Instructor Icahn Sch. of Med., Mount Sinai, United States
Disclosure(s):
Jeffrey Downey, PhD: No financial relationships to disclose
Introduction/Rationale: Hematopoietic stem cells (HSCs) are the continual source of all hematopoietic cells in the mammalian adult and persist for the entire lifespan. As such, HSPCs are exposed to a lifetime of stimuli. Far from inconsequential, it is increasingly understood that these exposures can epigenetically reprogram HSCs. This alters the fate and inflammatory phenotype of their progeny, which may have important consequences on the progression of chronic conditions like atherosclerosis. Although systemic infections by pathogens like Mycobacterium tuberculosis are well-known inducers of HSC rewiring, far less is known about how more constrained infections that do not directly replicate in the bone marrow may affect HSPCs.
Methods: WT and Ifnar1-/- mice were infected with influenza A virus (IAV). 28 days post-infection either ATAC-Seq was performed on sorted HSCs to describe epigenetic changes, or the bone marrow (BM) was transplanted into irradiated LDLR-/- hosts that were then fed a high cholesterol diet for 12 weeks. Effects of IAV infection on atherosclerosis were then determined by flow cytometry and histology.
Results: Antiviral type I interferon production generated in response to IAV infection reprograms HSCs. This reprogramming elicits circulating monocytes with a heightened interferon stimulated gene (ISG) signature that enhances their accumulation within atherosclerotic plaques, increases local macrophage proliferation, and promotes plaque destabilization. HSCs from Ifnar1-/- mice are protected from this rewiring. BM transfers from infected WT, but not Ifnar1-/-, mice confirmed that the pro-atherogenic effects of IAV was dependent upon HSCs, rather than local effects on the aorta or plaque. Interestingly, this phenotype required the recently described CD319+ pro-DC3 that became infected in the lung, trafficked to the BM, and locally sourced the IFN-I.
Conclusion: Our findings elucidate novel facets of stem cell biology and hint at why IAV infection greatly underscores cardiovascular disease risk.
