JAK2-TB · Human JAK2 genotypes underlying tuberculosis
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2027-06-01 → 2029-05-31
- EU contribution
- €242,261
- Participants
- 3
- Scheme
- HORIZON-TMA-MSCA-PF-EF
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Project objective
No single infectious agent has killed more humans historically than Mycobacterium tuberculosis (Mtb) and tuberculosis (TB) remains a leading cause of infectious mortality worldwide. Yet, only 5-10% of infected individuals develop TB. The molecular mechanisms underlying progression to active TB in otherwise healthy individuals remain poorly defined. Emerging evidence suggests that TB is not solely an infectious disease but can also be a true genetic disorder in some patients, with rare and common inborn errors of IFNγ-mediated immunity predisposing individuals to clinical disease. However, currently reported genetic causes explain only about 1% of TB cases in populations of European descent, with homozygosity for the common P1104A TYK2 variant.This project hypothesizes that rare loss-of-function mutations in human JAK2, a central kinase in the IL-12, IL-23, and IFNγ signaling axes, predispose to TB. Through a multidisciplinary approach that combines cutting edge bioinformatic analyses, population genetics, molecular biology, and immunological profiling, this research will identify rare and common JAK2 variants in TB patients, functionally characterize their impact on JAK2-dependent signaling using overexpression systems and patient-derived cell lines and assess the consequences of these variants on anti-mycobacterial immunity in patients’ primary immune cells.This is the first study to investigate germline JAK2 mutations as a genetic cause of infectious disease. The outcomes of this project will have high-impact translational value that can inform vaccine design, targeted therapies (such as recombinant IFNγ therapy), and genetic screening in at-risk populations, especially in light of the expanding clinical use of JAK2 inhibitors. By uncovering a hidden genetic driver of TB, this ambitious project will transform our understanding of host-pathogen interactions and support the development of precision medicine approaches to combat a resurgent global health threat.
Original text from CORDIS.
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Data: CORDIS, © European Union