In vivo animal models confirm an increased virulence potential and pathogenicity of the NAP1/RT027/ST01 genotype within
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t Pathogens Open Access
RESEARCH
In vivo animal models confirm an increased virulence potential and pathogenicity of the NAP1/RT027/ST01 genotype within the Clostridium difficile MLST Clade 2 Josué Orozco‑Aguilar1,2,3, Alejandro Alfaro‑Alarcón4, Luis Acuña‑Amador5, Esteban Chaves‑Olarte3,5, César Rodríguez3,5 and Carlos Quesada‑Gómez1,3,5*
Abstract Background: Based on MLST analyses the global population of C. difficile is distributed in eight clades, of which Clade 2 includes the “hypervirulent” NAP1/RT027/ST01 strain along with various unexplored sequence types (STs). Methods: To clarify whether this clinically relevant phenotype is a widespread feature of C. difficile Clade 2, we used the murine ileal loop model to compare the in vivo pro-inflammatory (TNF-α, IL-1β, IL-6) and oxidative stress activi‑ ties (MPO) of five Clade 2 clinical C. difficile isolates from sequence types (STs) 01, 41, 67, and 252. Besides, we infected Golden Syrian hamsters with spores from these strains to determine their lethality, and obtain a histological evalua‑ tion of tissue damage, WBC counts, and serum injury biomarkers (LDH, ALT, AST, albumin, BUN, creatinine, N a+, and − Cl ). Genomic distances were calculated using Mash and FastANI to explore whether the responses were dictated by phylogeny. Results: The ST01 isolate tested ranked first in all assays, as it induced the highest overall levels of pro-inflammatory cytokines, MPO activity, epithelial damage, biochemical markers, and mortality measured in both animal models. Statistically indistinguishable or rather similar outputs were obtained for a ST67 isolate in tests such as tissue dam‑ age, neutrophils count, and lethal activity. The results recorded for the two ST41 isolates tested were of intermediate magnitude and the ST252 isolate displayed the lowest pathogenic potential in all animal experiments. This ordering matched the genomic distance of the ST01 isolate to the non-ST01 isolates. Conclusions: Despite their close phylogenic relatedness, our results demonstrate differences in pathogenicity and virulence levels in Clade 2 C. difficile strains, confirm the high severity of infections caused by the NAP1/RT027/ST01 strain, and highlight the importance of C. difficile typing. Keywords: Pathogenicity, Virulence, Clostridium difficile, MLST Clade 2, NAP1/RT027/ST01
*Correspondence: [email protected] 5 Centro de Investigación en Enfermedades Tropicales and Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica Full list of author information is available at the end of the article
Introduction The main causative agent of nosocomial diarrhea associated with the use and abuse of antibiotics is Clostridium difficile; an anaerobic, Gram-positive, spore-forming bacterium. C. difficile infection (CDI) symptoms include watery diarrhea, anorexia and leukocytosis and in severe disease presentations these
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