Seasonal airway microbiome and transcriptome interactions promote childhood asthma exacerbations

National Institute of Allergy and Infectious Diseases–sponsored Inner-City Asthma Consortium

doi:10.1016/j.jaci.2022.01.020

Seasonal airway microbiome and transcriptome interactions promote childhood asthma exacerbations

National Institute of Allergy and Infectious Diseases–sponsored Inner-City Asthma Consortium

Pediatrics

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Background: Seasonal variation in respiratory illnesses and exacerbations in pediatric populations with asthma is well described, though whether upper airway microbes play season-specific roles in these events is unknown. Objective: We hypothesized that nasal microbiota composition is seasonally dynamic and that discrete microbe–host interactions modify risk of asthma exacerbation in a season-specific manner. Methods: Repeated nasal samples from children with exacerbation-prone asthma collected during periods of respiratory health (baseline; n = 181 samples) or first captured respiratory illness (n = 97) across all seasons, underwent bacterial (16S ribosomal RNA gene) and fungal (internal transcribed spacer region 2) biomarker sequencing. Virus detection was performed by multiplex PCR. Paired nasal transcriptome data were examined for seasonal dynamics and integrative analyses. Results: Upper airway bacterial and fungal microbiota and rhinovirus detection exhibited significant seasonal dynamics. In seasonally adjusted analysis, variation in both baseline and respiratory illness microbiota related to subsequent exacerbation. Specifically, in the fall, when respiratory illness and exacerbation events were most frequent, several Moraxella and Haemophilus members were enriched both in virus-positive respiratory illnesses and those that progressed to exacerbations. The abundance of 2 discrete bacterial networks, characteristically comprising either Streptococcus or Staphylococcus, exhibited opposing interactions with an exacerbation-associated SMAD3 nasal epithelial transcriptional module to significantly increase the odds of subsequent exacerbation (odds ratio = 14.7, 95% confidence interval = 1.50-144, P = .02; odds ratio = 39.17, 95% confidence interval = 2.44-626, P = .008, respectively). Conclusions: Upper airway microbiomes covary with season and with seasonal trends in respiratory illnesses and asthma exacerbations. Seasonally adjusted analyses reveal specific bacteria–host interactions that significantly increase risk of asthma exacerbation in these children.

Original language	English (US)
Pages (from-to)	204-213
Number of pages	10
Journal	Journal of Allergy and Clinical Immunology
Volume	150
Issue number	1
DOIs	https://doi.org/10.1016/j.jaci.2022.01.020
State	Published - Jul 2022

