# TOLLIP Deficiency, Immune Dysregulation, and Tuberculosis Susceptibility

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $451,000

## Abstract

Project Summary/Abstract
 Over one million people died from tuberculosis (TB) in 2016. Improved understanding of the host
factors that influence TB infection and TB disease severity is needed to improve TB treatments and vaccines.
Multiple lines of evidence show that excess inflammation worsens outcomes from M. tuberculosis (Mtb)
infection. After Mtb infection, macrophages and dendritic cells initiate the immune response, leading to
mycobacterial killing, granuloma formation, and T cell activation. The Toll-Interacting Protein (TOLLIP)
mediates the immune response to Mtb by dampening several innate immune pathways, including TLR and IL-1
signaling pathways. Our long-term goal is to determine the molecular and cellular mechanisms that influence
vaccine immunity and susceptibility to TB. Discovery of innate immune factors, including TOLLIP, that
influence vaccine development may influence vaccine design. The objective of this grant is to characterize the
role of TOLLIP in influencing T memory differentiation and persistence in the context of chronic TB or BCG
exposure. The central hypothesis is that TOLLIP deficiency – a phenotype we have discovered exists in
multiple population -- amplifies the innate immune response to Mtb in a deleterious fashion, weakening Mtb-
specific T cell responses and increasing TB susceptibility. The rationale is that identification of innate immune
factors that influence T cell immunity in a nuanced fashion provides a novel path toward rational vaccine
design. Our specific aims will test the following hypotheses: 1) TOLLIP deficiency in macrophages is caused by
alterations in the TOLLIP transcriptional complex and influences multiple signaling pathways within the
macrophage; 2) TOLLIP deficiency increases DC activation, which leads to increased T cell differentiation but
reduced vaccine effectiveness in humans, and 3) TOLLIP deficiency impairs lung-specific immunity,
particularly in the formation and persistence of resident memory T cells and exhausted T cells in knockout
mice. This contribution is significant because it will establish that TOLLIP regulates the innate immune
response and improves host defense against M. tuberculosis; this proposal may lead to improved vaccine
adjuvants and host-directed therapeutics to Mtb. The proposed work is innovative because we investigate the
mechanisms and effects of a functionally active variant of TOLLIP in humans and combine with a knockout
mouse model of infection, using novel tools to investigate an understudied, critical immune regulator. Insight
into immunoregulatory genes like TOLLIP is impactful because they may offer new targets for modifying the
immune response.

## Key facts

- **NIH application ID:** 9872107
- **Project number:** 5R01AI136921-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Javeed Ali Shah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,000
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872107

## Citation

> US National Institutes of Health, RePORTER application 9872107, TOLLIP Deficiency, Immune Dysregulation, and Tuberculosis Susceptibility (5R01AI136921-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9872107. Licensed CC0.

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