Clostridium difficile Research and Development; January 2014

Here is the latest from the Clostridium difficile research community:

C. difficile colonization and adherence to the gut are important steps in the pathogenesis of CDI.  Several outer membrane proteins and adherence factors have been identified in C.difficile such as S-layer protein (SLPs), flagella, etc.   Using a bioinformatics approach Kovacs-Simon et al. have been able to identify a novel adhesion factor, C. difficile lipoprotein CD0873. Recombinant lipoprotein CD0873 was able to binding Caco-2 cells in vitro.   Using ClosTron technology, mutants of C. difficile lipoprotein CD0873 showed decreased adherence to Caco-2 cells in culture. This novel target could be used as a method for preventing and treating colonization and infection by C.difficile

 

http://jid.oxfordjournals.org/content/early/2014/01/29/infdis.jiu070.full.pdf+html

 

The changing epidemiology of C. difficile infection (CDI) is partly due to the emergence of a hypervirulent strain of C. difficile (BI/NAP1/027). One of the novel features of these hypervirulent strains is the production of newly described binary toxin (CDT), in addition to C. difficile’s two major toxins, toxin A (TcdA) and toxin B (TcdB).  The role of CDT in symptomatic disease has been studied (January research update Kuehne et al).  In this publication, Schwan et al. show that CDT-induced protrusions are involved in vesicular transport.  CDT reroutes Rab11-positive vesicles containing fibronectin, which is involved in bacterial adherence, leading to the increased adherence of C.difficile, one of the first steps of colonization.

 

http://www.pnas.org/content/early/2014/01/23/1311589111.long

 

 

The use of antibiotics is one of the major risk factors for developing C. difficile infection (CDI).   Antibiotics lead to a loss of colonization resistance and lead to the overgrowth of pathogens such as C.difficile. Theriot et al show that in a murine model of CDI, antibiotic treatment induces substantial changes in the gut microbial community and in the metabolome.  Changes in the level of bile acids, especially taurocholate which is essential for C.difficile spore germination into vegetative cells in the gut favors the growth of C. difficile and makes these mice more susceptible to CDI.

 

http://www.nature.com/ncomms/2014/140120/ncomms4114/full/ncomms4114.html

 

 

Another source of C. difficile infection (CDI)! The zoo! Alvarez-Perez show that C.difficile was isolated from the following animals: chimpanzee (Pan troglodytes troglodytes), dwarf goat (Capra hircus), an Iberian ibex (Capra pyrenaica hispanica), with and plains zebra (Equus quagga burchellii).  Hypervirulent epidemic PCR ribotype 078, produced toxins A and B, and had the genes encoding binary toxin (i.e. A+B+CDT+ isolates) was the most common isolate followed PCR ribotypes 039 (ABCDT), 042 (A+B+CDT) and 110 (AB+CDT). All isolates were resistant to the fluoroquinolones ciprofloxacin, enrofloxacin and levofloxacin. A ribotype 078 isolate recovered from a male zebra foal initially showed in vitro resistance to metronidazole. 

 

http://www.sciencedirect.com/science/article/pii/S0378113513005968

 

Host humoral immune responses play an important role in the disease pathogenesis of C. difficile infection (CDI). Immune responses to the toxins have been associated with protection from symptomatic disease and also recurrence.   Whether the protection is due to systemic IgG and IgA as well as to mucosal IgA Ab to the toxins is not well-defined.  Johnston et al. use the murine model of CDI to parse out the individual role of the systemic and mucosal immune responses and the role they play in disease outcome. Wild-type C57BL/6 mice develop protective immunity against CDI and remain uninfected upon rechallenge.  CD4−/− mice also generated both mucosal and serum IgA anti-toxin Abs and were protected from CDI upon rechallenge without the expression of IgG anti-toxin Ab.  pIgR−/− mice, lacking the receptor to transcytose polymeric Ab, were also protected from CDI, suggesting that although mucosal anti-toxin Ab is not essential for protection. Therefore protection against CDI can be mediated via multiple mechanisms, depending on the host.

 

http://iai.asm.org/content/82/2/522.long

 

Chandrabali Ghose-Paul,MS,PhD, Chairperson of Research and Development