Funding

Disclosure of potential conflict of interest: M. A. Gill reports consulting fees from the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics. A. H. Liu reports consulting fees from Merck Sharp & Dohme and reports data-monitoring committee membership for an asthma study conducted by GlaxoSmithKline. G. T. O’Connor reports consulting fees from AstraZeneca and reports a grant from Janssen Pharmaceuticals paid to his employing institution. J. A. Pongracic reports provision of study drugs from GlaxoSmithKline, Teva, Merck, Boehringer-Ingelheim, and Genentech/Novartis for research studies outside of the scope of the submitted work. C. M. Kercsmar reports consulting fees from GlaxoSmithKline. S. J. Teach reports consulting fees from Novartis, grants from PCORI, the Fight for Children Foundation, EJF Philanthropies, and National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), and royalties from Uptodate. M. Kattan reports consulting fees from Novartis. L. B. Bacharier reports consulting fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Cephalon, DBV Technologies, Teva, Boehringer-Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Vectura, and Circassia. J. E. Gern reports consulting fees from Janssen, Regeneron, and PReP Biosciences and travel expenses from Boehringer-Ingelheim. W. W. Busse reports consulting fees from Boston Scientific, ICON, Novartis, GlaxoSmithKline, Genentech, Roche, Boehringer-Ingelheim, Sanofi Genzyme, AstraZeneca, Teva, 3M, PrEPBiopharm, Circassia, Regeneron, Peptinnovate, and Elsevier. D. J. Jackson reports consulting fees from Novartis, GlaxoSmithKline, Boehringer-Ingelheim, Pfizer, Commense, and Vectura and a grant from NIH/NHLBI. S. V. Lynch reports grants from the NIH/National Institute of Allergy and Infectious Diseases, NIH/National Institute on Drug Abuse, NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/Office of the Director, and the Crohn’s and Colitis Foundation of America; reports personal fees from Siolta Therapeutics outside the submitted work; has a patent “Reductive prodrug cancer chemotherapy (Stan449-PRV)” issued, a patent “Combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection (WO2010091189A1)” with royalties paid by KaloBios, a patent “Therapeutic microbial consortium for induction of immune tolerance” licensed to Siolta Therapeutics, a patent “Systems and methods for detecting antibiotic resistance (WO2012027302A3)” issued, a patent “Nitroreductase enzymes (US7687474B2)” issued, a patent “Sinusitis diagnostics and treatments (WO2013155370A1)” licensed by Reflourish, and a patent “Methods and systems for phylogenetic analysis (US20120264637A1)” issued; and is a cofounder of Siolta Therapeutics, a start-up developing a mixed-species microbial oral therapeutic for induction of immune tolerance. The rest of the authors declare that they have no relevant conflicts of interest. Supported by federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US Department of Health and Human Services , under contract 1UM1AI114271 awarded to W.W.B. and UM2AI117870 awarded to Rho Inc. Additional support came from CTSA UL1TR000150 and UL1TR001422 to J.A.P., 5UL1TR001425 to G.K.K.H., NCRR/NIH UL1TR000451 to M.A.G. and R.S.G., CTSI 1UL1TR001430 to G.T.O., CCTSI UL1TR001082 to A.H.L., 5UM1AI114271 to W.W.B. and J.E.G., NCATS/NIH UL1 TR001876 to S.J.T., and UL1TR002345 to L.B.B. NIAID staff members were involved in the study design, review of the findings, and preparation of the report for publication. Supported by federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US Department of Health and Human Services, under contract 1UM1AI114271 awarded to W.W.B. and UM2AI117870 awarded to Rho Inc. Additional support came from CTSA UL1TR000150 and UL1TR001422 to J.A.P., 5UL1TR001425 to G.K.K.H., NCRR/NIH UL1TR000451 to M.A.G. and R.S.G., CTSI 1UL1TR001430 to G.T.O., CCTSI UL1TR001082 to A.H.L., 5UM1AI114271 to W.W.B. and J.E.G., NCATS/NIH UL1 TR001876 to S.J.T., and UL1TR002345 to L.B.B. NIAID staff members were involved in the study design, review of the findings, and preparation of the report for publication. Disclosure of potential conflict of interest: M. A. Gill reports consulting fees from the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics. A. H. Liu reports consulting fees from Merck Sharp & Dohme and reports data-monitoring committee membership for an asthma study conducted by GlaxoSmithKline. G. T. O'Connor reports consulting fees from AstraZeneca and reports a grant from Janssen Pharmaceuticals paid to his employing institution. J. A. Pongracic reports provision of study drugs from GlaxoSmithKline, Teva, Merck, Boehringer-Ingelheim, and Genentech/Novartis for research studies outside of the scope of the submitted work. C. M. Kercsmar reports consulting fees from GlaxoSmithKline. S. J. Teach reports consulting fees from Novartis, grants from PCORI, the Fight for Children Foundation, EJF Philanthropies, and National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), and royalties from Uptodate. M. Kattan reports consulting fees from Novartis. L. B. Bacharier reports consulting fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Cephalon, DBV Technologies, Teva, Boehringer-Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Vectura, and Circassia. J. E. Gern reports consulting fees from Janssen, Regeneron, and PReP Biosciences and travel expenses from Boehringer-Ingelheim. W. W. Busse reports consulting fees from Boston Scientific, ICON, Novartis, GlaxoSmithKline, Genentech, Roche, Boehringer-Ingelheim, Sanofi Genzyme, AstraZeneca, Teva, 3M, PrEPBiopharm, Circassia, Regeneron, Peptinnovate, and Elsevier. D. J. Jackson reports consulting fees from Novartis, GlaxoSmithKline, Boehringer-Ingelheim, Pfizer, Commense, and Vectura and a grant from NIH/NHLBI. S. V. Lynch reports grants from the NIH/National Institute of Allergy and Infectious Diseases, NIH/National Institute on Drug Abuse, NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/Office of the Director, and the Crohn's and Colitis Foundation of America; reports personal fees from Siolta Therapeutics outside the submitted work; has a patent “Reductive prodrug cancer chemotherapy (Stan449-PRV)” issued, a patent “Combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection (WO2010091189A1)” with royalties paid by KaloBios, a patent “Therapeutic microbial consortium for induction of immune tolerance” licensed to Siolta Therapeutics, a patent “Systems and methods for detecting antibiotic resistance (WO2012027302A3)” issued, a patent “Nitroreductase enzymes (US7687474B2)” issued, a patent “Sinusitis diagnostics and treatments (WO2013155370A1)” licensed by Reflourish, and a patent “Methods and systems for phylogenetic analysis (US20120264637A1)” issued; and is a cofounder of Siolta Therapeutics, a start-up developing a mixed-species microbial oral therapeutic for induction of immune tolerance. The rest of the authors declare that they have no relevant conflicts of interest.

