Diaz Luis Alonso, Altman Norman H, Khan Wasif N, Serhan Charles N, Adkins Becky
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
Infect Immun. 2017 Sep 20;85(10). doi: 10.1128/IAI.00464-17. Print 2017 Oct.
Infants are generally highly susceptible to oral pathogens. Intestinal infection and the associated diarrhea are significant global causes of morbidity and mortality in infants. Among the enteric pathogens, enteropathogenic (EPEC) stands out as showing the highest risk for infection-induced death in infants ≤12 months old. We have developed an experimental model of infant infection with EPEC, using the mouse-specific pathogen Our murine infant model is similar to EPEC infection in human infants since infant mice are much more susceptible to infection than adult mice; infants infected with 50-fold fewer bacteria than the standard adult dose uniformly succumbed to the infection. Infant infection is characterized by high early and sustained bacterial titers and profound intestinal inflammation associated with extensive necrosis and systemic dissemination of the bacteria. Therefore, it seems likely that infant deaths result from sepsis secondary to intestinal damage. Recently, specialized proresolving mediators (SPM) have been found to exert profound beneficial effects in adult models of infection. Thus, we investigated the actions of two proresolving lipid mediators, resolvin D1 (RvD1) and resolvin D5 (RvD5), on the course of infection in infants. Strikingly, postinfection treatment with RvD1 and RvD5 reduced bacterial loads, mitigated inflammation, and rescued the infants from death. Furthermore, postinfection treatment with RvD1 and RvD5 led to protection from reinfection associated with -specific IgG responses comparable to those in adults. These results indicate that SPM may provide novel therapeutic tools for the treatment of pathological intestinal infections in infants.
婴儿通常对口腔病原体高度敏感。肠道感染及相关腹泻是全球婴儿发病和死亡的重要原因。在肠道病原体中，肠致病性大肠杆菌（EPEC）在12个月及以下婴儿中引发感染性死亡的风险最高。我们利用小鼠特定病原体开发了一种EPEC感染婴儿的实验模型。我们的小鼠婴儿模型与人类婴儿的EPEC感染相似，因为幼鼠比成年小鼠更容易感染；感染细菌数量比标准成年剂量少50倍的婴儿均死于感染。婴儿感染的特征是早期和持续的高细菌滴度以及与广泛坏死和细菌全身播散相关的严重肠道炎症。因此，婴儿死亡似乎是肠道损伤继发败血症所致。最近发现，特殊的促消退介质（SPM）在成人感染模型中具有显著的有益作用。因此，我们研究了两种促消退脂质介质，即消退素D1（RvD1）和消退素D5（RvD5）对婴儿感染过程的影响。令人惊讶的是，感染后用RvD1和RvD5治疗可降低细菌载量、减轻炎症，并使婴儿免于死亡。此外，感染后用RvD1和RvD5治疗可提供针对再次感染的保护，其特异性IgG反应与成人相当。这些结果表明，SPM可能为治疗婴儿病理性肠道感染提供新的治疗工具。
