Host antibacterial defense of 6-10 Gy gamma-irradiated mice subjected to lentiviral vector-based Gas5 gene therapy

Gut bacteria-associated sepsis is a serious concern in patients with gastrointestinal acute radiation syndrome (GIARS). In our previous studies, all mice exposed to 8 Gy of whole body gamma-irradiation (8 Gy GIARS-mice) died by sepsis stemming from bacterial translocation. M1M phi located in the bacterial translocation site (i.e., the mesenteric lymph nodes, MLNs) have been characterized as major antibacterial effector cells. However, M2bM phi, inhibitor cells for M1M phi polarization, predominated in the MLNs of these mice. The reduced expression of long noncoding RNA Gas5 was associated with M2bM phi polarization. In this study, we tried to reduce the mortality rate of 8 Gy GIARS-mice through Gas5 gene transduction using lentivirus (Gas5 lentivirus). After Gas5 lentivirus injection, Gas5 RNA was overexpressed in MLN-F4/80(+) cells of 8 Gy GIARS-mice, and these cells were identified as non-M2bM phi. All of the 8 Gy GIARS-mice injected with Gas5 lentivirus survived 30 days or more after irradiation, and bacterial translocation and subsequent sepsis were shown to be minimal in these mice. These results indicate that the antibacterial resistance of 8 Gy GIASR-mice can be restored through the modulation of M2bM phi located in the bacterial translocation site by Gas5 transduction.