Keywords

Microbiome
exacerbations
pediatric asthma
respiratory illness
transcriptomics
virus infection

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1016/j.jaci.2022.01.020

Cite this

@article{f774eace17fe4a4990014cbff5dfc41a,

title = "Seasonal airway microbiome and transcriptome interactions promote childhood asthma exacerbations",

abstract = "Background: Seasonal variation in respiratory illnesses and exacerbations in pediatric populations with asthma is well described, though whether upper airway microbes play season-specific roles in these events is unknown. Objective: We hypothesized that nasal microbiota composition is seasonally dynamic and that discrete microbe–host interactions modify risk of asthma exacerbation in a season-specific manner. Methods: Repeated nasal samples from children with exacerbation-prone asthma collected during periods of respiratory health (baseline; n = 181 samples) or first captured respiratory illness (n = 97) across all seasons, underwent bacterial (16S ribosomal RNA gene) and fungal (internal transcribed spacer region 2) biomarker sequencing. Virus detection was performed by multiplex PCR. Paired nasal transcriptome data were examined for seasonal dynamics and integrative analyses. Results: Upper airway bacterial and fungal microbiota and rhinovirus detection exhibited significant seasonal dynamics. In seasonally adjusted analysis, variation in both baseline and respiratory illness microbiota related to subsequent exacerbation. Specifically, in the fall, when respiratory illness and exacerbation events were most frequent, several Moraxella and Haemophilus members were enriched both in virus-positive respiratory illnesses and those that progressed to exacerbations. The abundance of 2 discrete bacterial networks, characteristically comprising either Streptococcus or Staphylococcus, exhibited opposing interactions with an exacerbation-associated SMAD3 nasal epithelial transcriptional module to significantly increase the odds of subsequent exacerbation (odds ratio = 14.7, 95% confidence interval = 1.50-144, P = .02; odds ratio = 39.17, 95% confidence interval = 2.44-626, P = .008, respectively). Conclusions: Upper airway microbiomes covary with season and with seasonal trends in respiratory illnesses and asthma exacerbations. Seasonally adjusted analyses reveal specific bacteria–host interactions that significantly increase risk of asthma exacerbation in these children.",

keywords = "Microbiome, exacerbations, pediatric asthma, respiratory illness, transcriptomics, virus infection",

