBI WorkingGroup Report. Am J Respir Crit Care Med 2018; 198: 256–263.9 Wee LE, Lye DC, Lee V. Developments in pneumonia and priorities for research. Lancet Respir Med 2023; 11:1046–1047.10 Long MB, Howden AJM, Keir HR, et al. Extensive acute and sustained changes to neutrophil proteomespost-SARS-CoV-2 infection. Eur Respir J 2024; 63: 2300787.11 Lee JS, Shin E-C. The type I interferon response in COVID-19: implications for treatment. Nat Rev Immunol2020; 20: 585–586.12 Jia H, Liu C, Li D, et al. Metabolomic analyses reveal new stage-specific features of COVID-19. Eur Respir J2022; 59: 2100284.13 Adrover JM, Aroca-Crevillén A, Crainiciuc G, et al. Programmed ‘disarming’ of the neutrophil proteomereduces the magnitude of inflammation. Nat Immunol 2020; 21: 135–144.14 Hartsell EM, Gillespie MN, Langley RJ. Does acute and persistent metabolic dysregulation in COVID-19 pointto novel biomarkers and future therapeutic strategies? Eur Respir J 2022; 59: 2102417.15 Wu P, Chen D, Ding W, et al. The trans-omics landscape of COVID-19. Nat Commun 2021; 12: 4543.16 Wilk AJ, Rustagi A, Zhao NQ, et al. A single-cell atlas of the peripheral immune response in patients withsevere COVID-19. Nat Med 2020; 26: 1070–1076.https://doi.org/10.1183/13993003.00137-2024 3EUROPEAN RESPIRATORY JOURNAL EDITORIAL | J. PANTALEON GARCIA AND S.E. EVANS17 Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severeCOVID-19 patients. Science 2020; 369: 718–724.18 Babačić H, Christ W, Araújo JE, et al. Comprehensive proteomics and meta-analysis of COVID-19 hostresponse. Nat Commun 2023; 14: 5921.19 Captur G, Moon JC, Topriceanu C-C, et al. Plasma proteomic signature predicts who will get persistentsymptoms following SARS-CoV-2 infection. EBioMedicine 2022; 85: 104293.20 Wang Y, Huang X, Li F, et al. Serum-integrated omics reveal the host response landscape for severe pediatriccommunity-acquired pneumonia. Crit Care 2023; 27: 79.21 Gupta RK, Rosenheim J, Bell LC, et al. Blood transcriptional biomarkers of acute viral infection for detectionof pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study. Lancet Microbe2021; 2: e508–e517.22 Zhu Z, Li Y, Freishtat RJ, et al. Epigenome-wide association analysis of infant bronchiolitis severity: amulticenter prospective cohort study. Nat Commun 2023; 14: 5495.23 Zhu Z, Freishtat RJ, Harmon B, et al. Nasal airway microRNA profiling of infants with severe bronchiolitis andrisk of childhood asthma: a multicentre prospective study. Eur Respir J 2023; 62: 2300502.24 Wang X, Ulloa L. Editorial: Omics in respiratory virus infectious diseases: integrating multi-omics to revealdata characteristics and mechanisms for the diagnosis and treatment of disease. Front Med (Lausanne) 2023;10: 1273662.25 Kulasinghe A, Tan CW, Ribeiro dos Santos Miggiolaro AF, et al. Profiling of lung SARS-CoV-2 and influenzavirus infection dissects virus-specific host responses and gene signatures. Eur Respir J 2022; 59: 2101881.26 Berger B, Yu YW. Navigating bottlenecks and trade-offs in genomic data analysis. Nat Rev Genet 2023; 24:235–250.27 Pantaleón García J, Kulkarni VV, Reese TC, et al. OBIF: an omics-based interaction framework to revealmolecular drivers of synergy. NAR Genom Bioinform 2022; 4: lqac028.https://doi.org/10.1183/13993003.00137-2024 4EUROPEAN RESPIRATORY JOURNAL EDITORIAL | J. PANTALEON GARCIA AND S.E. EVANS

Omics-based profiles and biomarkers of respiratory infections: are we there yet?

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Omics-based profiles and biomarkers of respiratory infections: are we there yet?

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