Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2

Clarissa M. Koch; Andrew D. Prigge; Kishore R. Anekalla; Avani Shukla; Hanh Chi Do Umehara; Leah Setar; Jairo Chavez; Hiam Abdala-Valencia; Yuliya Politanska; Nikolay S. Markov; Grant R. Hahn; Taylor Heald-Sargent; L. Nelson Sanchez-Pinto; William J. Muller; Benjamin D. Singer; Alexander V. Misharin; Karen M. Ridge; Bria M. Coates

doi:10.1165/rcmb.2021-0292OC

Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2

Clarissa M. Koch, Andrew D. Prigge, Kishore R. Anekalla, Avani Shukla, Hanh Chi Do Umehara, Leah Setar, Jairo Chavez, Hiam Abdala-Valencia, Yuliya Politanska, Nikolay S. Markov, Grant R. Hahn, Taylor Heald-Sargent, L. Nelson Sanchez-Pinto, William J. Muller, Benjamin D. Singer, Alexander V. Misharin, Karen M. Ridge, Bria M. Coates^*

^*Corresponding author for this work

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

25 Scopus citations

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 180 million people since the onset of the pandemic. Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2-infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2-infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.

Original language	English (US)
Pages (from-to)	206-222
Number of pages	17
Journal	American journal of respiratory cell and molecular biology
Volume	66
Issue number	2
DOIs	https://doi.org/10.1165/rcmb.2021-0292OC
State	Published - Feb 2022

Funding

Acknowledgments: The authors thank the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University’s high-performance computing facility, to advance research in genomics. Figure E5 was created using BioRender.com. They also thank all the participants for enrolling in this study. The authors thank Rogan Grant for his help with the RNA-seq pipeline and G.R.S. Budinger for their thoughtful discussions. The authors thank the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg's Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University's high-performance computing facility, to advance research in genomics. Figure E5 was created using BioRender.com. They also thank all the participants for enrolling in this study. The authors thank Rogan Grant for his help with the RNA-seq pipeline and G.R.S. Budinger for their thoughtful discussions. Supported by the Gorter Family Foundation (A.D.P.); National Institutes of Health grants U19AI135964, P01AG049665, and R01HL153312, and Northwestern University Clinical and Translational Sciences Institute COVID-19 Rapid Response Grant (A.V.M.); National Institutes of Health grants P01AG049665 and P01GM096971 (K.M.R.); Stanley Manne Research Institute COVID-19 Springboard Exploratory Research Award, American Thoracic Society Unrestricted Grant: Pulmonary, and National Institutes of Health grant K08HL143127 (B.M.C.); National Institutes of Health grants R01HL149883, R01HL153122, and R01HL114800 (B.D.S.); and the Stanley Manne Research Institute COVID-19 Springboard Exploratory Research Award (T.H.-S. and L.N.S.-P.).

Keywords

COVID-19
IFNs
Pneumonia
T cells
Viral infections

ASJC Scopus subject areas

Molecular Biology
Pulmonary and Respiratory Medicine
Clinical Biochemistry
Cell Biology

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10.1165/rcmb.2021-0292OC

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Koch, C. M., Prigge, A. D., Anekalla, K. R., Shukla, A., Do Umehara, H. C., Setar, L., Chavez, J., Abdala-Valencia, H., Politanska, Y., Markov, N. S., Hahn, G. R., Heald-Sargent, T., Sanchez-Pinto, L. N., Muller, W. J., Singer, B. D., Misharin, A. V., Ridge, K. M., & Coates, B. M. (2022). Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2. American journal of respiratory cell and molecular biology, 66(2), 206-222. https://doi.org/10.1165/rcmb.2021-0292OC

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abstract = "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 180 million people since the onset of the pandemic. Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2-infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2-infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.",

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doi = "10.1165/rcmb.2021-0292OC",

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Koch, CM, Prigge, AD, Anekalla, KR, Shukla, A, Do Umehara, HC, Setar, L, Chavez, J, Abdala-Valencia, H, Politanska, Y, Markov, NS, Hahn, GR, Heald-Sargent, T , Sanchez-Pinto, LN , Muller, WJ , Singer, BD , Misharin, AV , Ridge, KM & Coates, BM 2022, 'Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2', American journal of respiratory cell and molecular biology, vol. 66, no. 2, pp. 206-222. https://doi.org/10.1165/rcmb.2021-0292OC

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AU - Koch, Clarissa M.

AU - Prigge, Andrew D.

AU - Anekalla, Kishore R.

AU - Shukla, Avani

AU - Do Umehara, Hanh Chi

AU - Setar, Leah

AU - Chavez, Jairo

AU - Abdala-Valencia, Hiam

AU - Politanska, Yuliya

AU - Markov, Nikolay S.

AU - Hahn, Grant R.

AU - Heald-Sargent, Taylor

AU - Sanchez-Pinto, L. Nelson

AU - Muller, William J.

AU - Singer, Benjamin D.

AU - Misharin, Alexander V.

AU - Ridge, Karen M.

AU - Coates, Bria M.

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N2 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 180 million people since the onset of the pandemic. Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2-infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2-infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.

AB - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 180 million people since the onset of the pandemic. Despite similar viral load and infectivity rates between children and adults, children rarely develop severe illness. Differences in the host response to the virus at the primary infection site are among the mechanisms proposed to account for this disparity. Our objective was to investigate the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compare it with the host response to respiratory syncytial virus (RSV) and influenza virus. We analyzed clinical outcomes and gene expression in the nasal mucosa of 36 children with SARS-CoV-2, 24 children with RSV, 9 children with influenza virus, 16 adults with SARS-CoV-2, and 7 healthy pediatric and 13 healthy adult controls. In both children and adults, infection with SARS-CoV-2 led to an IFN response in the nasal mucosa. The magnitude of the IFN response correlated with the abundance of viral reads, not the severity of illness, and was comparable between children and adults infected with SARS-CoV-2 and children with severe RSV infection. Expression of ACE2 and TMPRSS2 did not correlate with age or presence of viral infection. SARS-CoV-2-infected adults had increased expression of genes involved in neutrophil activation and T-cell receptor signaling pathways compared with SARS-CoV-2-infected children, despite similar severity of illness and viral reads. Age-related differences in the immune response to SARS-CoV-2 may place adults at increased risk of developing severe illness.

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KW - IFNs

KW - Pneumonia

KW - T cells

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Age-related Differences in the Nasal Mucosal Immune Response to SARS-CoV-2

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