author = "{National Institute of Allergy and Infectious Diseases–sponsored Inner-City Asthma Consortium} and McCauley, {Kathryn E.} and Kaitlin Flynn and Agustin Calatroni and Vincent DiMassa and Brandon LaMere and Fadrosh, {Douglas W.} and Lynch, {Kole V.} and Gill, {Michelle A.} and Pongracic, {Jacqueline A.} and {Khurana Hershey}, {Gurjit K.} and Kercsmar, {Carolyn M.} and Liu, {Andrew H.} and Johnson, {Christine C.} and Haejin Kim and Meyer Kattan and O'Connor, {George T.} and Bacharier, {Leonard B.} and Teach, {Stephen J.} and Gergen, {Peter J.} and Wheatley, {Lisa M.} and Alkis Togias and Petra LeBeau and Scott Presnell and Boushey, {Homer A.} and Busse, {William W.} and Gern, {James E.} and Jackson, {Daniel J.} and Altman, {Matthew C.} and Lynch, {Susan V.}",

note = "Funding Information: Disclosure of potential conflict of interest: M. A. Gill reports consulting fees from the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics. A. H. Liu reports consulting fees from Merck Sharp & Dohme and reports data-monitoring committee membership for an asthma study conducted by GlaxoSmithKline. G. T. O{\textquoteright}Connor reports consulting fees from AstraZeneca and reports a grant from Janssen Pharmaceuticals paid to his employing institution. J. A. Pongracic reports provision of study drugs from GlaxoSmithKline, Teva, Merck, Boehringer-Ingelheim, and Genentech/Novartis for research studies outside of the scope of the submitted work. C. M. Kercsmar reports consulting fees from GlaxoSmithKline. S. J. Teach reports consulting fees from Novartis, grants from PCORI, the Fight for Children Foundation, EJF Philanthropies, and National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), and royalties from Uptodate. M. Kattan reports consulting fees from Novartis. L. B. Bacharier reports consulting fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Cephalon, DBV Technologies, Teva, Boehringer-Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Vectura, and Circassia. J. E. Gern reports consulting fees from Janssen, Regeneron, and PReP Biosciences and travel expenses from Boehringer-Ingelheim. W. W. Busse reports consulting fees from Boston Scientific, ICON, Novartis, GlaxoSmithKline, Genentech, Roche, Boehringer-Ingelheim, Sanofi Genzyme, AstraZeneca, Teva, 3M, PrEPBiopharm, Circassia, Regeneron, Peptinnovate, and Elsevier. D. J. Jackson reports consulting fees from Novartis, GlaxoSmithKline, Boehringer-Ingelheim, Pfizer, Commense, and Vectura and a grant from NIH/NHLBI. S. V. Lynch reports grants from the NIH/National Institute of Allergy and Infectious Diseases, NIH/National Institute on Drug Abuse, NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/Office of the Director, and the Crohn{\textquoteright}s and Colitis Foundation of America; reports personal fees from Siolta Therapeutics outside the submitted work; has a patent “Reductive prodrug cancer chemotherapy (Stan449-PRV)” issued, a patent “Combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection (WO2010091189A1)” with royalties paid by KaloBios, a patent “Therapeutic microbial consortium for induction of immune tolerance” licensed to Siolta Therapeutics, a patent “Systems and methods for detecting antibiotic resistance (WO2012027302A3)” issued, a patent “Nitroreductase enzymes (US7687474B2)” issued, a patent “Sinusitis diagnostics and treatments (WO2013155370A1)” licensed by Reflourish, and a patent “Methods and systems for phylogenetic analysis (US20120264637A1)” issued; and is a cofounder of Siolta Therapeutics, a start-up developing a mixed-species microbial oral therapeutic for induction of immune tolerance. