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IFITM1 differentially regulates antibacterial immunity and immunopathology but is dispensable for antiparasitic
Sibongiseni K L Poswayo1,2, Mumin Ozturk3,4, Rudranil Hazra1,2
1Division of Medical Microbiology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Abstract:
Interferon-induced transmembrane (IFITM) proteins underpin antiviral responses, yet their role in bacterial infections remains underexplored, particularly for parasites. We probed the role of IFITM1 in Mycobacterium tuberculosis (Mtb), Listeria monocytogenes (Lm), and Leishmania major infection using IFITM1 knockout mice. Notably, IFITM1 was upregulated in murine and human macrophages, as well as in PBMCs during active tuberculosis (TB), subsiding with therapy. IFITM1 also accumulated in the lungs of outbred mice and macaques that progressed to TB. IFITM1-deficient mice displayed no differences in the acute phase; however, chronic Mtb infection revealed lower bacterial loads, mitigated lung pathology, dampened inflammatory cell recruitment, and decreased cytokines. IFITM1-/- macrophages curbed intracellular H37RV and HN878 growth, skewing proinflammatory cytokine (IL-1α, IL-1β, IL-6, and nitric oxide) production while phagosome maturation and autophagy remained unaffected. Furthermore, HN878-infected IFITM1-/- mice exhibited increased lung cell death by TUNEL staining, driving enhanced mortality. Lm similarly increased IFITM1 expression in macrophages, liver, and spleen. IFITM1-/- mice exhibited reduced early tissue burdens and serum IFN-γ, TNF, and IL-6, yet liver pathology escalated, driving mortality and suggesting dysregulated inflammation. These macrophages also limited intracellular Lm growth, with increased necrosis. By contrast, L. major footpad swelling and parasitic loads remained unaffected in knockout animals. Together, IFITM1 exacerbates TB and listeriosis pathology by calibrating inflammation against bacterial control, but plays no role in cutaneous leishmaniasis. These findings reveal IFITM1-specific contributions to bacterial but not parasitic infections, favoring disease tolerance.
Insights
Interferon-induced transmembrane protein 1 (IFITM1) worsens tuberculosis and listeriosis by altering inflammation, but does not impact parasitic infections like leishmaniasis.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Interferon-induced transmembrane (IFITM) proteins are crucial for antiviral immunity.
- The role of IFITM proteins in bacterial and parasitic infections is not well understood.
- IFITM1's specific function in infections caused by Mycobacterium tuberculosis, Listeria monocytogenes, and Leishmania major requires investigation.
Purpose of the Study:
- To investigate the role of IFITM1 in Mycobacterium tuberculosis (Mtb), Listeria monocytogenes (Lm), and Leishmania major infections.
- To determine IFITM1's impact on host immune responses and disease pathology during these infections.
- To elucidate IFITM1's contribution to bacterial control versus inflammatory responses.
Main Methods:
- Utilized IFITM1 knockout (IFITM1-/-) mice for infection models.
- Assessed bacterial and parasitic loads, lung and liver pathology, inflammatory cell recruitment, and cytokine profiles.
- Analyzed macrophage responses, including intracellular bacterial growth, cytokine production, phagosome maturation, and autophagy.
- Employed TUNEL staining to evaluate lung cell death.
Main Results:
- IFITM1 was upregulated in macrophages and PBMCs during active tuberculosis (TB) and in infected lungs.
- IFITM1-/- mice showed reduced Mtb bacterial loads and lung pathology but increased mortality due to lung cell death.
- IFITM1-/- mice had reduced Lm burdens but escalated liver pathology and mortality, with increased macrophage necrosis.
- IFITM1 played no role in Leishmania major infection, with no effects on swelling or parasitic loads.
Conclusions:
- IFITM1 exacerbates pathology in Mtb and Lm infections by modulating inflammation, favoring bacterial persistence over host control.
- IFITM1 deficiency leads to increased mortality in certain bacterial infections, suggesting a complex role in disease tolerance.
- IFITM1 is specifically involved in bacterial infections, not parasitic infections, highlighting distinct roles in host defense.
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