Monika Esser1, Tobias R Kollmann2, Brian A Reikie2,3, Rozanne C M Adams1, Aleksandra Leligdowicz2, Kevin Ho2, Shalena Naidoo1, Candice E Rusk2, Corena de Beer4, Wolfgang Preiser4, Mark F Cotton5, David P Speert2. 1. Immunology Unit, Division of Medical Microbiology, Department of Pathology, NHLS and Stellenbosch University, PO 19063, Tygerberg 7505 South Africa. 2. Division of Infectious & Immunological Diseases, and Centre for Understanding and Preventing Infections in Children, Department of Pediatrics, University of British Columbia, Vancouver, V5Z 4H4, Canada. 3. Leaders in Medicine Program, University of Calgary, Calgary, T2N 4N1, Canada. 4. Division of Medical Virology, Department of Pathology, NHLS and Stellenbosch University, PO 19063, Tygerberg 7505 South Africa. 5. Department of Paediatrics and Child Health, Tygerberg Children's Hospital and Stellenbosch University, PO 19063, Tygerberg 7505 South Africa.
Abstract
BACKGROUND: Early in life, HIV-exposed uninfected (HEU) infants are at an increased risk of morbidity and mortality from infectious disease compared with HIV-unexposed (UE) infants. To improve our understanding of the mechanisms underlying their increased risk, we contrasted innate immune development between HEU and UE infants in a developing world setting, where early life infectious disease risk is exceptionally high. METHODS: A prospective longitudinal cohort of HEU and UE newborns was established, and the most detailed characterization to date of HEU infant immune development was performed. Single-cell cytokine production was analyzed by flow cytometry after stimulation of whole blood with pathogen-associated molecular patterns (PAMPs). RESULTS: Monocyte, classical dendritic cell, and plasmacytoid dendritic cell composition was similar between HEU and UE infants throughout the first year of life. However, HEU mononuclear cells mounted an enhanced pro-inflammatory response to PAMP stimulation, both in quantity of cytokine produced per cell and in proportion of responder cells. Significant differences in cytokine production were detected on the single-cell level in a PAMP-specific pattern, but only at 2 and 6 weeks of age; all differences normalized by 12 months of age. CONCLUSIONS: This time course of innate immune deviation early in life corresponds to the clinical window of vulnerability to infections in HEU infants and may be at least partially responsible for their increased morbidity and mortality from infectious disease.
BACKGROUND: Early in life, HIV-exposed uninfected (HEU) infants are at an increased risk of morbidity and mortality from infectious disease compared with HIV-unexposed (UE) infants. To improve our understanding of the mechanisms underlying their increased risk, we contrasted innate immune development between HEU and UE infants in a developing world setting, where early life infectious disease risk is exceptionally high. METHODS: A prospective longitudinal cohort of HEU and UE newborns was established, and the most detailed characterization to date of HEUinfant immune development was performed. Single-cell cytokine production was analyzed by flow cytometry after stimulation of whole blood with pathogen-associated molecular patterns (PAMPs). RESULTS: Monocyte, classical dendritic cell, and plasmacytoid dendritic cell composition was similar between HEU and UE infants throughout the first year of life. However, HEU mononuclear cells mounted an enhanced pro-inflammatory response to PAMP stimulation, both in quantity of cytokine produced per cell and in proportion of responder cells. Significant differences in cytokine production were detected on the single-cell level in a PAMP-specific pattern, but only at 2 and 6 weeks of age; all differences normalized by 12 months of age. CONCLUSIONS: This time course of innate immune deviation early in life corresponds to the clinical window of vulnerability to infections in HEUinfants and may be at least partially responsible for their increased morbidity and mortality from infectious disease.
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