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Supported by federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US Department of Health and Human Services , under contract 1UM1AI114271 awarded to W.W.B. and UM2AI117870 awarded to Rho Inc. Additional support came from CTSA UL1TR000150 and UL1TR001422 to J.A.P., 5UL1TR001425 to G.K.K.H., NCRR/NIH UL1TR000451 to M.A.G. and R.S.G., CTSI 1UL1TR001430 to G.T.O., CCTSI UL1TR001082 to A.H.L., 5UM1AI114271 to W.W.B. and J.E.G., NCATS/NIH UL1 TR001876 to S.J.T., and UL1TR002345 to L.B.B. NIAID staff members were involved in the study design, review of the findings, and preparation of the report for publication. Funding Information: Supported by federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US Department of Health and Human Services, under contract 1UM1AI114271 awarded to W.W.B. and UM2AI117870 awarded to Rho Inc. Additional support came from CTSA UL1TR000150 and UL1TR001422 to J.A.P., 5UL1TR001425 to G.K.K.H., NCRR/NIH UL1TR000451 to M.A.G. and R.S.G., CTSI 1UL1TR001430 to G.T.O., CCTSI UL1TR001082 to A.H.L., 5UM1AI114271 to W.W.B. and J.E.G., NCATS/NIH UL1 TR001876 to S.J.T., and UL1TR002345 to L.B.B. NIAID staff members were involved in the study design, review of the findings, and preparation of the report for publication. Disclosure of potential conflict of interest: M. A. Gill reports consulting fees from the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics. A. H. Liu reports consulting fees from Merck Sharp & Dohme and reports data-monitoring committee membership for an asthma study conducted by GlaxoSmithKline. G. T. O'Connor reports consulting fees from AstraZeneca and reports a grant from Janssen Pharmaceuticals paid to his employing institution. J. A. Pongracic reports provision of study drugs from GlaxoSmithKline, Teva, Merck, Boehringer-Ingelheim, and Genentech/Novartis for research studies outside of the scope of the submitted work. C. M. Kercsmar reports consulting fees from GlaxoSmithKline. S. J. Teach reports consulting fees from Novartis, grants from PCORI, the Fight for Children Foundation, EJF Philanthropies, and National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), and royalties from Uptodate. M. Kattan reports consulting fees from Novartis. L. B. Bacharier reports consulting fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Cephalon, DBV Technologies, Teva, Boehringer-Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Vectura, and Circassia. J. E. Gern reports consulting fees from Janssen, Regeneron, and PReP Biosciences and travel expenses from Boehringer-Ingelheim. W. W. Busse reports consulting fees from Boston Scientific, ICON, Novartis, GlaxoSmithKline, Genentech, Roche, Boehringer-Ingelheim, Sanofi Genzyme, AstraZeneca, Teva, 3M, PrEPBiopharm, Circassia, Regeneron, Peptinnovate, and Elsevier. D. J. Jackson reports consulting fees from Novartis, GlaxoSmithKline, Boehringer-Ingelheim, Pfizer, Commense, and Vectura and a grant from NIH/NHLBI. S. V. Lynch reports grants from the NIH/National Institute of Allergy and Infectious Diseases, NIH/National Institute on Drug Abuse, NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/Office of the Director, and the Crohn's and Colitis Foundation of America; reports personal fees from Siolta Therapeutics outside the submitted work; has a patent “Reductive prodrug cancer chemotherapy (Stan449-PRV)” issued, a patent “Combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection (WO2010091189A1)” with royalties paid by KaloBios, a patent “Therapeutic microbial consortium for induction of immune tolerance” licensed to Siolta Therapeutics, a patent “Systems and methods for detecting antibiotic resistance (WO2012027302A3)” issued, a patent “Nitroreductase enzymes (US7687474B2)” issued, a patent “Sinusitis diagnostics and treatments (WO2013155370A1)” licensed by Reflourish, and a patent “Methods and systems for phylogenetic analysis (US20120264637A1)” issued; and is a cofounder of Siolta Therapeutics, a start-up developing a mixed-species microbial oral therapeutic for induction of immune tolerance. The rest of the authors declare that they have no relevant conflicts of interest. Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = jul,

