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ResearchIn-Press PreviewImmunologyInfectious diseaseMetabolism Open Access | 10.1172/jci.insight.206942

Multi-omics analyses reveal key immunological and metabolic correlates of mortality in HIV-associated Pneumocystis pneumonia

Peter Rossi-Smith,1 Ayanda Trevor Mnguni,2 Dora Pungan,3 Robert J. Samuels,3 Vaishnavi R. Kumaran,3 Leena Syed,1 Trevor Ferris,4 Kamil Skirlo,4 Joseph N. Jarvis,5 Nelesh P. Govender,6 Graeme Meintjes,7 Sean Wasserman,8 Jay K. Kolls,3 and Rachel P.J. Lai1

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Rossi-Smith, P. in: PubMed | Google Scholar

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Mnguni, A. in: PubMed | Google Scholar

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Pungan, D. in: PubMed | Google Scholar |

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Samuels, R. in: PubMed | Google Scholar

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Kumaran, V. in: PubMed | Google Scholar

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Syed, L. in: PubMed | Google Scholar

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Ferris, T. in: PubMed | Google Scholar

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

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

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

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

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Govender, N. in: PubMed | Google Scholar

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Meintjes, G. in: PubMed | Google Scholar

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Wasserman, S. in: PubMed | Google Scholar

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

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

1Department of Infectious Disease, Imperial College London, London, United Kingdom

2Department of Internal Medicine, University of Stellenbosch, Stellenbosch, South Africa

3Center for Translational Research in Infection and Inflammation, Tulane University, New Orleans, United States of America

4Agilent Measurement Suite, Department of Chemistry, Imperial College London, London, United Kingdom

5Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

6Africa Unit, MRC Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom

7Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

8Blizard Institute, Queen Mary University of London, London, United Kingdom

Find articles by Lai, R. in: PubMed | Google Scholar

Published October 6, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.206942.
Copyright © 2026, Rossi-Smith 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 October 6, 2026 - Version history
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Abstract

Pneumocystis jirovecii pneumonia (PCP) remains a major cause of life-threatening respiratory failure in people with advanced HIV, yet the biological factors associated with mortality are incompletely understood. We performed integrated transcriptomic, proteomic, and metabolomic profiling of bronchoalveolar lavage fluid from 42 adults with HIV-associated PCP, relating molecular signatures to mortality. We found that fungal burden, measured by sputum immunofluorescence, Pneumocystis qPCR, and 1,3-β-D-glucan, did not differ between survivors and non-survivors or correlate with baseline gas exchange. Instead, non-survivors exhibited a bronchoalveolar immunometabolic failure signature characterised by marked depletion of immunoglobulins and complement, reduced pattern recognition receptors and fibroblast growth factor family proteins, and broad disruption of extracellular matrix organisation. Metabolomic profiling revealed enrichment of arginine-urea cycle and tricarboxylic acid pathways, with coordinated accumulation of arginine, citrulline, and TCA cycle intermediates consistent with nitrosative and mitochondrial stress. An integrated proteo-metabolomic score summarising this state was significantly higher in non-survivors and did not correlate with fungal burden or cytomegalovirus co-infection. In an immunodeficient precision-cut lung slice model, antigen-screened intravenous immunoglobulin restored macrophage-mediated Pneumocystis clearance, providing proof-of-concept for opsonic augmentation. Our findings indicate that mortality in HIV-PCP is defined by profound immunometabolic failure, highlighting humoral depletion and impaired alveolar repair as potential targets for host-directed adjunctive therapy.

Graphical Abstract
graphical abstract
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  • Version 1 (October 6, 2026): In-Press Preview
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