Research ArticleGeneticsInfectious disease
Open Access | 10.1172/JCI179822
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Ivie, J. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
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1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
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1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Peterson, G. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Benchek, P. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
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1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Veith, L. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
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1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Ha, D. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
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1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
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1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Stein, C. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Khor, C. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Thwaites, G. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Hai, H. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Thuong, N. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Chang, X. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Dunstan, S. in: PubMed | Google Scholar
1Department of Global Health and
2Department of Medicine, University of Washington, Seattle, Washington, USA.
3Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
4Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda.
5Pham Ngoc Thanh Hospital, Ho Chi Minh City, Vietnam.
6Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
7Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
8Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam.
9Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
10Genome Institute of Singapore, A-STAR, Singapore.
11Singapore Eye Research Institute, Singapore National Eye Centre and Eye ACP, Duke–National University of Singapore, Singapore.
12Department of Biochemistry, National University of Singapore, Singapore.
13Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
14Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia.
Address correspondence to: Joshua J. Ivie, Seattle Children’s Research Institute, 1900 9th Avenue, Seattle, Washington 98101, USA. Phone: 206.884.3239; Email: jivie@uw.edu. Or to: Thomas R. Hawn, Department of Medicine, University of Washington, 750 Republican Street Box 358061, Seattle, Washington 98195-8061, USA. Phone: 206.616.4124; Email: thawn@uw.edu.
Find articles by Hawn, T. in: PubMed | Google Scholar
Published May 22, 2025 - More info
Published in Volume 135, Issue 14 on July 15, 2025Immune and clinical outcomes to Mycobacterium tuberculosis (Mtb) infection vary greatly between individuals, yet the underlying genetic and cellular mechanisms driving this heterogeneity remain poorly understood. We performed a cellular genome-wide association study to identify genetic variants associated with Mtb-induced monocyte transcriptional expression of IL1B, IL6, TNF, and IFNB1 via RNA-Seq in a Ugandan cohort. Significantly associated variants were assessed for transferability in an independent Seattle cohort, further validated in vitro, and assessed for clinical phenotype associations. We identified 77 loci suggestively associated with Mtb-induced cytokine expression in monocytes in Uganda. SNPs associated with Mtb-induced TNF were enriched within α-linolenic acid metabolism pathway genes, which was validated in vitro using PLA2 inhibitors. Four loci maintained significant associations in Seattle. We validated a cytokine effect with siRNA knockdown for two of these loci, which mapped to the genes SLIT3 and SLC1A1. Furthermore, exogenous treatment of macrophages with SLIT3 enhanced Mtb intracellular replication. Finally, SLC1A1 and SLIT3 variants were associated with susceptibility to tuberculous meningitis and subsequent survival, respectively, in a Vietnamese cohort. In summary, we identified multiple variants and pathways associated with Mtb-induced cytokine transcriptional responses that were validated in vitro and were associated with clinical tuberculosis susceptibility.
IntroductionTuberculosis (TB) is a leading cause of death worldwide, including 1.3 million deaths in 2022 (1). Clinical outcomes after exposure to Mycobacterium tuberculosis (Mtb) are varied and include pathogen clearance, asymptomatic infection, pulmonary TB, and tuberculous meningitis (TBM) (2). Although parts of the heterogeneity of clinical outcomes are attributable to known clinical risk factors, the majority of mechanisms are poorly understood (3). One hypothesis is that genetic variation in the host immune response regulates the pleiotropic outcomes after Mtb exposure. Mtb has a long coevolutionary history with humans allowing for the accumulation of numerous genetic adaptations in both pathogen and host that regulate pivotal responses (4, 5). Defining the genetic variants responsible for controlling the Mtb-induced host response may yield important insights into differences in host progression and identify novel areas of Mtb-response biology for further research.
Several lines of evidence suggest that genetic factors regulate susceptibility to Mtb infection and TB disease (6–19). Mendelian studies in pediatric populations support an important role of IL-12/IFN-γ–mediated pathways for controlling mycobacterial infection (20). Several variants have been associated with pulmonary TB across a number of genome-wide association studies (GWAS) (8, 12–19). However, despite numerous findings of genome-wide significance, there is little concordance between studies. Although susceptibility to TB clinical outcomes has consistently been found to be highly heritable, the variants previously identified only explain a small portion of the genetically indicated effect (8, 9, 11). Potential reasons for this missing heritability include cohort sample size, heterogeneity of clinical phenotypes, lack of adjustment for non-genetic risk factors, and Mtb strain diversity. A cellular GWAS approach addresses these limitations by examining genetic variants associated with inter-individual intermediate traits measured by in vitro assays (21). Unencumbered by many of the same limitations of clinical studies, variants regulating essential pathogen-induced cellular traits can be identified. These variants can then be used to identify important host response factors and further elucidate previous clinical GWAS findings by yielding mechanistic insight. This technique has been used to characterize the genetic regulation of multiple cellular phenotypes, including cytokine production in response to a variety of microbial stimuli, cell death, and intracellular replication of infections such as Salmonella and Chlamydia (21–28).
Macrophages are pivotal innate immune cells in TB pathogenesis owing to their early roles in initial detection of Mtb, serving as a cellular home for persistent infection, and involvement in clearance of infection (2, 29). Macrophage signaling pathways are important at each of these steps to modulate pathogenesis. In particular, the host cytokine response plays a large role in determining infection outcomes, requiring a sufficient response to control infection without over-responding and causing tissue pathology (30). Interleukin-1β (IL1B), interleukin-6 (IL6), tumor necrosis factor (TNF), and interferon-β (IFNB1), as key components of this response, have important functions in initial detection of Mtb, controlling infection, initiating effective T cell responses, and modulating immunopathology (31–40). To our knowledge, genome-wide assessment of genetic regulation of live virulent Mtb-induced cytokine responses in macrophages has not been assessed previously.
In the current study, we characterized the cytokine transcriptional profile of monocytes and macrophages isolated from two distinct human population cohorts in response to live Mtb infection in vitro and performed genome-wide assessment of the major genetic variants and genetically regulated pathways associated with differential Mtb-induced cytokine response. The genes, SLIT3 and SLC1A1, and the α-linolenic acid signaling pathway were identified as candidate response regulators and were validated using in vitro macrophage assays. Lastly, we investigated whether the SLIT3 and SLC1A1 variants affecting the Mtb-induced cytokine response were further associated with clinical TB phenotypes and found significant differences in TBM susceptibility and subsequent survival.
ResultsMtb-induced cytokine GWAS yields 77 genomic loci with suggestive associations. To discover genetic variants associated with differential Mtb-induced cytokine production, we examined 100 individuals in a Ugandan cohort with a previously generated RNA-Seq dataset of CD14+ monocytes infected for 6 hours with H37Rv Mtb compared with media control (Figure 1A and Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/JCI179822DS1) (41, 42). We examined IL1B, IL6, TNF, and IFNB1 log2 fold change in expression levels in this dataset, which were all highly increased during Mtb infection (Supplemental Figure 1A). All 100 individuals were simultaneously genotyped and imputed, yielding 8.3 million testable SNPs. We assessed each SNP using a linear model in the GENESIS package in R, adjusting for sex, age, and batch, and controlled for ancestry and population structure by adjusting for genotypic principal components (PCs), PC1, PC2, and kinship (Supplemental Figure 2). We then clustered individual SNP results into independent genomic loci using linkage disequilibrium–based (LD-based) clumping to t
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