Fettucciari Katia, Fruganti Alessandro, Marchegiani Andrea, Brancorsini Stefano, Marconi Pierfrancesco, Bassotti Gabrio
Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy.
School of Biosciences and Veterinary Medicine, University of Camerino, Macerata, Italy.
J Inflamm Res. 2021 Jan 11;14:57-62. doi: 10.2147/JIR.S287096. eCollection 2021.
infection (CDI) has a serious impact on the healthcare system, and most of its pathogenic effects are mainly due to the activity of toxins A and B (TcdA and TcdB, respectively). The molecular mechanisms of their cytotoxic activity are well known, especially in the colon, where the infection occurs and normally remains localized. However, the mechanisms causing toxic effects on various systemic organs (extraintestinal manifestations) with frequent lethal outcomes in some patients affected by CDI are still poorly understood. Few studies are available that demonstrate low serum levels of Tcds in both experimental animal models and patients with CDI. Until now, it has remained unclear how low levels of circulating Tcds could lead to serious toxic effects. On the basis of our previous in vitro studies, in which the proinflammatory cytokines TNF-alpha and IFN-gamma strongly potentiated the toxic activity of low doses of TcdB, we hypothesize that the presence of both TcdB in the circulation and a systemic proinflammatory cytokine storm may be responsible for the selective severe effects of TcdB in some patients. This may occur in patients with severe CDI and systemic Tcds, in whom proinflammatory cytokines such as TNF-alpha and IFN-gamma reach a significant concentration in the circulation. This hypothesis could identify therapeutic interventions based on the reduction or neutralization of the indirect toxic action of these cytokines.
艰难梭菌感染（CDI）对医疗系统有严重影响，其大部分致病作用主要归因于毒素A和毒素B（分别为TcdA和TcdB）的活性。它们细胞毒性活性的分子机制已为人熟知，尤其是在感染发生且通常局限于结肠的情况下。然而，对于在一些CDI患者中导致对各种全身器官产生毒性作用（肠外表现）并常伴有致命后果的机制仍知之甚少。在实验动物模型和CDI患者中，仅有少数研究表明血清中Tcds水平较低。到目前为止，尚不清楚循环中低水平的Tcds如何导致严重的毒性作用。基于我们之前的体外研究，其中促炎细胞因子TNF-α和IFN-γ强烈增强了低剂量TcdB的毒性活性，我们推测循环中存在TcdB以及全身性促炎细胞因子风暴可能是导致TcdB在一些患者中产生选择性严重影响的原因。这可能发生在患有严重CDI和全身性Tcds的患者中，其中TNF-α和IFN-γ等促炎细胞因子在循环中达到显著浓度。这一假设可以确定基于减少或中和这些细胞因子间接毒性作用的治疗干预措施。
