# Determining the role of sphingolipids in Mycobacterium tuberculosis infection

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $382,147

## Abstract

Project Summary/Abstract
Nearly one-third of the world population is infected with Mycobacterium tuberculosis (Mtb), the causative agent
of tuberculosis (TB). This reservoir contributes towards an increasing incidence of TB, with about 11 million
new cases and 1.8 million deaths every year. The profound success of Mtb in causing disease depends on its
ability to effectively utilize the host's lipid metabolism, including the sphingolipid biosynthesis pathway, to
subvert the immune system. The granuloma, the pathological hallmark of TB infection, is characterized by the
presence of lipid-loaded immune cells such as foamy macrophages that have a significantly reduced capability
in controlling bacterial growth. Although Mtb is known for modulating lipid metabolism, and in particular the
sphingolipid pathways during infection, there is no systematic understanding of how infective bacteria alter the
host lipidome. We recently found that sphingolipids, a distinct class of lipids with a sphingoid base backbone
that are enriched in cellular membranes, are essential for entry and killing of Mtb. We plan to extend our
investigation to define the role of each sphingolipid repertoire in Mtb pathogenesis. The main goal of the
proposed work is to systematically perturb the key sphingolipid biosynthetic pathways of the host to uncover
their function in Mtb pathogenesis and antimicrobial cellular processes such as the inflammasome. For this
purpose, individual knockout macrophage cell lines that lack key genes involved in the biosynthesis of
sphingolipids will be generated using CRISPR/Cas9-technology. We will use multifunctional sphingolipid
precursor analogs to define the flux, localization and the interactome of sphingolipids during infection in time-
and space-dependent manner. Furthermore, we will study the significance of sphingolipids in the
inflammasome, an innate immune process that is important in controlling Mtb infection. Understanding these
pathways or processes essential for the pathogenesis of Mtb is crucial, as they represent potential targets for
new therapeutics.

## Key facts

- **NIH application ID:** 10302302
- **Project number:** 5R01AI141549-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Fikadu G. Tafesse
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,147
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10302302

## Citation

> US National Institutes of Health, RePORTER application 10302302, Determining the role of sphingolipids in Mycobacterium tuberculosis infection (5R01AI141549-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10302302. Licensed CC0.

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