Clostridium difficile (C. diff) Research Community Update

Here’s the latest from the Clostridium difficile research community:

Hansen et al reports that the toxin A and toxin B induced CXCL8/Il-8 release and subsequent intestinal barrier dysfunction is mediated via the activation of P2Y6 receptor in in vitro Caco-2 cells and also in a mouse model of toxin-mediated inflammation and tissue damage.  The novel role of P2Y6 receptor in toxin-mediated C. difficile infection may be utilized in designing a novel therapeutic target for C. difficile infection.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0081491

Toxins A and B are essential for symptomatic disease, however, the role of toxins in colonization is unknown.  C.difficile preferentially binds to the basolateral surface of epithelial cells.   Kasendra et al. show that sub-lethal concentrations of toxin A can alter cell-polarity allowing C.difficile to gain access to basolateral receptors needed for successful colonization of colonic mucosa.

http://jid.oxfordjournals.org/content/early/2013/11/22/infdis.jit617.long

C.difficile toxin B plays an important role in disease outcome. Epidemic BI/NAP1/027 has been associated with more severe disease although the exact reason is still unknown.  Lanis et al show that toxin B from the epidemic BI/NAP1/027 strain of C. difficile is more lethal, causes more extensive brain hemorrhage, and is antigenically variable from toxin B from a reference strain. Lanis et al also show carboxy-terminal domain (CTD) encodes at least 11 epitopes that differ between toxin B from the two strains. Toxin B antiserum against the CTD from one strain does not cross-neutralize toxin B from other and vice versa, thus reducing the likelihood of a universal toxin vaccine that could provide cross-protection against infection by varying strains.

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003523

C.difficile Surface-Layer Protein A (SlpA) is an important colonization and adhesion factor that may play an essential role in C. difficile infection.  Merrigan et al show that SlpA from thirty-six epidemic-associated and non-epidemic associated C. difficile clinical isolates displayed intra- and inter-clade differences in attachment that were unrelated to toxin production.  The novel role of SlpA in adhesion and C. difficile infection may be utilized in designing a novel therapeutic target for C. difficile infection.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0078404

Madan et al look at the role of leptin in the mucosal immune response to C. difficile infection. A previously described mutation in the leptin receptor, LEPR, has been associated with a greater susceptibility to infectious colitis and liver abscess due to Entamoeba histolytic. Here the authors report that individuals homozygous for the LEPR Q223R mutation were at an increased risk of C. difficile infection.  This phenomenon was also studied in vivo in mice lacking the leptin receptor, with results showing a decreased clearance of C.difficile and lower levels of inflammation. These data suggest a protective role of leptin against C.difficile infection and suggests a connection between host metabolism and immunity.

http://iai.asm.org/content/early/2013/10/22/IAI.00972-13.long

SpoA is the global regulator of C. difficile sporulation and may in turn regulate potential virulence factors that may play a role in C.difficile infection. Previous conflicting data from various studies have failed to show a regulatory role of Spo0A in toxin A and toxin B production by C. difficile.  Mackin et al report that Spo0A acts as a negative regulator of toxin A and toxin B production in two ribotype 027 isolates but not in strain 630Δerm. In addition, Spo0A may be involved in regulating some aspects of C. difficile motility.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0079666

C.difficile spores play an important role in disease pathogenesis.  Spores can survive in the environment for long periods and are generally resistant to household cleaners. Spore proteins present on the outer layer of spores, the exosporium, may be essential for the initiation and persistence of C. difficile infection. Pizarro-Guajardo et al report that three C.difficile collagen-like exosporium proteins (BclA) are expressed during sporulation and localize to the spore, although they do not contribute to spores hydrophobicity and BclA1 has low immunogenicity. This is the first detailed study of collagen-like proteins in C. difficile.

http://www.sciencedirect.com/science/article/pii/S1075996413001881

December 2, 2013