Role of TLR1 and TLR6 in the host defense against disseminated candidiasis

Toll-like receptor-1 (TLR1) and TLR6 are receptors of the TLR family that form heterodimers with TLR2. The role of TLR1 and TLR6 for the recognition of the fungal pathogen Candida albicans was investigated. TLR1 is not involved in the recognition of C. albicans, and TLR1 knock-out (TLR1-/-) mice showed a normal susceptibility to disseminated candidiasis. In contrast, recognition of C. albicans by TLR6 modulated the balance between Th1 and Th2 cytokines, and TLR6 knock-out mice displayed a defective production of IL-10 and an increased IFN-gamma release. Production of the monocyte-derived cytokines tumor necrosis factor, IL-1, and IL-6 was normal in TLR6-/- mice, and this was accompanied by a normal susceptibility to disseminated candidiasis. In conclusion, TLR6 is involved in the recognition of C. albicans and modulates the Th1/Th2 cytokine balance, but this results in a mild phenotype with a normal susceptibility of TLR6-/- mice to Candida infection.     

Remodeling of host glycoproteins during bacterial infection

Protein glycosylation is a common post-translational modification found in all living organisms. This modification in bacterial pathogens plays a pivotal role in their infectious processes including pathogenicity, immune evasion, and host-pathogen interactions. Importantly, many key proteins of host immune systems are also glycosylated and bacterial pathogens can notably modulate glycosylation of these host proteins to facilitate pathogenesis through the induction of abnormal host protein activity and abundance. In recent years, interest in studying the regulation of host protein glycosylation caused by bacterial pathogens is increasing to fully understand bacterial pathogenesis. In this review, we focus on how bacterial pathogens regulate remodeling of host glycoproteins during infections to promote the pathogenesis.     

Role of inflammasomes in host defense against Citrobacter rodentium infection

Citrobacter rodentium is an enteric bacterial pathogen of the mouse intestinal tract that triggers inflammatory responses resembling those of humans infected with enteropathogenic and enterohemorrhagic Escherichia coli. Inflammasome signaling is emerging as a central regulator of inflammatory and host responses to several pathogens, but the in vivo role of inflammasome signaling in host defense against C. rodentium has not been characterized. Here, we show that mice lacking the inflammasome components Nlrp3, Nlrc4, and caspase-1 were hypersusceptible to C. rodentium-induced gastrointestinal inflammation. This was due to defective interleukin (IL)-1β and IL-18 production given that il-1β(-/-) and il-18(-/-) mice also suffered from increased bacterial burdens and exacerbated histopathology. C. rodentium specifically activated the Nlrp3 inflammasome in in vitro-infected macrophages independently of a functional bacterial type III secretion system. Thus, production of IL-1β and IL-18 downstream of the Nlrp3 and Nlrc4 inflammasomes plays a critical role in host defense against enteric infections caused by C. rodentium.     

Role of anti-beta-glucan antibody in host defense against fungi

We have recently detected an anti-beta-glucan antibody in normal human and normal mouse sera. The anti-beta-glucan antibody showed reactivity to pathogenic fungal Aspergillus and Candida cell wall glucan. Anti-beta-glucan antibody could bind whole Candida cells. It also enhanced the candidacidal activity of macrophages in vitro. The anti-beta-glucan antibody titer of DBA/2 mice intravenously administered either Candida or Aspergillus solubilized cell wall beta-glucan decreased remarkably dependent on dose. Moreover, in deep mycosis patients, the anti-beta-glucan antibody titer decreased, and this change correlated with clinical symptoms and other parameters such as C-reactive protein. It was suggested that the anti-beta-glucan antibody formed an antigen-antibody complex and participated in the immune response as a molecule recognizing pathogenic fungi.     

Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor

IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R) plays a critical role in chronic inflammation and cancer. Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling but was described to not interfere with classic signaling via the membrane-bound IL-6R. Physiological and most pathophysiological conditions are characterized by a molar excess of serum sIL-6R over IL-6 characterized by free IL-6 and IL-6 found in IL-6·sIL-6R complexes allowing both classic and trans-signaling. Surprisingly, under these conditions, sgp130 was able to trap all free IL-6 molecules in IL-6·sIL-6R·sgp130 complexes, resulting in inhibition of classic signaling. Because a significant fraction of IL-6 molecules did not form complexes with sIL-6R, our results demonstrate that compared with the anti-IL-6R antibody tocilizumab or the anti-trans-signaling monoclonal antibody 25F10, much lower concentrations of the dimeric sgp130Fc were sufficient to block trans-signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, indicating that the colon is a prominent target of IL-6 trans-signaling. Our results point to a so far unanticipated role of sgp130 in the blockade of classic signaling and indicate that in vivo only low therapeutic concentrations of sgp130Fc guarantee blockade of IL-6 trans-signaling without affecting IL-6 classic signaling.     

小鼠萎缩性胃炎模型的构建及与血清胃泌素 17、白介素 8的关系

目的建立小鼠慢性萎缩性胃炎(CAG)模型;用此模型探讨胃泌素-17(gastrin-17,G-17)及白介素-8(IL-8)在CAG诊断和病程进展中的应用价值。方法选取SPF级、体质量22～24 g、5～7周龄雄性C57BL/6小鼠40只,随机分为阴性对照组(A组,超纯水)、高盐组(B组,1.8%NaCl溶液)、H.pylori组(C组,H.pylori悉尼菌株SS1)和高盐+H.pylori组(D组,1.8%NaCl溶液+SS1菌株)4组,每组10只,分别对各组小鼠进行灌胃处理。于第16周和第24周每组分别处死5只小鼠,通过免疫组化观察H.pylori情况、胃黏膜病理组织学变化,酶联免疫吸附法(ELISA)检测小鼠血清G-17和IL-8的表达水平。结果灌胃处理16周可观察到B、D两组小鼠CAG造模成功,G-17表达水平差异无统计学意义(χ~2=6.591,P0.05);C、D两组小鼠IL-8表达水平较A、B两组明显升高(F=25.241,P0.05)。24周后可观察到B、C、D三个实验组均CAG造模成功:B、D组小鼠G-17表达水平较A组明显降低(χ~2=15.006,P0.05),C组G-17水平与A组差异无统计学意义(Z=-1.681,P0.05);H.pylori处理组(C、D)小鼠的IL-8水平明显升高(F=31.941,P0.05)。结论高盐饮食和胃黏膜H.pylori定植均可成功构建C57BL/6小鼠CAG模型,且高盐饮食可加快该模型的建立;血清G-17表达水平与CAG病情严重程度呈负相关,而IL-8的表达水平与是否H.pylori感染有关。     

重组人肿瘤坏死因子α和白细胞介素6融合基因的构建和表达

本文利用ＰＣＲ技术和基因定位突变技术,将编码人肿瘤坏死因子α（ｈＴＮＦα）和白细胞介素６（ｈＩＬ－６）成熟肽的基因通过中间接头连接成编码单一蛋白的基因,构建了融合蛋白表达载体ｐＢＩＴ,并在大肠杆菌中得到了表达。ＳＤＳ－ＰＡＧＥ的电泳胶薄层扫描显示,融合蛋白的表达量是菌体总蛋白量的２０％,其分子量约为３７ｋＤ。活性检测证实,融合蛋白既有ＴＮＦ活性,又有ＩＬ－６活性。     

病毒感染引起的炎症反应：宿主对抗病毒的“双刃剑”

