# Pattern Recognition Receptors and Autophagy in Mtb Control in AIDS

> **NIH NIH R37** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2021 · $483,582

## Abstract

Mycobacterium tuberculosis (Mtb) is a human pathogen of worldwide significance. Despite the global and
domestic importance of Mtb, we do not have a full understanding of key processes in tuberculosis (TB)
pathogenesis. This includes the intracellular survival of Mtb in infected macrophages, progression to active
disease vs. latent Mtb infection, persistent patterns of active disease in TB patients even after successful
chemotherapy, and excessive lung damage with long-term consequences. These issues are further
complicated by HIV-Mtb co-pathogenesis and multidrug-resistant Mtb. While progress has been made in
development of new Mtb antibiotic regimens, less conventional approaches including host-directed therapies
(HDT) are currently being considered including autophagy-based HDT.
Understanding the role and mechanisms of autophagy in control of TB has been, and remains, the central
topic of our program. In this project, we look beyond the yeast-centric core ATG genes, the focus of many
studies to date. We propose a paradigm shift to focus instead on mammalian systems and unique human
autophagy factors and to close the significant knowledge gap in this area. Our long-term goal is to delineate
how human/mammalian autophagy factors protect against Mtb infection, control associated cellular damage,
and prevent excessive inflammation and tissue destruction. In this project we will define the molecular entities
that conduct autophagic control of intracellular Mtb, minimize damage to human cells, and prevent cascading
inflammation and tissue destruction. The focus is on two classes of human/mammalian regulators of
autophagy: (i) the tripartite motif-containing (TRIM) proteins, represented by TRIM16, in combination with
pattern recognition receptors termed Galectins and their interactors, and (ii) immunity-related GTPases,
represented specifically by human IRGM and effectors that it controls. We hypothesize that these factors play
key roles in organizing the human autophagic apparatus that protects us against Mtb. The project has the
following specific aims:
Specific Aim 1. Determine how the mammalian autophagic apparatus recognizes phagosomal damage
caused by virulent Mtb and how this contributes to autophagic control of Mtb. We will delineate the role
of Galectins and TRIMs in recognizing intracellular Mtb and determine how they orchestrate mammalian
autophagic machinery and cell-protective responses.
Specific Aim 2. Define the mechanism of human IRGM action in autophagic maturation and in control
of the autophagosomal-lysosomal system in response to intracellular Mtb. We will delineate the IRGM-
directed molecular mechanisms of autophagosomal-lysosomal fusion in Mtb infected macrophages. We will
determine how the HIV factor Nef impairs IRGM's capacity to orchestrate autophagic maturation and prevents
activation of TFEB, a master regulator of the autophagosomal-lysosomal system in human cells.

## Key facts

- **NIH application ID:** 10129255
- **Project number:** 5R37AI042999-24
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** VOJO P DERETIC
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $483,582
- **Award type:** 5
- **Project period:** 1998-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129255

## Citation

> US National Institutes of Health, RePORTER application 10129255, Pattern Recognition Receptors and Autophagy in Mtb Control in AIDS (5R37AI042999-24). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129255. Licensed CC0.

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