doi = "10.1016/j.jaci.2022.01.020",

language = "English (US)",

volume = "150",

pages = "204--213",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "1",

}

TY - JOUR

T1 - Seasonal airway microbiome and transcriptome interactions promote childhood asthma exacerbations

AU - National Institute of Allergy and Infectious Diseases–sponsored Inner-City Asthma Consortium

AU - McCauley, Kathryn E.

AU - Flynn, Kaitlin

AU - Calatroni, Agustin

AU - DiMassa, Vincent

AU - LaMere, Brandon

AU - Fadrosh, Douglas W.

AU - Lynch, Kole V.

AU - Gill, Michelle A.

AU - Pongracic, Jacqueline A.

AU - Khurana Hershey, Gurjit K.

AU - Kercsmar, Carolyn M.

AU - Liu, Andrew H.

AU - Johnson, Christine C.

AU - Kim, Haejin

AU - Kattan, Meyer

AU - O'Connor, George T.

AU - Bacharier, Leonard B.

AU - Teach, Stephen J.

AU - Gergen, Peter J.

AU - Wheatley, Lisa M.

AU - Togias, Alkis

AU - LeBeau, Petra

AU - Presnell, Scott

AU - Boushey, Homer A.

AU - Busse, William W.

AU - Gern, James E.

AU - Jackson, Daniel J.

AU - Altman, Matthew C.

AU - Lynch, Susan V.

