革兰氏阳性细菌铁摄取机制的研究进展

铁是大多数细菌生长存活的基本营养物质,细菌能否从宿主体内摄取足够的铁对于其毒力和致病起着关键的作用.铁在宿主体内主要以游离铁、含铁蛋白和血红素三种形式存在.细菌可以通过复杂的铁摄取机制来获得宿主体内的铁进而感染宿主.因此,探究细菌的铁摄取机制有助更好的了解细菌的生长和致病过程.     

Hepcidin研究进展

Hepcidin(Hepc)是肝脏分泌的一种小分子肽 ,属防卫素蛋白家族。机体铁状况、贫血、缺氧、细菌、致炎物质和细胞因子等均可影响Hepc的表达水平。Hepc具有抑制某些细菌和真菌生长繁殖的作用 ,是机体“天然免疫”重要的效应分子 ,同时可抑制肠道铁吸收和单核巨噬细胞系统铁释放 ,是一种重要的负性铁调节激素 ,在遗传性血色病、慢性病贫血等铁代谢相关性疾病发病机制方面发挥着重要作用 ,可能是机体铁稳态调控途径中关键性的效应分子。     

能量应激介导的铁死亡在肿瘤中的研究进展

铁死亡是一种铁离子依赖的非凋亡的新的细胞死亡形式, 主要表现为外源性或内源性氧化还原失衡导致的细胞膜脂质过氧化。肿瘤细胞的存活依赖于能量物质的供给, 营养物质剥夺会诱发能量应激介导的代谢紊乱, 进而触发铁死亡。本文从营养物质剥夺、营养转运体抑制和内源性铁死亡防御系统3个方面在肿瘤铁死亡中的研究进展作一综述, 为靶向能量代谢途径诱导肿瘤铁死亡提供理论基础。     

源自人肠道微生物组的共生菌混合物诱导抗肿瘤免疫反应

<正>据Tanoue T 2019年1月23日(Nature,2019 Jan 23. doi:10.1038/s41586-019-0878-z.)报道,日本研究人员开发一种新的免疫介导的疾病治疗方法,基于合理确定的源自人类微生物组的细菌混合物,产生抗肿瘤免疫,即利用人体肠道菌群诱导产生干扰素γ(IFNγ)的CD8+T细胞在肠道和肿瘤中积累,来增强抗癌免疫。Honda K及其团队鉴定并筛选出一种合理确定的源自人类微生物组的细菌菌株混合物,该细菌菌株混合物     

髓源性抑制细胞在感染性疾病中的作用北大核心

感染性疾病是指病原微生物感染人体后引起的疾病,常见的病原微生物主要包括病毒、细菌、真菌和寄生虫等。近年来,由于受易感人群递增、新病原微生物出现及细菌耐药性增加等多种因素影响,感染性疾病的治疗已陷入瓶颈,急需寻找新的更加高效低毒的治疗途径。而免疫因素在感染性疾病中扮演着重要角色,其在感染性疾病进程中的调控作用已被证明与感染性疾病的发生、发展密切相关。髓源性抑制细胞(myeloid-derived suppressor cell,MDSC)在机体的免疫机制中占据重要地位,是一种具有代表性的发挥免疫抑制作用的未成熟细胞,其在肿瘤免疫、自身免疫性疾病等方面的作用已被广泛证明,但在感染性疾病中研究甚少。该文系统总结MDSC在由各种病原微生物引起的感染性疾病中的研究进展及其作用机制,以期寻找以MDSC为调控靶点的治疗感染性疾病的新思路和新方法。     

衰老以及低蛋白饮食对肠粘膜中免疫成份的影响

胃肠道对食物中化学物质和微生物病原体的入侵是一重要屏障。肠道中sIgA能与细菌或病毒结合,减少微生物的粘附和生长,肠粘膜中淋巴细胞还具有细胞介导的免疫功能。     

可疑糖尿病足骨髓炎患者骨微生物培养及骨病理资料分析

目的分析临床上可疑糖尿病足骨髓炎患者的骨组织微生物学和病理检查的结果,提高对糖尿病足骨髓炎的诊断水平。方法取26例符合糖尿病足溃疡合并蜂窝组织炎、可探及骨质或溃疡中有骨暴露的住院糖尿病足患者换药清创的骨组织行骨微生物培养及骨病理检查。分析骨微生物培养及骨组织病理检查的阳性率、菌种及对常见抗生素的敏感情况和患者的临床特点。结果骨微生物培养联合骨组织病理检查确诊84.6%(22/26)的患者为糖尿病足骨髓炎。共进行38例次骨微生物培养,培养出20种细菌,1种真菌。13例患者进行了多次的骨微生物培养,10例患者骨微生物培养出多种细菌。行多次骨培养和培养出多种菌种的患者的糖尿病足病程短于一次培养组和一种菌种组,白细胞计数、中性粒细胞绝对值、血沉、C-反应蛋白和D-二聚体水平均高于一次培养组和一种菌种组,而血红蛋白、红细胞压积、白蛋白、血清铁低于一次培养组和一种菌种组。结论骨微生物培养和骨病理检查能够确诊糖尿病足骨髓炎。需要行多次骨清创或骨微生物培养出多种细菌的糖尿病足患者糖尿病足感染更严重、营养状态更差。     

