Cohen Taylor S, Hilliard Jamese J, Jones-Nelson Omari, Keller Ashley E, O'Day Terrence, Tkaczyk Christine, DiGiandomenico Antonio, Hamilton Melissa, Pelletier Mark, Wang Qun, Diep Binh An, Le Vien T M, Cheng Lily, Suzich JoAnn, Stover C Kendall, Sellman Bret R
Department of Infectious Disease, MedImmune, Gaithersburg, MD 20878, USA.
Department of Translational Science, MedImmune, Gaithersburg, MD 20878, USA.
Sci Transl Med. 2016 Mar 9;8(329):329ra31. doi: 10.1126/scitranslmed.aad9922.
Broad-spectrum antibiotic use may adversely affect a patient's beneficial microbiome and fuel cross-species spread of drug resistance. Although alternative pathogen-specific approaches are rationally justified, a major concern for this precision medicine strategy is that co-colonizing or co-infecting opportunistic bacteria may still cause serious disease. In a mixed-pathogen lung infection model, we find that the Staphylococcus aureus virulence factor α toxin potentiates Gram-negative bacterial proliferation, systemic spread, and lethality by preventing acidification of bacteria-containing macrophage phagosomes, thereby reducing effective killing of both S. aureus and Gram-negative bacteria. Prophylaxis or early treatment with a single α toxin neutralizing monoclonal antibody prevented proliferation of co-infecting Gram-negative pathogens and lethality while also promoting S. aureus clearance. These studies suggest that some pathogen-specific, antibody-based approaches may also work to reduce infection risk in patients colonized or co-infected with S. aureus and disparate drug-resistant Gram-negative bacterial opportunists.
使用广谱抗生素可能会对患者有益的微生物群产生不利影响，并助长耐药性的跨物种传播。尽管针对特定病原体的替代方法在理论上是合理的，但这种精准医学策略的一个主要担忧是，共同定植或共同感染的机会性细菌仍可能导致严重疾病。在一个混合病原体肺部感染模型中，我们发现金黄色葡萄球菌毒力因子α毒素通过阻止含细菌的巨噬细胞吞噬体酸化，增强革兰氏阴性菌的增殖、全身扩散和致死率，从而减少对金黄色葡萄球菌和革兰氏阴性菌的有效杀伤。用单一的α毒素中和单克隆抗体进行预防或早期治疗可防止共同感染的革兰氏阴性病原体增殖和致死，同时还能促进金黄色葡萄球菌的清除。这些研究表明，一些针对特定病原体的基于抗体的方法也可能有助于降低金黄色葡萄球菌与不同耐药革兰氏阴性菌机会性感染患者的感染风险。
