Immune Protection against Lethal Fungal-Bacterial Intra-Abdominal Infections.
Immune Protection against Lethal Fungal-Bacterial Intra-Abdominal Infections.
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DOI：
10.1128/mbio.01472-17
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发表时间：
2018-01-16
期刊：
影响因子：
6.4
通讯作者：
Noverr MC
中科院分区：
文献类型：
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作者：
Lilly EA;Ikeh M;Nash EE;Fidel PL Jr;Noverr MC
多微生物腹腔内感染（IAIs）是临床上普遍存在的，引起显著的发病率和死亡率，特别是那些涉及真菌的感染。我们的实验室建立了IAI小鼠模型，并证明腹腔接种白色念珠菌或其他毒力强的非白色念珠菌（NAC）和金黄色葡萄球菌可导致70%至80%的死亡率在48至72小时内，由于强烈的局部和全身炎症（败血症）。令人惊讶的是，接种dublini念珠菌或光念珠菌与金黄色葡萄球菌导致的死亡率最低，并且这些小鼠再次感染致命的白色念珠菌/S。金黄色葡萄球菌（即合并感染）的保护率为90%。本研究的目的是确定dubliniensis/S的需要量。金黄色葡萄球菌介导的保护和询问保护反应的机制。dubliniensis单独或杀死的C. dubliniensis加活的金黄色葡萄球菌具有保护作用。金黄色葡萄球菌单独不具有保护作用，杀死的金黄色葡萄球菌损害了dubliniensis诱导的保护作用。c . dubliniensis / S。金黄色葡萄球菌对NAC +金黄色葡萄球菌的致命攻击也有保护作用，并且在初次攻击和白色念珠菌/金黄色葡萄球菌之间可以保护60天。球菌重新)。出乎意料的是，缺乏T细胞和B细胞的小鼠（rag1敲除[KO]）在最初的C. dubliniensis/S中都存活了下来。金黄色葡萄球菌和白色念珠菌。金黄色葡萄球菌再挑战，表明适应性免疫没有发挥作用。同样，在再挑战之前，巨噬细胞被耗尽的小鼠也受到保护。相反，再攻毒后4小时内腹腔灌洗液中大量的Gr-1+多形核白细胞（PMNLs）与保护作用相关，再攻毒前体内Gr-1+细胞的消耗使保护作用失效。这些结果表明，念珠菌可以诱导对致命的白色念珠菌/S的保护。由PMNLs介导的金黄色葡萄球菌IAI，被认为是一种独特的训练先天免疫形式。多微生物腹腔感染是临床上具有破坏性的感染，死亡率高，特别是那些涉及真菌病原体，包括念珠菌。即使在接受积极抗微生物治疗的患者中，死亡率仍然高得令人无法接受。由于感染的多微生物性质，目前尚无针对IAI的可用疫苗。IAI导致致死性全身性炎症（败血症），这在药理学上很难定位，因为炎症反应的成分也需要控制感染。我们的研究表明，事先接种低毒力的念珠菌可以提供强大的保护，防止随后致命的白色念珠菌和金黄色葡萄球菌感染。令人惊讶的是，保护是长期存在的，但不是由适应性（特异性）免疫介导的。相反，这种保护依赖于先天免疫系统的细胞（非特异性免疫），并提供对其他有毒念珠菌物种的保护。这一发现表明，一种训练有素的先天免疫可能在临床上对多微生物IAI有效。
Polymicrobial intra-abdominal infections (IAIs) are clinically prevalent and cause significant morbidity and mortality, especially those involving fungi. Our laboratory developed a mouse model of IAI and demonstrated that intraperitoneal inoculation with Candida albicans or other virulent non-albicans Candida (NAC) species plus Staphylococcus aureus resulted in 70 to 80% mortality in 48 to 72 h due to robust local and systemic inflammation (sepsis). Surprisingly, inoculation with Candida dubliniensis or Candida glabrata with S. aureus resulted in minimal mortality, and rechallenge of these mice with lethal C. albicans/S. aureus (i.e., coninfection) resulted in >90% protection. The purpose of this study was to define requirements for C. dubliniensis/S. aureus-mediated protection and interrogate the mechanism of the protective response. Protection was conferred by C. dubliniensis alone or by killed C. dubliniensis plus live S. aureus. S. aureus alone was not protective, and killed S. aureus compromised C. dubliniensis-induced protection. C. dubliniensis/S. aureus also protected against lethal challenge by NAC plus S. aureus and could protect for a long-term duration (60 days between primary challenge and C. albicans/S. aureus rechallenge). Unexpectedly, mice deficient in T and B cells (Rag-1 knockouts [KO]) survived both the initial C. dubliniensis/S. aureus challenge and the C. albicans/S. aureus rechallenge, indicating that adaptive immunity did not play a role. Similarly, mice depleted of macrophages prior to rechallenge were also protected. In contrast, protection was associated with high numbers of Gr-1hi polymorphonuclear leukocytes (PMNLs) in peritoneal lavage fluid within 4 h of rechallenge, and in vivo depletion of Gr-1+ cells prior to rechallenge abrogated protection. These results suggest that Candida species can induce protection against a lethal C. albicans/S. aureus IAI that is mediated by PMNLs and postulated to be a unique form of trained innate immunity. Polymicrobial intra-abdominal infections are clinically devastating infections with high mortality rates, particularly those involving fungal pathogens, including Candida species. Even in patients receiving aggressive antimicrobial therapy, mortality rates remain unacceptably high. There are no available vaccines against IAI, which is complicated by the polymicrobial nature of the infection. IAI leads to lethal systemic inflammation (sepsis), which is difficult to target pharmacologically, as components of the inflammatory response are also needed to control the infection. Our studies demonstrate that prior inoculation with low-virulence Candida species provides strong protection against subsequent lethal infection with C. albicans and S. aureus. Surprisingly, protection is long-lived but not mediated by adaptive (specific) immunity. Instead, protection is dependent on cells of the innate immune system (nonspecific immunity) and provides protection against other virulent Candida species. This discovery implies that a form of trained innate immunity may be clinically effective against polymicrobial IAI.