N1 - Funding Information: Disclosure of potential conflict of interest: M. A. Gill reports consulting fees from the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics. A. H. Liu reports consulting fees from Merck Sharp & Dohme and reports data-monitoring committee membership for an asthma study conducted by GlaxoSmithKline. G. T. O’Connor reports consulting fees from AstraZeneca and reports a grant from Janssen Pharmaceuticals paid to his employing institution. J. A. Pongracic reports provision of study drugs from GlaxoSmithKline, Teva, Merck, Boehringer-Ingelheim, and Genentech/Novartis for research studies outside of the scope of the submitted work. C. M. Kercsmar reports consulting fees from GlaxoSmithKline. S. J. Teach reports consulting fees from Novartis, grants from PCORI, the Fight for Children Foundation, EJF Philanthropies, and National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), and royalties from Uptodate. M. Kattan reports consulting fees from Novartis. L. B. Bacharier reports consulting fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Cephalon, DBV Technologies, Teva, Boehringer-Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Vectura, and Circassia. J. E. Gern reports consulting fees from Janssen, Regeneron, and PReP Biosciences and travel expenses from Boehringer-Ingelheim. W. W. Busse reports consulting fees from Boston Scientific, ICON, Novartis, GlaxoSmithKline, Genentech, Roche, Boehringer-Ingelheim, Sanofi Genzyme, AstraZeneca, Teva, 3M, PrEPBiopharm, Circassia, Regeneron, Peptinnovate, and Elsevier. D. J. Jackson reports consulting fees from Novartis, GlaxoSmithKline, Boehringer-Ingelheim, Pfizer, Commense, and Vectura and a grant from NIH/NHLBI. S. V. Lynch reports grants from the NIH/National Institute of Allergy and Infectious Diseases, NIH/National Institute on Drug Abuse, NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/Office of the Director, and the Crohn’s and Colitis Foundation of America; reports personal fees from Siolta Therapeutics outside the submitted work; has a patent “Reductive prodrug cancer chemotherapy (Stan449-PRV)” issued, a patent “Combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection (WO2010091189A1)” with royalties paid by KaloBios, a patent “Therapeutic microbial consortium for induction of immune tolerance” licensed to Siolta Therapeutics, a patent “Systems and methods for detecting antibiotic resistance (WO2012027302A3)” issued, a patent “Nitroreductase enzymes (US7687474B2)” issued, a patent “Sinusitis diagnostics and treatments (WO2013155370A1)” licensed by Reflourish, and a patent “Methods and systems for phylogenetic analysis (US20120264637A1)” issued; and is a cofounder of Siolta Therapeutics, a start-up developing a mixed-species microbial oral therapeutic for induction of immune tolerance. The rest of the authors declare that they have no relevant conflicts of interest. Funding Information: Supported by federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US Department of Health and Human Services , under contract 1UM1AI114271 awarded to W.W.B. and UM2AI117870 awarded to Rho Inc. Additional support came from CTSA UL1TR000150 and UL1TR001422 to J.A.P., 5UL1TR001425 to G.K.K.H., NCRR/NIH UL1TR000451 to M.A.G. and R.S.G., CTSI 1UL1TR001430 to G.T.O., CCTSI UL1TR001082 to A.H.L., 5UM1AI114271 to W.W.B. and J.E.G., NCATS/NIH UL1 TR001876 to S.J.T., and UL1TR002345 to L.B.B. NIAID staff members were involved in the study design, review of the findings, and preparation of the report for publication. Funding Information: Supported by federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US Department of Health and Human Services, under contract 1UM1AI114271 awarded to W.W.B. and UM2AI117870 awarded to Rho Inc. Additional support came from CTSA UL1TR000150 and UL1TR001422 to J.A.P., 5UL1TR001425 to G.K.K.H., NCRR/NIH UL1TR000451 to M.A.G. and R.S.G., CTSI 1UL1TR001430 to G.T.O., CCTSI UL1TR001082 to A.H.L., 5UM1AI114271 to W.W.B. and J.E.G., NCATS/NIH UL1 TR001876 to S.J.T., and UL1TR002345 to L.B.B. NIAID staff members were involved in the study design, review of the findings, and preparation of the report for publication. Disclosure of potential conflict of interest: M. A. Gill reports consulting fees from the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics. A. H. Liu reports consulting fees from Merck Sharp & Dohme and reports data-monitoring committee membership for an asthma study conducted by GlaxoSmithKline. G. T. O'Connor reports consulting fees from AstraZeneca and reports a grant from Janssen Pharmaceuticals paid to his employing institution. J. A. Pongracic reports provision of study drugs from GlaxoSmithKline, Teva, Merck, Boehringer-Ingelheim, and Genentech/Novartis for research studies outside of the scope of the submitted work. C. M. Kercsmar reports consulting fees from GlaxoSmithKline. S. J. Teach reports consulting fees from Novartis, grants from PCORI, the Fight for Children Foundation, EJF Philanthropies, and National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), and royalties from Uptodate. M. Kattan reports consulting fees from Novartis. L. B. Bacharier reports consulting fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Cephalon, DBV Technologies, Teva, Boehringer-Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Vectura, and Circassia. J. E. Gern reports consulting fees from Janssen, Regeneron, and PReP Biosciences and travel expenses from Boehringer-Ingelheim. W. W. Busse reports consulting fees from Boston Scientific, ICON, Novartis, GlaxoSmithKline, Genentech, Roche, Boehringer-Ingelheim, Sanofi Genzyme, AstraZeneca, Teva, 3M, PrEPBiopharm, Circassia, Regeneron, Peptinnovate, and Elsevier. D. J. Jackson reports consulting fees from Novartis, GlaxoSmithKline, Boehringer-Ingelheim, Pfizer, Commense, and Vectura and a grant from NIH/NHLBI. S. V. Lynch reports grants from the NIH/National Institute of Allergy and Infectious Diseases, NIH/National Institute on Drug Abuse, NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/Office of the Director, and the Crohn's and Colitis Foundation of America; reports personal fees from Siolta Therapeutics outside the submitted work; has a patent “Reductive prodrug cancer chemotherapy (Stan449-PRV)” issued, a patent “Combination antibiotic and antibody therapy for the treatment of Pseudomonas aeruginosa infection (WO2010091189A1)” with royalties paid by KaloBios, a patent “Therapeutic microbial consortium for induction of immune tolerance” licensed to Siolta Therapeutics, a patent “Systems and methods for detecting antibiotic resistance (WO2012027302A3)” issued, a patent “Nitroreductase enzymes (US7687474B2)” issued, a patent “Sinusitis diagnostics and treatments (WO2013155370A1)” licensed by Reflourish, and a patent “Methods and systems for phylogenetic analysis (US20120264637A1)” issued; and is a cofounder of Siolta Therapeutics, a start-up developing a mixed-species microbial oral therapeutic for induction of immune tolerance. The rest of the authors declare that they have no relevant conflicts of interest. Publisher Copyright: © 2022

