Penicillin Resistance Compromises Nod1-Dependent Proinflammatory Activity and Virulence Fitness of Neisseria meningitidis

• Penicillin G-resistant meningococcal (PenI) strains have altered peptidoglycan (PGN)
• PGN from PenI strains are impaired for Nod1-dependent proinflammatory activity
• Meningococcal disease in a mouse model is Nod1 dependent
• PenI strains are attenuated in vivo and induce reduced inflammatory responses

SummaryNeisseria meningitidis is a life-threatening human bacterial pathogen responsible for pneumonia, sepsis, and meningitis. Meningococcal strains with reduced susceptibility to penicillin G (PenI) carry a mutated penicillin-binding protein (PBP2) resulting in a modified peptidoglycan structure. Despite their antibiotic resistance, PenI strains have failed to expand clonally. We analyzed the biological consequences of PBP2 alteration among clinical meningococcal strains and found that peptidoglycan modifications of the PenI strain resulted in diminished in vitro Nod1-dependent proinflammatory activity. In an influenza virus-meningococcal sequential mouse model mimicking human disease, wild-type meningococci induced a Nod1-dependent inflammatory response, colonizing the lungs and surviving in the blood. In contrast, isogenic PenI strains were attenuated for such response and were out-competed by meningococci sensitive to penicillin G. Our results suggest that antibiotic resistance imposes a cost to the success of the pathogen and may potentially explain the lack of clonal expansion of PenI strains.