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ResearchIn-Press PreviewCOVID-19Infectious disease Open Access | 10.1172/JCI188222

CXCL12 ameliorates neutrophilia and disease severity in SARS-CoV-2 infection

Jian Zheng,1 Hima Dhakal,1 Enya Qing,2 Rejeena Shrestha,1 Anne E. Geller,1 Samantha M. Morrissey,1 Divyasha Saxena,3 Xiaoling Hu,4 Hong Li,5 Haiyan Li,4 Kevin Wilhelmsen,6 Linder H. Wendt,7 Klaus Klumpp,6 Patrick S. Hume,8 William J. Janssen,8 Rachel Brody,9 Kenneth E. Palmer,3 Silvia M. Uriarte,10 Patrick P. Ten Eyck,7 David K. Meyerholz,11 Michael L. Merchant,12 Kenneth McLeish,12 Tom Gallagher,2 Jiapeng Huang,13 Jun Yan,1 and Stanley Perlman14

1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

Find articles by McLeish, K. in: JCI | PubMed | Google Scholar |

1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

Find articles by Huang, J. in: JCI | PubMed | Google Scholar |

1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

Find articles by Yan, J. in: JCI | PubMed | Google Scholar |

1Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, United States of America

2Department of Microbiology and Immunology, Loyola University Chicago, Maywood, United States of America

3Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, United States of America

4Division of Immunotherapy, the Hiram C. Polk, Jr., MD, Department of Surger, University of Louisville School of Medicine, Louisville, United States of America

5Functional Immunomics Core, Brown Cancer Center, University of Louisville School of Medicine, Louisville, United States of America

6BIOAGE Labs, Richmond, United States of America

7Institute for Clinical and Translational Science, University of Iowa, Iowa City, United States of America

8Department of Medicine, Division of Pulmonary and Critical Care, National Jewish Health, Denver, United States of America

9Department of Pathology, Molecular and Cell based Medicine, Icahn School of Medicine at Mount Sinai, New York, United States of America

10Department of Oral Immunology and Infectious Diseases, University of Louisville School of Medicine, Louisville, United States of America

11Department of Pathology, University of Iowa, Iowa City, United States of America

12Department of Medicine, Division of Nephrology and Hypertension, University of Louisville School of Medicine, Louisville, United States of America

13Department of Anesthesiology and Perioperative Medicine, University of Louisville School of Medicine, Louisville, United States of America

14Department of Microbiology and Immunology, University of Iowa, Iowa City, United States of America

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Published January 7, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI188222.
Copyright © 2025, Zheng et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 7, 2025 - Version history
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Abstract

Neutrophils, particularly low-density neutrophils (LDNs), are believed to contribute to acute COVID-19 severity. Here, we showed that neutrophilia can be detected acutely and even months after SARS-CoV-2 infection in patients and mice, while neutrophil depletion reduced disease severity in mice. A key factor in neutrophilia and severe disease in infected mice was traced to the chemokine CXCL12 secreted by bone marrow cells and unexpectedly, endothelial cells. CXCL12 levels were negatively correlated with LDN numbers in longitudinal analyses of patient blood samples. CXCL12 blockade in SARS-CoV-2-infected mice increased blood/lung neutrophil numbers thereby accelerating disease progression without changing lung virus titers. The exaggerated mortality caused by CXCL12 blockade can be reversed by neutrophil depletion. In addition, blocking interactions between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) reduced CXCL12 levels, suggesting a signal transduction from virus-mediated ACE2 ligation to increased CXCL12 secretion. Collectively, these results demonstrate a previously unappreciated role of CXCL12 in diminishing neutrophilia, including low density neutrophilia, and its deleterious effects in SARS-CoV-2 infections. The results also support the involvement of SARS-CoV-2-endothelial cell interactions in viral pathogenesis.

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