AI discovery of TLR agonist-driven phenotypes reveals unique features of peripheral cells from healthy donors and ART-suppressed people living with HIV Article Swipe
Robert W. Omange
,
Samuel Kim
,
Nikita Kolhatkar
,
Tempest Plott
,
Will Van Trump
,
Kenneth Zhang
,
Hope O’Donnell
,
Daniel Chen
,
Ahmed Hosny
,
Michael Wiest
,
Zach Barry
,
Elisa Cambronero Addiego
,
Meron Mengistu
,
Pamela M. Odorizzi
,
Yanhui Cai
,
Rachel Jacobson
,
Jeffrey J. Wallin
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.3389/fimmu.2025.1541152
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.3389/fimmu.2025.1541152
Background Selective and potent Toll-like receptor (TLR) agonists are currently under evaluation in preclinical models and clinical studies to understand how the innate immune system can be harnessed for therapeutic potential. These molecules are designed to modulate innate and adaptive immune responses, making them promising therapeutic candidates for treating diseases such as cancer or chronic viral infections. Much is known about the expression and signaling of TLRs which varies based on cell type, cellular localization, and tissue distribution. However, the downstream effects of different TLR agonists on cellular populations and phenotypes are not well understood. This study aimed to investigate the impact of TLR pathway stimulation on peripheral blood mononuclear cell (PBMC) cultures from people living with HIV (PLWH) and healthy donors. Methods The effects of TLR4, TLR7, TLR7/8, TLR8 and TLR9 agonists were evaluated on cytokine production, cell population frequencies, and morphological characteristics of PBMC cultures over time. Changes in the proportions of different cell populations in blood and morphological features were assessed using high-content imaging and analyzed using an AI-driven approach. Results TLR4 and TLR8 agonists promoted a compositional shift and accumulation of small round (lymphocyte-like) PBMCs, whereas TLR9 agonists led to an accumulation of large round (myeloid-like) PBMCs. A related increase was observed in markers of cell death, most prominently with TLR4 and TLR8 agonists. All TLR agonists were shown to promote some features associated with cellular migration. Furthermore, a comparison of TLR agonist responses in healthy and HIV-positive PBMCs revealed pronounced differences in cytokine/chemokine responses and morphological cellular features. Most notably, higher actin contraction and nuclear fragmentation was observed in response to TLR4, TLR7, TLR7/8 and TLR9 agonists for antiretroviral therapy (ART)-suppressed PLWH versus healthy PBMCs. Conclusions These data suggest that machine learning, combined with cell imaging and cytokine quantification, can be used to better understand the cytological and soluble immune responses following treatments with immunomodulatory agents in vitro. In addition, comparisons of these responses between disease states are possible with the appropriate patient samples.
Related Topics
Concepts
TLR9
TLR7
Peripheral blood mononuclear cell
TLR4
Chemokine
Immunology
Immune system
Cytokine
Innate immune system
Toll-like receptor
Biology
Agonist
Population
Receptor
Medicine
Gene expression
In vitro
Environmental health
Biochemistry
Gene
DNA methylation
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3389/fimmu.2025.1541152
- https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1541152/pdf
- OA Status
- gold
- Cited By
- 2
- References
- 64
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4408815530
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4408815530Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.3389/fimmu.2025.1541152Digital Object Identifier
- Title
-
AI discovery of TLR agonist-driven phenotypes reveals unique features of peripheral cells from healthy donors and ART-suppressed people living with HIVWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2025Year of publication
- Publication date
-
2025-03-25Full publication date if available
- Authors
-
Robert W. Omange, Samuel Kim, Nikita Kolhatkar, Tempest Plott, Will Van Trump, Kenneth Zhang, Hope O’Donnell, Daniel Chen, Ahmed Hosny, Michael Wiest, Zach Barry, Elisa Cambronero Addiego, Meron Mengistu, Pamela M. Odorizzi, Yanhui Cai, Rachel Jacobson, Jeffrey J. WallinList of authors in order
- Landing page
-
https://doi.org/10.3389/fimmu.2025.1541152Publisher landing page
- PDF URL
-
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1541152/pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1541152/pdfDirect OA link when available
- Concepts
-
TLR9, TLR7, Peripheral blood mononuclear cell, TLR4, Chemokine, Immunology, Immune system, Cytokine, Innate immune system, Toll-like receptor, Biology, Agonist, Population, Receptor, Medicine, Gene expression, In vitro, Environmental health, Biochemistry, Gene, DNA methylationTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
2Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 2Per-year citation counts (last 5 years)
- References (count)
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64Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.TLR9 | 131, 190, 270 |
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