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Deciphering HTLV-1-associated Lung Pathology: Inflammation, Monocyte Recruitment and Differentiation Triggered by HTLV-1-exposed Alveolar Epithelial Cells

ABSTRACT: Individuals with Human T-Lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis are prone to pulmonary complications (e.g., bronchiectasis), linked to chronic inflammation. This study assessed the impact of HTLV-1 infection on lung inflammation by analyzing the alveolar transcriptome of A549 epithelial cells following exposure to HTLV-1. Co-culture with HTLV-1-infected MT-2 cells caused transcriptomic changes related to viral response, NF-kB activation, and inflammation. RT-qPCR confirmed elevated expression of the chemokine monocyte chemotactic protein-1 (MCP-1/CCL2) and CSF-1 in A549 MT-2 co-cultures. Increased CSF-1 expression was mechanistically linked to NF-kB signaling, using CRISPR/Cas9 RELA knockout. Supernatant from A549 MT-2 co-cultures triggered chemotaxis and macrophage differentiation of THP-1 and primary monocytes. STRING analysis revealed enrichment in pathways associated with monocyte infiltration and bronchiectasis, aligning with clinical and multi-ancestry GWAS data. Overall, this study highlights HTLV-1's role in driving inflammation and monocyte recruitment in the alveolar epithelium, potentially contributing to viral persistence and immune evasion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312068 | GEO | 2026/06/10

REPOSITORIES: GEO

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Project description:Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurodegenerative disease that affects motor, urinary, intestinal, and sensory functions. Typically, HAM/TSP is slowly progressive, but it may vary from limited motor disability after decades (very slow progression) to loss of motor function in a few years from disease onset (rapid). In this study, we aimed to identify prognostic biomarkers for HAM/TSP to support patient management. Thus, proteomic analysis of the cerebrospinal fluid (CSF) was performed with samples from HTLV-1 asymptomatic carriers (AC) (n=13) and HAM/TSP patients (n=21) with rapid, typical, and very slow progression using quantitative label-free liquid chromatography/tandem mass spectrometry. Enrichment analyses were also carried out to identify key biological processes associated with distinct neurological conditions in HTLV-1 infection. Candidate biomarkers were validated by ELISA in paired CSF and serum samples, and samples from HTLV-1-seronegative individuals (n=9) were used as controls. CSF analysis identified 602 proteins. Leukocyte/cell activation, immune response processes and neurodegeneration pathways were enriched in rapid progressors. Conversely, HTLV-1 AC and HAM/TSP patients with typical and very slow progression had enriched processes for nervous system development. Differential expression analysis showed that soluble vascular cell adhesion molecule 1 (sVCAM-1), chitotriosidase 1 (CHIT1), and cathepsin C (CTSC) were upregulated in HAM/TSP. However, only CHIT1 was significantly elevated after validation, particularly in HAM/TSP rapid progressors. In contrast, none of these biomarkers were altered in serum. Additionally, CSF CHIT1 levels in HAM/TSP patients positively correlated with the speed of HAM/TSP progression, defined as points in the IPEC-2 HAM/TSP disability scale per year of disease, and with CSF levels of phosphorylated neurofilament heavy chain, neopterin, CXCL5, CXCL10, and CXCL11. In conclusion, higher CSF levels of CHIT1 were associated with HAM/TSP rapid progression and correlated with other biomarkers of neuroinflammation and neurodegeneration. Therefore, we propose CHIT1 as a surrogate CSF biomarker to identify HAM/TSP patients with a worse prognosis.

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Deciphering HTLV-1-associated Lung Pathology: Inflammation, Monocyte Recruitment and Differentiation Triggered by HTLV-1-exposed Alveolar Epithelial Cells

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