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Currently, AMPs are awakening the interest of medical researchers due to their potential to become novel weapons to target multi\u2010drug resistant (MDR) pathogens and thereby overcome the limitations of traditional antibiotics. Among AMPs, human RNases belonging to the RNase A superfamily stand out as promising agents for therapeutic uses given their high antimicrobial activity, wide spectrum against multiple pathogens and low toxicity. However, a better understanding of how human RNases perform their antimicrobial actions in tissues is necessary to develop novel therapies. Mouse infectious disease models can be extremely useful to study the function of AMPs in vivo and have already provided valuable knowledge about RNase role in tissues such as the intestine and urinary tract. Therefore, it is necessary to understand the genetic and functional divergences that exist between human and mouse RNases to design experiments that are poised for clinical translation. 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