先天性免疫系统作为宿主抵抗外来病原入侵的第一道防线,也是最迅速的防御系统。宿主先天性免疫系统中的模式识别受体识别入侵信号并激活炎症信号通路,诱导产生大量促炎性细胞因子,引起炎症反应。病毒感染是激活炎症反应的条件之一,诱导机体产生强烈的免疫应答,强大的炎症反应调控网络在宿主抗病毒过程中发挥关键作用,以维持机体的平衡。本文综述了病毒感染引起的炎症反应,重点介绍了宿主对炎症反应的调控网络,以及DNA和RNA病毒对炎症反应的调节机制,为病毒感染引起的免疫性疾病的治疗提供参考。     

Modulation of neutrophil function in host defense against disseminated Candida albicans infection in mice

Neutrophils (PMNs) constitute the main mechanism of host defense against acute invasive and disseminated candidiasis. Recent studies have demonstrated that tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF) play an important role in the recruitment of PMNs at the site of invasive Candida infection. In the absence of either TNFalpha or IL-6, the course of experimental disseminated candidiasis is more severe, due to defective PMN recruitment. Treatment of mice with recombinant G-CSF (rG-CSF) leads to a significantly reduced mortality during disseminated candidiasis. The outgrowth of Candida albicans from the organs of rG-CSF-treated mice is significantly decreased. Treatment with the combination of rG-CSF and fluconazole has an additive effect on the reduction of fungal load in the organs. In subacute or chronic disseminated Candida infection, rG-CSF is less effective, indicating that neutrophil recruitment and activation are crucial in acute, life-threatening candidiasis, whereas other host defense mechanisms control the outcome of less overwhelming invasive Candida infection.     

维生素D及白细胞介素-6水平在结直肠癌患者预后评估中的价值

目的 探讨维生素D及白细胞介素-6水平在结直肠癌患者预后评估中的价值。方法 选取树兰（杭州）医院2016—2017年经病理学证实的结直肠癌患者45例和同期健康体检者53例,检测患者外周血中维生素D、白细胞介素-6水平。根据检测结果,将结直肠癌患者分为维生素D高表达组和低表达组以及白细胞介素-6高表达组和低表达组,分别比较各组患者临床病理参数,并对患者进行预后评估。结果 结直肠癌患者外周血中维生素D含量为（6.43±3.71）ng/mL,低于健康对照组的（10.21±3.54）ng/mL,（P<0.01）。白细胞介素-6水平为17.5（8.97~42.92）ng/Ml,高于健康对照组的9.15（3.51~13.79）ng/mL,（P<0.01）,且二者在结直肠癌组织中的水平可能具有相关性（χ2=7.4,P<0.01）。维生素D及白细胞介素-6水平与结直肠癌患者是否发生淋巴结核转移、TNM分期和肿瘤浸润深度密切相关。预后分析发现,血清维生素D浓度与患者预后呈正相关,血清白细胞介素-6水平与患者预后呈负相关。结论 维生素D及白细胞介素-6水平与结直肠癌患者预后有关,可作为判断结直肠癌患者预后的新型、有效的生物学指标。     

细菌感染与Gasdermin家族介导的宿主细胞程序性死亡的研究进展

侵入宿主后,细菌生长、繁殖并与宿主相互作用,引发机体不同程度的病理变化。为抑制细菌致病过程,宿主免疫系统产生抗感染免疫应答,感染的发生和发展取决于细菌对机体的致病性与机体抗细菌免疫的相互抗争。在细菌所致感染性疾病的发生、发展过程中,细菌与宿主细胞的拮抗往往涉及程序性细胞死亡(programmed cell death, PCD)这一过程。新近发现Gasdermin家族成员Gasdermin D和Gasdermin E参与PCD过程,并在其中发挥重要作用,跟踪其研究进展将有助于应对细菌感染造成的威胁。     

