# Microbial Disruption of Dendritic Cell Maturation and Function

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2020 · $620,801

## Abstract

Several human pathogens express structurally divergent forms of lipid A, the biologically active moiety of LPS,
as a strategy to evade innate immune detection and establish chronic infection. The oral mucosal pathogen
Porphyromonas gingivalis intrinsically expresses underacylated lipid A moieties and can modify the
phosphorylation of lipid A, leading to altered TLR4 signaling. In addition to local immunopathology, significant
clinical and experimental evidence implicate P. gingivalis as risk factor for the development of chronic
systemic inflammatory diseases including rheumatoid arthritis, cancer, and cardiovascular disease.
Dysregulated T cell responses are believed to play a role in these inflammatory disorders. While the role of
lipid A modifications in evasion of innate immune signaling is established, how this influences adaptive immune
responses that contribute to dysregulation of host immunity has not been explored. Myeloid dendritic cells
(DCs) and their blood monocyte precursors play an important role in bridging the innate and adaptive arms of
the immune system during Gram-negative bacterial infection. TLR4 activation in these cells induces a distinct
maturation phenotype that promotes their mobilization to immune T cell areas for initiation of antigen-specific
immunity. Despite the wealth of studies on P. gingivalis pathogenesis in the oral cavity, the immunological
mechanisms underlying P. gingivalis mediated systemic inflammation are not well defined.
We propose in this application to define the impact of P. gingivalis lipid A moieties on DC responses and T cell
activation that contribute to P. gingivalis mediated systemic immunopathology. We hypothesize that the
different lipid A species expressed by P. gingivalis drive DC responses leading to distinct T cell activation
pathways that contribute to P. gingivalis-mediated systemic inflammatory outcomes. The following Aims are
proposed to test this hypothesis: Aim 1. To define the role of P. gingivalis lipid A species and TLR4 signaling
in DC responses and T cell activation in vitro. Aim 2.To define the role of P. gingivalis lipid A species on TLR4-
dependent DC and T cell responses following P. gingivalis oral infection. Aim 3. To define the role of P.
gingivalis distinct lipid A species and DC-specific TLR4 signaling in the development of P. gingivalis induced
immunopathology in vivo.
Strikingly, several Gram-negative bacteria that express immune-evasive lipid A are associated with increased
risk of autoimmune disease, atherosclerosis, and cancer. Thus, these studies have broad implications and will
provide important insights into the mechanisms by which Gram-negative pathogens alter systemic adaptive
immune responses resulting immunopathology.
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## Key facts

- **NIH application ID:** 9987517
- **Project number:** 5R01AI142628-03
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Caroline A Genco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $620,801
- **Award type:** 5
- **Project period:** 2018-09-24 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987517

## Citation

> US National Institutes of Health, RePORTER application 9987517, Microbial Disruption of Dendritic Cell Maturation and Function (5R01AI142628-03). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9987517. Licensed CC0.

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