Make It Less difficile: Understanding Genetic Evolution and Global Spread of Clostridioides difficile

Abstract

Clostridioides difficile is an obligate anaerobic pathogen among the most common causes of healthcare-associated infections. It poses a global threat due to the clinical outcomes of infection and resistance to antibiotics recommended by international guidelines for its eradication. In particular, C. difficile infection can lead to fulminant colitis associated with shock, hypotension, megacolon, and, in severe cases, death. It is therefore of the utmost urgency to fully characterize this pathogen and better understand its spread, in order to reduce infection rates and improve therapy success. This review aims to provide a state-of-the-art overview of the genetic variation of C. difficile, with particular regard to pathogenic genes and the correlation with clinical issues of its infection. We also summarize the current typing techniques and, based on them, the global distribution of the most common ribotypes. Finally, we discuss genomic surveillance actions and new genetic engineering strategies as future perspectives to make it less difficile.

Clostridioides difficile, a New “Superbug”

“…There are two variants of cdtR, one is truncated cdtR, and the other has a 68 bp deletion; in both cases, the levels of secreted toxins decrease. The exact role of CDT is not clear, and the reported data shows that only CDT is usually not enough to cause a disease, but in combination with the high amount of TcdA/B toxins, it can cause a severe disease [17][18][19]. The complexity of the problem is shown by the fact that there are rare cases of tcdA − tcdB − and cdtA/B positive isolates that can cause symptomatic CDI.…”

“…It displays high amounts of TcdA/TcdB toxins due to the inactivation of tcdC by an 18 bp deletion and production of binary toxin. Another commonly detected hypervirulent strain belonged to ribotype 078 [9,17,22].…”

“…A specific case was the asymptomatic carriage of C. difficile after recovery; patients can carry C. difficile for around a month [9,17]. Children aged less than 2 years can also carry C. difficile without symptoms since they do not have receptors for the toxins [17]. Asymptomatic carriage is one of the main drivers of C. difficile dissemination.…”

Unique growth and morphology properties of Clade 5Clostridioides difficilestrains revealed by single-cell time-lapse microscopy

“…Between the five remaining phylogenetic clades, there are notable differences in geographic and host distributions. Clade 1 is the largest and most heterogeneous (and likely ancient) clade, containing over 200 STs that have the broadest geographic distribution (15, 16). It includes both toxin-producing and non-toxigenic strains, including the well-characterized, genetically tractable toxigenic strain 630 (9).…”

“…This damage triggers a significant inflammatory response that can cause disease pathologies ranging from mild diarrhea to pseudomembranous colitis, and even death (2, 4). Beyond these acute complications, C. difficile frequently causes recurrent infections (∼20% of infections), which can lead to more severe disease symptoms (14–16) (2, 7, 8).…”