人乳铁蛋白的免疫单扩散测定

<正> 乳铁蛋白(Lectoferrin简称LF)是一种结合铁的糖蛋白。人乳尤其是初乳内LF的含量很高。LF与铁营养的抗菌、抗感染免疫有关。作者在人乳LF分离纯化和制备抗血清的基础上,建立了免疫单扩散测     

病毒诱导的免疫调节

高度复杂的细胞及分子机制调节着微生物及免疫防御系统间的相互作用。现在已经知道了不少关于细菌和病毒等微生物抗原,对正常个体免疫反应的机制,微生物既可促进也可抑制体液及细胞免疫。但是这些传染性因子究竟是如何作用于免疫系统的,却知道得并不多。许多微生物产生一些物质,这种物质或者能保护细菌不受宿主免疫反应所破坏,或者能完全抑制免疫反应。另外,有一些微生物在某种条件下释放免疫刺激物,促进免疫反应,而在另种条件下可能起抑制免疫反应的作用。     

微生物相关肿瘤的发病机制及其治疗的研究进展

肿瘤是多因素参与和多阶段发病的疾病，其中生物致癌因素主要有致癌性病毒、细菌及寄生虫，常见的包括乙型肝炎病毒(HBV)与肝细胞癌、EB病毒(EBV)与鼻咽癌、人乳头瘤病毒(HPV)与宫颈癌、幽门螺杆菌(Hp)与MALT淋巴瘤及胃癌等。肿瘤的发生发展与微生物密不可分，微生物可通过以下几种机制施展致癌促癌作用：产生毒性物质、诱导毒性效应、诱导炎性反应发生、影响免疫应答等。本文将微生物的致癌促癌机制相关进展做简要总结，并展望以微生物作为早期肿瘤筛查的生物标志物和以微生物作为靶点研发药物的新思路。     

Effect of iron on antibacterial immunity in vaccinated mice.

The effect of iron on resistance to Salmonella typhimurium was investigated in mice inoculated with vaccines prepared from live and avirulent (SL3770) or killed and virulent (SR11 or LT2) bacteria. It has been found that mice vaccinated with SL3770 vaccine develop an immunity which can be neutralized with iron. Iron promoted the development of lethal infections by serving as a growth-essential nutrilite for infecting bacteria and by neutralizing the acquired immunity. The titration of this dual effect of iron showed that more iron was needed to neutralize the immunity in vaccinated animals than to promote bacterial growth in normal animals. In the presence of a sufficient amount of exogenous iron, as few as 10 bacteria caused lethal infections in normal and immune mice with the same effectiveness. This iron-sensitive immunity could be changed to iron-resistant immunity by the immunological stimulation of SL3770-vaccinated mice with a sonicated vaccine prepared from heat-killed SR11 or LT2 bacteria. In distinction to iron-sensitive immunity, iron-resistant immunity could be transferred from SR11- or LT2-stimulated to normal mice with serum. Although effective in the transfer of antibacterial immunity, sera of SR11- or LT2-stimulated mice supported the growth of virulent bacteria as well as did sera of normal mice. The absorption of immune serum with either SR11 or LT2 bacteria removed its protective quality, but the sensitized bacteria remained as infectious as untreated bacteria for iron-treated normal mice. Only in SL3770-vaccinated mice were the immune serum-sensitized bacteria not able to cause the infection in spite of daily treatment with iron. These results suggest that iron-resistant immunity is due to the synergistic action of specific antibody and phagocytes of immunologically stimulated animals.     

Immune response to the iron-deprivation-induced proteins of Salmonella typhi in typhoid fever.

Iron starvation conditions limited the growth of Salmonella typhi, as evidenced by an increase in the lag phase of a culture and a decrease in the number of bacteria reached in the stationary phase. The analysis of the outer membrane of bacteria grown under these conditions identified new protein components with apparent molecular weights of 83,000, 78,000, and 69,000. The extent of induction of these proteins was regulated by increased iron deprivation. Immunoblot analysis showed that the serum of patients with typhoid fever exhibited an immunoglobulin G response to these iron-deprivation-induced proteins. The results of bioassays and DNA-DNA hybridization experiments indicated that pathogenic strains of S. typhi produced enterochelin but not aerobactin. Immunodetection with an anti-FepA antiserum confirmed that one of the induced proteins is the S. typhi analog of the Escherichia coli fepA gene product. These studies suggest a role for iron uptake in the pathogenesis of typhoid fever and confirm the immunogenicity of some of the outer membrane proteins of this pathogen.     

