Angiotensin Converting Enzyme (ACE) Over‐expression in Mouse Macrophages Up Regulates iNOS and Markedly Increases Resistance to Listeria and MRSA

We substituted control of ACE expression from the endogenous promoter to the c‐ fms promoter. The result is a mouse model called ACE 10/10 in which ACE is over expressed by monocytes, macrophages and similar lineage cells. To study the immune response to bacterial infection, we challenged ACE 10/10 with L. monocytogenes or methicillin resistant S. aureus (MRSA). ACE 10/10 mice have a significantly enhanced immune response to both bacteria in vivo and in vitro . For example, 5 days after Listeria infection, the spleen and liver of ACE 10/10 mice had 8.0‐ and 5.2‐fold less bacteria than WT mice. In a model of MRSA skin infection, ACE 10/10 mice had 50‐fold less bacteria than WT mice. Histology showed a prominent infiltrate of ACE positive mononuclear cells in the skin lesions from ACE 10/10. Increased bacterial resistance in ACE 10/10 is directly due to over‐expression of ACE, as it is eliminated by an ACE inhibitor. Critical to increased immunity in ACE 10/10 is the over‐expression of iNOS and reactive nitrogen intermediates, as inhibition of iNOS by the inhibitor 1400W eliminated all in vitro and in vivo differences in innate bacterial resistance between ACE 10/10 and WT mice. Increased resistance to MRSA was transferable by bone marrow transplantation. The over‐expression of ACE and iNOS by myelomonocytic cells substantially boosts innate immunity and may represent a new means to address serious bacterial infections.