Aging and Host Responses to Severe Infection: Proteomic Analysis of a Prospective Multicenter Cohort From Uganda

Abstract

Objective: Severe infectious diseases are a leading cause of morbidity and mortality worldwide, particularly in sub-Saharan Africa (SSA), where young and middle-aged adults are disproportionately affected. Although age-related immune changes such as inflammaging and immunosenescence have been well characterized in high-income countries, their relevance to host responses during infection in SSA remains poorly understood. We aimed to characterize age-associated differences in immune, metabolic, and endothelial responses to severe infection in a prospective, multicenter cohort of adults in Uganda.

Design: Prospective cohort study.

Setting: Two public referral hospitals in Uganda.

Patients: Non-pregnant adults (18 yr old or older) hospitalized with severe, undifferentiated infection.

Interventions: None.

Measurements and main results: We analyzed clinical data and serum Olink proteomic profiles from 434 participants (median age: 45 yr old, interquartile range : 31-57). Clinically, illness severity and mortality were highest and comparable among adults 35-44, 45-59, and 60 years old or older, relative to younger adults. HIV prevalence peaked in the 35-44 and 45-59 age groups. Although most host responses were conserved across age groups after adjustment for sex and high-burden co-infections, patients 60 years old or older exhibited distinct immune dysregulation characterized by signs of Th1-predominant innate immune activation (increased CXCL9, CCL18, MCP1, and MCP4 expression, reduced interleukin-13 expression), dysregulated adaptive immunity (increased soluble CD27 and CD70 expression, reduced CD21 [CR2] expression), and increased cellular turnover and endothelial remodeling.

Conclusions: Older age (60 yr old or older) is associated with distinct host responses to severe infection in SSA. These findings may inform development of age-stratified, host-directed treatment strategies for severe infectious diseases.

Keywords: Africa; aging; immunology; infection; proteomics.

Figure 1.

Host responses by age group. First two principal components of proteomic variance stratified by age as continuous (A) or categorical variable (B). C, Volcano plot of differential protein expression in patients 60 yr old or older vs. 18–24 yr old, adjusted for sex, illness duration before enrollment, and HIV, malaria, and tuberculosis coinfection. Interleukin (IL)-1a, IL-33, latent-transforming growth factor beta-binding protein 2, and fibroblast activation protein (alpha) excluded as less than 20% of log₂-normalized protein expression values were above each Olink panel’s estimated limits of detection. Red shading indicates proteins differentially expressed at Benjamini-Hochberg-adjusted p value of less than or equal to 0.05 (n = 149; two patients with missing HIV status excluded). See Tables S6–S9 (https://links.lww.com/CCX/B561) for detailed differential expression results by age group. ADGRG1 = adhesion G-protein coupled receptor G1, CA3 = carbonic anhydrase 3, COMP = cartilage oligomeric matrix protein, CR2 = complement receptor type 2, DCN = decorin, Dim1 = principal component 1, Dim2 = principal component 2, EFEMP1 = EGF-containing fibulin-like extracellular matrix protein 1, FASLG = Fas ligand (tumor necrosis factor ligand superfamily member 6), GAL9 = galectin-9, GAS6 = growth arrest-specific protein 6, IGFBP3 = insulin-like growth factor-binding protein 3, IGLC2 = immunoglobulin lambda constant 2, KIR3DL1 = killer cell immunoglobulin-like receptor 3DL1, KIT = mast/stem cell growth factor receptor kit (proto-oncogene c-kit), MCP1 = monocyte chemoattractant protein 1 (CCL2), MCP4 = monocyte chemoattractant protein 4 (CCL13), MMP7 = matrix metalloproteinase-7 (Matrilysin), PCOLCE = procollagen C-endopeptidase enhancer 1, PRSS2 = protease, serine, 2 (trypsin-2), PTN = pleiotrophin, SELL = L-selectin (selectin L), TNFRSF12A = Tumor necrosis factor receptor superfamily member 12A, TNXB = tenascin-XB, UMOD = uromodulin.