We study one of the great unsolved problems in modern medicine: How does Mycobacterium tuberculosis (Mtb) survive inside the very immune cells designed to destroy it?
TB infects about 10 million people and kills over 1 million every year. Mtb hides inside macrophages — human white blood cells whose entire job is to eat and kill bacteria — and turns them into safe houses.
Research Theme 1: PolyP — The “Don’t Kill Me” Signal
We discovered that Mtb secretes polyphosphate (polyP), which acts as a powerful signal to macrophages. It blocks phagosome acidification and reduces lysosomal activity — the two main weapons macrophages use to kill bacteria.
We have shown this in primary human macrophages (monocyte-derived macrophages, MDMs) and in THP-1 macrophage-like cells. Published work:
- PolyP blocks phagosome acidification in human macrophages — Rijal et al., PNAS, 2020
- Pharmacological inhibitors restore human macrophage killing of Mtb, Legionella, and Listeria — Rijal & Gomer, Microbiol Spectr, 2025
We hold a PCT patent on methods for activating immune cells to kill bacteria using polyP pathway inhibitors
Research Theme 2: PolyP and Antibiotic Tolerance
We found that antibiotic treatment with isoniazid triggers Mtb to increase its polyP production. This extra polyP helps Mtb thicken its cell envelope, making it harder for antibiotics to work.
We showed that gallein — which inhibits PPK — can prevent this thickening, boost isoniazid killing in human macrophages, and disrupt Mtb’s metabolic stress response.
Our work combines complementary experimental systems and techniques, including:
- Infection models using human macrophages (primary cells and THP-1) and bacterial pathogens, including Mtb
- Genetically tractable eukaryotic model systems (Dictyostelium discoideum)
- Cell and molecular biology approaches, including CRISPR interference, recombinant protein expression, and biochemical assays
- High-resolution imaging, including confocal and electron microscopy
- Multi-omics analyses (genomics, transcriptomics, proteomics, metabolomics)
- Small-molecule perturbation and therapeutic screening approaches
Why PolyP? Why Now?
PolyP is found in all living things — bacteria, yeast, plants, and humans. But the enzyme that makes it in bacteria (PPK) is absent in humans. This means we can target bacterial PPK without disrupting human polyP metabolism. Human cells do produce their own polyP — through different molecular machinery — where it plays roles in blood clotting and stress. Bacterial long-chain polyP is structurally distinct from human short-chain polyP, and this difference is exactly what we are working to exploit therapeutically.
Our Approach
- Primary human macrophages (MDMs) — isolated from healthy blood donors
- THP-1 macrophage cell lines — genetically tractable human model
- Live Mtb infection — BSL-3 experiments with virulent Mtb
- Mouse infection models — in vivo validation
Methods: fluorescence imaging (pHrodo, LysoTracker, BODIPY), flow cytometry, CRISPRi knockdowns in Mtb, RNA-seq, proteomics, pharmacological inhibitor studies, metabolomics
RIJAL LAB 