地衣芽孢杆菌对儿童诺如病毒性肠炎患者血清PCT、IL6、IL8水平的影响

目的探讨地衣芽孢杆菌对诺如病毒性肠炎患儿血清前降钙素(PCT)、白介素-6(IL-6)和白介素-8(IL-8)水平的影响。方法将86例诺如病毒性肠炎患儿随机分为观察组和对照组,各43例。两组患儿均予以蒙脱石散等对症治疗,观察组患儿加用地衣芽孢杆菌活菌胶囊,1粒/次,3次/d,连续治疗7 d。采用免疫荧光法测定患儿血清PCT水平,采用ELISA法测定患儿IL-6和IL-8的水平,观察两组患儿治疗前后PCT、IL-6和IL-8水平的变化。结果治疗后,观察组患儿血清PCT、IL-6和IL-8水平分别为(4.1±1.8)μg/L、(26.5±5.4)ng/L和(33.5±4.9)ng/L,对照组患儿血清PCT、IL-6和IL-8水平分别为(7.2±2.3)μg/L、(51.2±8.3)ng/L和(58.4±9.0)ng/L,与治疗前相比均显著降低,且观察组各指标水平显著优于对照组(t=6.960、16.357、15.934,均P0.001)。结论地衣芽孢杆菌活菌胶囊辅助治疗能显著降低诺如病毒性肠炎患儿血清PCT、IL-6和IL-8水平,抑制炎症反应,值得推广使用。     

The induction of host cell autophagy triggers defense mechanisms against Trypanosoma cruzi infection in vitro

Trypanosoma cruzi causes Chagas disease, a neglected illness that affects millions of people worldwide, especially in Latin America. The balance between biochemical pathways triggered by the parasite and host cells response will ultimately define the progression of a life-threatening disease, justifying the efforts to understand cellular mechanisms for infection restrain. In this interaction, parasite and host cells are affected by different physiological responses as autophagy modulation, which could be under intense cellular stress, such as nutrient deprivation, hormone depletion, or infection. Autophagy is a constitutive pathway that leads to degradation of macromolecules and cellular structures and may induce cell death. In Trypanosoma cruzi infection, the relevance of host autophagy is controversial regarding in vitro parasite intracellular life cycle. In the present study, we evaluated host cell autophagy during T. cruzi infection in phagocytic and non-professional phagocytic cells. We described that the presence of the parasite increased the number of LC3 puncta, a marker for autophagy, in cardiac cells and peritoneal macrophages in vitro. The induction of host autophagy decreased infection in macrophages in early and late time-periods. We suggest that starved phagocytic cells reduced internalization, also confirmed by inert particles and dead trypomastigotes. Whereas, in cardiac cells, starvation-induced autophagy decreased lipid droplets and infection in later time-point, by reducing parasite differentiation/proliferation. In ATG5 knockout MEF cells, we confirmed our hypothesis of autophagy machinery activation during parasite internalization, increasing infection. Our data suggest that host autophagy downregulates T. cruzi infection through impairing parasite intracellular life cycle, reducing the infection in primary culture cells.     

应用特异性抗原刺激树突细胞增强小鼠抵抗烟曲霉感染的能力

目的 探讨曲霉抗原刺激树突细胞(DC)应用于小鼠后对小鼠抵抗曲霉感染能力的影响.方法 小鼠骨髓制备DC,尾静脉接种小鼠;腹腔内注射环磷酰胺后,鼻腔内滴入烟曲霉孢子制备侵袭性肺曲霉病小鼠模型;获取小鼠肺组织并进行匀浆,假丝酵母(念珠菌)显色培养基接种后进行菌落计数,酶联免疫吸附试验(ELISA)检测mγ干扰素(mIFN-γ)含量,部分肺组织进行HE和GMS染色;以反转录-聚合酶链反应(RT-PCR)的方法检测小鼠脾脏中细胞因子IFN-γ的mRNA表达.结果 与单纯接种DC和热灭活烟曲霉(HAF)的小鼠相比,烟曲霉抗原刺激DC回输的小鼠存活率显著增高,脾脏内IFN-γ的mRNA表达增加,肺组织烟曲霉负荷明显降低,肺组织匀浆中IFN-γ含量(3.60±1.57ng/ml)亦高于非刺激DC免疫小鼠(HAF,1.35±0.47ng/ml;单纯DC,1.1±0.42ng/ml,P＜0.01),接受单纯DC和HAF的小鼠肺组织可见烟曲霉孢子、菌丝生长,有支气管壁的破坏,支气管周围坏死,肺泡和间质内炎症细胞浸润,而接受烟曲霉抗原刺激DC的小鼠肺内浸润炎症细胞减少,未发现坏死和真菌生长.结论 应用烟曲霉抗原刺激DC,可以在小鼠体内诱导特异性Th1型反应,增强小鼠抵抗烟曲霉感染的能力.     

