Abstract Rationale Bacterial pneumonia remains a leading cause of global mortality. The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has limited treatment options and highlights the need for host-targeted therapeutics. Absent in Melanoma 2 (AIM2) is a cytosolic DNA sensor that activates the inflammasome and contributes to host defense against intracellular pathogens and DNA viruses. However, its role in gram-positive bacterial lung infections remains unknown. We investigated whether AIM2 is critical to regulate host defense against MRSA-induced pneumonia. Methods Age-matched female C57BL/6 wild-type (WT) and AIM2-deficient (Aim2−/−) mice were infected intratracheally with 50μl of 5 × 107 CFU of MRSA (USA300). At 12- and 24-hours post-infection, bronchoalveolar lavage fluid (BALF), lung, liver, and spleen were collected to quantify bacterial burden. BALF was assessed for total and differential leukocyte counts and inflammatory mediators. Formalin-fixed, paraffin-embedded lung tissues from WT and Aim2−/−mice (infected and uninfected), as well as human healthy and pneumonic lung samples (IRB-approved), were stained with H&E and used for immunohistochemistry. Granulopoiesis and neutrophil maturation were evaluated in bone marrow and peripheral blood by flow cytometry. Reciprocal bone marrow transplantation (WT→Aim2−/− and Aim2−/−→WT) was performed to distinguish hematopoietic from non-hematopoietic-derived AIM2 in host defense. Results Aim2−/− mice exhibited reduced bacterial loads in the lungs, BALF, liver, and spleen compared to WT mice at both 12- and 24-hours post-infection. Increased recruitment of neutrophils and macrophages was observed in the BALF of Aim2−/− mice. In the bone marrow, Aim2−/− mice displayed a marked increase in early granulocyte progenitors and a reduction in mature Ly6G+CD11b+ neutrophils. Bone marrow chimera studies suggest that loss of AIM2 in hematopoietic cells contributes to the protective phenotype. These findings indicate that AIM2 expression in hematopoietic cells mediates susceptibility to MRSA infection. Conclusions AIM2 functions as a negative regulator of antibacterial immunity during MRSA pneumonia. Targeting AIM2-dependent pathways may represent a novel host-directed strategy to improve outcomes in the setting of antibiotic-resistant bacterial pneumonia. This abstract is funded by: R01AI-157353, R01AI-140500, and P20GM-13055
Kulatheepan et al. (Fri,) studied this question.
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