ColV plasmid-specific aerobactin synthesis by invasive strains of Escherichia coli.

Certain strains of Escherichia coli associated with bacteremia of humans and domestic animals harbor plasmids that promote efficient iron uptake. The mechanism, which is an important component of the virulence of invasive strains, is independent of the enterobactin system for iron uptake. Plasmid-specified siderophore was assayed by its ability to support the growth of a chelator-deficient mutant in conditions of iron deprivation. The chelator, which was chemically determined to be a hydroxamate compound, was identical on the basis of field desorption mass spectrometry with aerobactin, a siderophore synthesized by Aerobacter aerogenes. In conditions of iron stress, aerobactin is secreted into the culture medium of plasmid-bearing E. coli strains. Reconstruction experiments involving a chelator-deficient mutant growing with exogenous chelator suggested that association of a small fraction of the total siderophore synthesized with cellular material is due to transient binding of aerobactin to membrane receptors during active bacterial growth.     

Effects of Injected Iron and Siderophores on Infections in Normal and Immune Mice

The fate of virulent and avirulent strains of Salmonella typhimurium in untreated and iron-injected mice and in transferrin-containing media demonstrated a direct relationship between bacterial virulence and the ability of bacteria to acquire transferrin-bound iron. Effects of injected iron on the development of infections with virulent and avirulent bacterial strains were determined in normal and immune mice by determinations of bacterial numbers in tissue homogenates and the mortality of infected animals. Results showed that infected and iron-injected mice died much more rapidly and frequently from overwhelming infections than infected and saline-injected mice. The infection-promoting effect of iron varied with the degree of bacterial virulence; the more virulent the bacteria, the more helpful was iron for the development of lethal infections. Siderophores promoted lethal infections in mice infected with virulent but not with avirulent bacteria. Experiments with vaccinated animals showed that iron exerted a deleterious effect on acquired immunity. Immune mice infected with virulent bacteria and injected with iron developed lethal infections as rapidly and nearly as frequently as similarly treated normal mice. Siderophores did not promote the development of lethal infections in immune mice. The effectiveness of iron, but not of siderophores, to promote bacterial infections in vaccinated mice revealed that acquired immunity is dependent upon the activity of an iron-neutralizable antibacterial system.     

The role of iron in infections with intracellular bacteria

The requirement for iron as a critical component for cellular processes has long been appreciated. During infection with intracellular bacteria, iron is required by both the host cell and the pathogen that inhabits the host cell. Macrophages require iron as a cofactor for the execution of important antimicrobial effector mechanisms, including the NADPH dependent oxidative burst and the production of nitrogen radicals catalysed by the inducible nitric oxide synthase. On the other side of the equation, intracellular bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis have an obligate requirement for iron to support their growth and survival inside cells. This brief report summarises the background to our work on iron modulation in infections with these two organisms and highlights key observations on how modulation of host iron status disturbs the equilibrium between host and pathogen and can determine the outcome of infection.     

Investigation into the mechanism of gamma interferon-mediated inhibition of Toxoplasma gondii in murine astrocytes

Toxoplasma gondii is an obligate intracellular parasite that is a common opportunistic pathogen of the central nervous system in AIDS patients. Gamma interferon (IFN-gamma) alone or in combination with interleukin-1 (IL-1), IL-6, or tumor necrosis factor alpha significantly inhibits the growth of T. gondii in murine astrocytes, suggesting these are important nonimmune effector cells in the brain. Inhibition was found to be independent of a nitric oxide-mediated or tryptophan starvation mechanism. Both reactive oxygen intermediates and iron deprivation are IFN-gamma-mediated mechanisms known to operate against intracellular parasites in other cell types. Astrocytes generated from mice genetically deficient in the production of reactive oxygen intermediates (phox(-/-) mice) were found to inhibit growth of T. gondii when stimulated with IFN-gamma alone or in combination with other cytokines. The reactive oxygen inhibitor catalase and the reactive oxygen scavengers mannitol and thiourea failed to reverse the IFN-gamma-induced inhibition of T. gondii in astrocytes. These data indicate that IFN-gamma-induced inhibition in astrocytes is independent of reactive oxygen intermediates. IFN-gamma-induced inhibition could not be reversed by the addition of iron salts, ferric citrate, ferric nitrate, or ferric transferrin. Pretreatment of astrocytes with desferrioxamine also did not induce the inhibition of T. gondii. These data indicate that the mechanism of IFN-gamma inhibition was not due to iron deprivation. IFN-gamma had no effect on T. gondii invasion of astrocytes, but inhibition of growth and loss of tachyzoite vacuoles were evident in IFN-gamma-treated astrocytes by 24 h after invasion. Overall, these data suggest that IFN-gamma-activated astrocytes inhibit T. gondii by an as-yet-unknown mechanism.     

