Differential susceptibility of C57BL/6NCr and B6.Cg-Ptprca mice to commensal bacteria after whole body irradiation in translational bone marrow transplant studies

Abstract

Background: The mouse is an important and widely utilized animal model for bone marrow transplant (BMT) translational studies. Here, we document the course of an unexpected increase in mortality of congenic mice that underwent BMT.

Methods: Thirty five BMTs were analyzed for survival differences utilizing the Log Rank test. Affected animals were evaluated by physical examination, necropsy, histopathology, serology for antibodies to infectious disease, and bacterial cultures.

Results: Severe bacteremia was identified as the main cause of death. Gastrointestinal (GI) damage was observed in histopathology. The bacteremia was most likely caused by the translocation of bacteria from the GI tract and immunosuppression caused by the myeloablative irradiation. Variability in groups of animals affected was caused by increased levels of gamma and X-ray radiation and the differing sensitivity of the two nearly genetically identical mouse strains used in the studies.

Conclusion: Our retrospective analysis of thirty five murine BMTs performed in three different laboratories, identified C57BL/6NCr (Ly5.1) as being more radiation sensitive than B6.Cg-Ptprca/NCr (Ly5.2). This is the first report documenting a measurable difference in radiation sensitivity and its effects between an inbred strain of mice and its congenic counterpart eventually succumbing to sepsis after BMT.

Figure 1

Gross examination showed marked facial and submandibular swelling (A). Histopathology of cervical (B) and mesenteric (C, D) lymph nodes showing acute, severe, necrotizing lymphdenitis and cellulitis with intralesional bacteria at 4× (B), 10× (C) and 20× (D) magnification. Acute severe necrosis (C) of mesenteric lymph node.

Figure 2

Histopathology of the heart (A), liver (B), bone marrow (C), and small intestine (D). Acute, severe bacterial myocarditis with intralesional bacteria (A) 10×. Acute hepatic necrosis (arrow) (B) 20×. Leukocyte deficient bone marrow (C) 10×. Blunted villi (arrow) in small intestine (D) 10×.

Figure 3

B6 (Ly5.1) mice are more sensitive to irradiation than B6-Ly5.2. (A) Survival comparison in the Ly5.1 mice after different irradiation doses. Ly5.1 are susceptible to irradiation doses ≥ 1100 cGy. All animals received a BMT the same day of irradiation (B). Survival comparison between congenic B6-Ly5.2 mice and Ly5.1 mice post irradiation doses of 1100 cGy, 1000 cGy or less. Ly5.2 mice are more radioresistant than Ly5.1 mice at TBI doses of 1100 cGy. *p < 0.001, **p = 0.068.