女性2型糖尿病患者尿液细菌分布及其与血清IL-6的相关性

目的检测女性2型糖尿病(T2DM)患者尿液细菌多样性特征,分析其与白细胞介素-6(IL-6)水平的相关性。方法选择2016年1月至2019年6月于本院诊治的女性T2DM患者60例作为T2DM组。选择同期于本院行尿液细菌检测的健康女性60例作为健康组。收集两组对象尿液样本,采用细菌DNA测序法对样本内细菌16S rRNA-cDNA高可变区进行测序,比较两组对象尿液细菌分布特征。采用ELISA法测定血清IL-6水平,根据IL-6检出情况分为IL-6组和非IL-6组,比较两组对象尿液细菌的组成情况及其与IL-6的关系。结果 T2DM组患者尿液微生物多样性、Shannon指数、谱系多样性、菌种丰富度指数均低于健康组(均P0.05)。共发现35个细菌门,其中T2DM组33个,健康组35个。T2DM组患者相对丰度较多的细菌为变形菌门(50.77%)、拟杆菌门(21.62%)和厚壁菌门(14.46%)。健康组相对丰度较多的细菌为变形菌门(54.49%)、拟杆菌门(22.81%)和厚壁菌门(10.02%)。T2DM组患者尿液中绿弯菌门、硝化螺旋菌门、疣微菌门相对丰度均低于健康组(均P0.05),其他菌门差异无统计学意义(均P0.05)。共发现438个细菌属,其中T2DM组438个,健康组421个。T2DM组和健康组共有30个菌属水平差异有统计学意义(均P0.05)。IL-6组和非IL-6组患者尿液微生物多样性、Shannon指数、谱系多样性、菌种丰富度指数比较差异均无统计学意义(均P0.05)。多元回归分析显示,共有15种细菌属与血清IL-6水平有线性相关关系。结论女性T2DM患者尿液菌群紊乱且与IL-6互为影响,应关注患者尿液菌群和膀胱炎症情况。     

LL-37-mediated activation of host receptors is critical for defense against group A streptococcal infection

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糖尿病并发尿路感染患者病原菌分布与危险因素分析

目的 研究糖尿病并发尿路感染患者病原菌分布情况及其影响因素,为此类患者的治疗提供参考.方法 选取我院2016年1月至2019年6月收治的60例糖尿病合并尿路感染患者为观察组,选取同期我院治疗的60例单纯性糖尿病患者为对照组,分析糖尿病合并尿路感染患者病原菌分布情况,并分析糖尿病患者合并尿路感染的危险因素.结果 患者尿路...     

Roles of Toxoplasma gondii-derived heat shock protein 70 in host defense against T. gondii infection

C57BL/6 mice receiving intraperitoneal injection of Toxoplasma gondii -derived heat shock protein 70 (T.g. HSP70) on day 3 post T. gondii infection succumbed by day 9 post infection, while vector protein-injected control mice survived more than 6 months. The deteriorating effect of T.g. HSP70 on host immune responses was dose-dependent. By T.g. HSP70 injection, T. gondii loads increased in various organs of T. gondii-infected mice. Th2 cytokines such as IL-4 and IL-10 were continuously produced from spleen and peritoneal exudate cells of T. gondii -infected mice by injection of T.g. HSP70. Furthermore, nitric oxide production from peritoneal macrophages in T. gondii-infected mice was reduced by T.g. HSP70.