Microbiome-Independent Effects of Antibiotics in a Murine Model of Nosocomial Infections

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common causes of hospital-acquired pneumonia. To better manage patients with MRSA pneumonia, we require a greater understanding of the host-pathogen interactions during infection. MRSA research focuses on highly virulent and cytotoxic strains, which demonstrate robust phenotypes in animal models of infection. However, nosocomial infections are often caused by hospital-acquired MRSA (HA-MRSA) isolates that exhibit low cytotoxicity and few or no phenotypes in mice, thereby confounding mechanistic studies of pathogenesis. Consequently, virulence pathways utilized by HA-MRSA in nosocomial pneumonia are largely unknown. Here, we report that conditioning mice with broad-spectrum antibiotics lowers the barrier to pneumonia, thereby transforming otherwise avirulent HA-MRSA isolates into lethal pathogens. HA-MRSA isolates are avirulent in gnotobiotic mice, mimicking results in conventional animals. Thus, the observed enhanced susceptibility to infection in antibiotic-treated mice is not due to depletion of the microbiota. More generally, we found that antibiotic conditioning leads to increased susceptibility to infection by diverse antimicrobial-resistant (AMR) pathogens of low virulence. Treatment with antibiotics leads to dehydration and malnutrition, suggesting a potential role for these clinically relevant and reducible hospital complications in susceptibility to pathogens. In sum, the model described here mitigates the impact of low virulence in immunocompetent mice, providing a convenient model to gain fundamental insight into the pathogenesis of nosocomial pathogens. IMPORTANCE Antimicrobial-resistant (AMR) pathogens are responsible for over 2.8 million infections and over 35,000 deaths per year in the United States. To study these microbes, animal models that are susceptible to these pathogens are required. However, many of these pathogens exhibit low virulence in conventional mice, which has negatively impacted mechanistic studies. Here, we show that mice treated with antibiotics in their drinking water become exquisitely susceptible to low-virulence AMR pathogens. Surprisingly, the increased susceptibility was independent of the impact of antibiotics on the microbiome and seems to be due to an unintended consequence of antibiotic treatment: weight loss due to dehydration and caloric restriction. Unlike other models used to sensitize mice to low-virulence pathogens, our model does not reduce phagocyte numbers. Thus, here, we describe an immunocompetent mouse model to facilitate the identification of novel targets and accelerate the development of preventives and therapeutics to combat infections by AMR pathogens.