# C-type Lectin Receptor Pathways in the Pathogenesis of TB/HIV Co-infection

> **NIH NIH R33** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $775,668

## Abstract

Tuberculosis (TB) and Human immunodeficiency virus (HIV) cooperate to drive a deadly co-epidemic that
results in approximately 12 million new infections and 4.5 million deaths annually. TB is the leading cause of
death in people living with HIV infection, and the risk for new Mycobacterium tuberculosis (Mtb) infections and
TB relapse continue despite restoration of T cells by anti-retroviral (ARV) therapy. A spectrum of immune
dysfunction in human subjects with dual disease is well described, including both immune suppression and
inappropriate inflammation. The mechanistic bases for many of these outcomes of co-infected individuals,
however, are poorly understood and represent an important gap for development of host directed interventions
to: 1) restore protective immune responses, 2) reduce pulmonary damage, and 3) complement standard drug
therapy. We exploited our access to relevant human tissues and biologicals, and utilized our humanized mouse
co-infection model, to identify novel candidate mechanisms for co-infection pathophysiology. As a result, we
have preliminary data supporting an HIV-mediated effect to compromise the function of an immune-regulatory
C-type lectin receptor in lung macrophages (Mɸ). The objective of this R01 application is to identify HIV-mediated
defects in human Mɸ due to native and experimental infection, and demonstrate the impact of these defects in
the setting of pulmonary TB. Our hypothesis is that that HIV modulates immunoregulatory CLRs in pulmonary
Mɸ and compromises an important innate signaling pathway for recognition and resolution of tissue damaging
inflammation in Mtb-infected lungs. We propose the following two aims to test this hypothesis: 1) Determine how
compromise of immunoregulatory CLR pathways by HIV promotes pulmonary inflammation following Mtb
infection, and 2) Identify mechanism(s) whereby HIV compromises CLR pathways as therapeutic targets to
reduce inflammatory outcomes in Mtb/HIV co-infected lungs. These aims will be accomplished by using bio-
banked biologicals and tissue from HIV+ donors, in vitro systems, gene deficient mice, and humanized mice.
We are well positioned to carry out these studies as our interdisciplinary TB/HIV co-infection team includes
immunology, pathology, molecular biology, animal model, and medicinal chemistry expertise. In phase I, we
propose to demonstrate that HIV infection interferes with the anti-inflammatory function of MGL and demonstrate
the consequences of MGL dysfunction in the Mtb-infected lung. In phase II, we will establish the mechanisms
for HIV-mediated disturbance of MGL and explore novel CLR pathway targets as potential therapeutic
approaches to reduce pulmonary damage in the setting of TB.

## Key facts

- **NIH application ID:** 10092516
- **Project number:** 4R33AI138328-03
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Janice J Endsley
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $775,668
- **Award type:** 4N
- **Project period:** 2018-04-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092516

## Citation

> US National Institutes of Health, RePORTER application 10092516, C-type Lectin Receptor Pathways in the Pathogenesis of TB/HIV Co-infection (4R33AI138328-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10092516. Licensed CC0.

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