PY - 2022/7

Y1 - 2022/7

N2 - Background: Seasonal variation in respiratory illnesses and exacerbations in pediatric populations with asthma is well described, though whether upper airway microbes play season-specific roles in these events is unknown. Objective: We hypothesized that nasal microbiota composition is seasonally dynamic and that discrete microbe–host interactions modify risk of asthma exacerbation in a season-specific manner. Methods: Repeated nasal samples from children with exacerbation-prone asthma collected during periods of respiratory health (baseline; n = 181 samples) or first captured respiratory illness (n = 97) across all seasons, underwent bacterial (16S ribosomal RNA gene) and fungal (internal transcribed spacer region 2) biomarker sequencing. Virus detection was performed by multiplex PCR. Paired nasal transcriptome data were examined for seasonal dynamics and integrative analyses. Results: Upper airway bacterial and fungal microbiota and rhinovirus detection exhibited significant seasonal dynamics. In seasonally adjusted analysis, variation in both baseline and respiratory illness microbiota related to subsequent exacerbation. Specifically, in the fall, when respiratory illness and exacerbation events were most frequent, several Moraxella and Haemophilus members were enriched both in virus-positive respiratory illnesses and those that progressed to exacerbations. The abundance of 2 discrete bacterial networks, characteristically comprising either Streptococcus or Staphylococcus, exhibited opposing interactions with an exacerbation-associated SMAD3 nasal epithelial transcriptional module to significantly increase the odds of subsequent exacerbation (odds ratio = 14.7, 95% confidence interval = 1.50-144, P = .02; odds ratio = 39.17, 95% confidence interval = 2.44-626, P = .008, respectively). Conclusions: Upper airway microbiomes covary with season and with seasonal trends in respiratory illnesses and asthma exacerbations. Seasonally adjusted analyses reveal specific bacteria–host interactions that significantly increase risk of asthma exacerbation in these children.

AB - Background: Seasonal variation in respiratory illnesses and exacerbations in pediatric populations with asthma is well described, though whether upper airway microbes play season-specific roles in these events is unknown. Objective: We hypothesized that nasal microbiota composition is seasonally dynamic and that discrete microbe–host interactions modify risk of asthma exacerbation in a season-specific manner. Methods: Repeated nasal samples from children with exacerbation-prone asthma collected during periods of respiratory health (baseline; n = 181 samples) or first captured respiratory illness (n = 97) across all seasons, underwent bacterial (16S ribosomal RNA gene) and fungal (internal transcribed spacer region 2) biomarker sequencing. Virus detection was performed by multiplex PCR. Paired nasal transcriptome data were examined for seasonal dynamics and integrative analyses. Results: Upper airway bacterial and fungal microbiota and rhinovirus detection exhibited significant seasonal dynamics. In seasonally adjusted analysis, variation in both baseline and respiratory illness microbiota related to subsequent exacerbation. Specifically, in the fall, when respiratory illness and exacerbation events were most frequent, several Moraxella and Haemophilus members were enriched both in virus-positive respiratory illnesses and those that progressed to exacerbations. The abundance of 2 discrete bacterial networks, characteristically comprising either Streptococcus or Staphylococcus, exhibited opposing interactions with an exacerbation-associated SMAD3 nasal epithelial transcriptional module to significantly increase the odds of subsequent exacerbation (odds ratio = 14.7, 95% confidence interval = 1.50-144, P = .02; odds ratio = 39.17, 95% confidence interval = 2.44-626, P = .008, respectively). Conclusions: Upper airway microbiomes covary with season and with seasonal trends in respiratory illnesses and asthma exacerbations. Seasonally adjusted analyses reveal specific bacteria–host interactions that significantly increase risk of asthma exacerbation in these children.

KW - Microbiome

KW - exacerbations

KW - pediatric asthma

KW - respiratory illness

KW - transcriptomics

KW - virus infection

UR - http://www.scopus.com/inward/record.url?scp=85125628670&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85125628670&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2022.01.020

DO - 10.1016/j.jaci.2022.01.020

M3 - Article

C2 - 35149044

AN - SCOPUS:85125628670

SN - 0091-6749

VL - 150

SP - 204

EP - 213

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 1

ER -

Seasonal airway microbiome and transcriptome interactions promote childhood asthma exacerbations

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