Estrogen-dependent changes in serum iron levels as a translator of the adverse effects of estrogen during infection: A conceptual framework

Elevated levels of estrogen often associate with increased susceptibility to infection. This has been attributed to the ability of estrogen to concomitantly enhance the growth and virulence of pathogens and suppress host immunity. But the exact mechanism of how estrogen mediates such effects, especially in cases where the pathogen and/or the immune components in question do not express estrogen receptors, has yet to be elucidated. Here we propose that translating the adverse effects of estrogen during infection is dependent to a significant degree upon its ability to manipulate iron homeostasis. For elevated levels of estrogen alter the synthesis and/or activity of several factors involved in iron metabolism including hypoxia inducible factor 1α (HIF-1α) and hepcidin among others. This leads to the inhibition of hepcidin synthesis in hepatocytes and the maintenance of ferroportin (FPN) integrity on the surface of iron-releasing duodenal enterocytes, hepatocytes, and macrophages. Intact FPN permits the continuous efflux of dietary and stored iron into the circulation, which further enhances pathogen growth and virulence on the one hand and suppresses host immunity on the other. This new conceptual framework may help explain a multitude of disparate clinical and experimental observations pertinent to the relationship between estrogen and infection.     

Estrogen-dependent changes in serum iron levels as a translator of the adverse effects of estrogen during infection: A conceptual framework

Elevated levels of estrogen often associate with increased susceptibility to infection. This has been attributed to the ability of estrogen to concomitantly enhance the growth and virulence of pathogens and suppress host immunity. But the exact mechanism of how estrogen mediates such effects, especially in cases where the pathogen and/or the immune components in question do not express estrogen receptors, has yet to be elucidated. Here we propose that translating the adverse effects of estrogen during infection is dependent to a significant degree upon its ability to manipulate iron homeostasis. For elevated levels of estrogen alter the synthesis and/or activity of several factors involved in iron metabolism including hypoxia inducible factor 1α (HIF-1α) and hepcidin among others. This leads to the inhibition of hepcidin synthesis in hepatocytes and the maintenance of ferroportin (FPN) integrity on the surface of iron-releasing duodenal enterocytes, hepatocytes, and macrophages. Intact FPN permits the continuous efflux of dietary and stored iron into the circulation, which further enhances pathogen growth and virulence on the one hand and suppresses host immunity on the other. This new conceptual framework may help explain a multitude of disparate clinical and experimental observations pertinent to the relationship between estrogen and infection.     

Iron limitation and the gamma interferon-mediated antihistoplasma state of murine macrophages.

The zoopathogenic fungus Histoplasma capsulatum requires iron for growth. Intracellular growth of the fungus within mouse peritoneal macrophages is inhibited by recombinant murine gamma interferon (IFN-gamma). Such treatment of mouse peritoneal macrophages induces a marked downshift in transferrin receptors. We tested whether the antihistoplasma effect of IFN-gamma-treated macrophages is the result of iron deprivation. Treatment of mouse peritoneal macrophages with the intracellular iron chelator deferoxamine inhibits the intracellular growth of H. capsulatum. Exposure of macrophages to holotransferrin antagonizes the effect of both recombinant murine IFN-gamma and deferoxamine treatments. These results suggest that iron restriction may be one of the bases for the IFN-gamma-induced antihistoplasma effect of mouse macrophages.     

Bombyx mori transferrin: Genomic structure,expression and antimicrobial activity of recombinant protein

Transferrin (Tf) is a multifunctional, iron binding protein found in both vertebrates and invertebrates. Although transferrin has been suggested to play a role in innate immunity, its immunological function during infection has not been characterized. In this study, we identified and characterized Bombyx mori transferrin (BmTf). The promoter region of BmTf has numerous putative NF-κB binding sites, suggesting its possible function in innate immunity. Analysis of BmTf gene expression shows that it is highly inducible in response to a wide variety of pathogens including bacteria, fungus, and viruses. Recombinant BmTf protein produced in a baculovirus system exhibits iron binding capacity and antibacterial activity against various Gram-positive and -negative bacteria. Taken together, our results indicate that BmTf is an inducible immune effector molecule that may play an important role in pathogen clearance of insect innate immunity.