Pathogens and disease最新文献

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Title: A Comprehensive Review on Classifying Fast-acting and Slow-acting Antimalarial Agents Based on Time of Action and Target Organelle of Plasmodium sp. 题目:基于疟原虫作用时间和靶细胞器分类快效和慢效抗疟药的综述。

IF 3.3 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-05-19 DOI: 10.1093/femspd/ftac015

Monika Marie Bernard, Abhinab Mohanty, V. Rajendran

The clinical resistance towards malarial parasites has rendered many antimalarials ineffective, likely due to a lack of understanding of time of action and stage specificity of all life stages. Therefore, to tackle this problem a more incisive comprehensive analysis of the fast and slow-acting profile of antimalarial agents relating to parasite time-kill kinetics and the target organelle on the progression of blood-stage parasites was carried out. It is evident from numerous findings that drugs targeting food vacuole, nuclear components, and endoplasmic reticulum mainly exhibit a fast-killing phenotype within 24h affecting first-cycle activity. Whereas drugs targeting mitochondria, apicoplast, microtubules, parasite invasion and egress exhibit a largely slow-killing phenotype within 96-120h, affecting second-cycle activity with few exemptions as moderately fast-killing. It is essential to understand the susceptibility of drugs on rings, trophozoites, schizonts, merozoites, and the appearance of organelle at each stage of 48h intraerythrocytic parasite cycle. Therefore, these parameters may facilitate the paradigm for understanding the timing of antimalarials action in deciphering its precise mechanism linked with time. Thus, classifying drugs based on the time of killing may promote designing new combination regimens against varied strains of P. falciparum and evaluating potential clinical resistance.

对疟疾寄生虫的临床耐药性使许多抗疟药物无效，这可能是由于缺乏对所有生命阶段的作用时间和阶段特异性的了解。因此，为了解决这一问题，我们对抗疟药物与寄生虫时间杀伤动力学和靶细胞器在血期寄生虫进展中的关系进行了更深入全面的快速和慢效分析。大量研究结果表明，靶向食物液泡、核组分和内质网的药物主要在24小时内表现为快速杀伤表型，影响第一周期活性。而靶向线粒体、顶质体、微管、寄生虫入侵和出口的药物在96-120h内表现出很大程度上的慢杀表型，影响第二周期活性，很少有中等快杀的例外。了解药物对48h红细胞内寄生周期各阶段环、滋养体、分裂体、分裂子的敏感性和细胞器外观的影响是至关重要的。因此，这些参数可能有助于理解抗疟药物作用时间的范式，从而破译其与时间相关的精确机制。因此，基于杀伤时间对药物进行分类可能有助于设计新的联合方案，以对抗不同类型的恶性疟原虫，并评估潜在的临床耐药性。

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引用次数: 1

Discovery of spirooxindole-pyrrolidine heterocyclic hybrids with potent antifungal activity against fungal pathogens. 具有抗真菌活性的螺旋菌吲哚-吡咯烷杂环杂交种的发现。

IF 3.3 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-05-05 DOI: 10.1093/femspd/ftac013

H. Dowdy, Raju Suresh Kumar, A. Almansour, N. Arumugam, Shatha IbrahimAlaqeel, Shankar Thangamani

Fungal pathogens mainly Candida and Cryptococcus species causes serious life-threating infections to humans, especially in individuals who are immunocompromised. Increasing frequency of antifungal drug resistance along with paucity of FDA-approved drugs suggest a dire need for new antifungal drugs. Our screening of newly synthesized spirooxindole heterocyclic hybrid compounds revealed that the novel small molecule, DPA-3, has potent antifungal activity without inducing mammalian cell cytotoxicity. Furthermore, DPA-3 significantly reduced hyphal and biofilm formation of Candida albicans ATCC 10231 strain, out-competing two FDA approved antifungal drugs. The results of our study conclude that DPA-3 is a compelling candidate for further development as an antifungal drug.

真菌病原体主要是念珠菌和隐球菌，对人类造成严重的危及生命的感染，特别是在免疫功能低下的个体中。越来越多的抗真菌药物耐药性以及fda批准的药物的缺乏表明迫切需要新的抗真菌药物。我们对新合成的螺氧吲哚杂环杂化化合物的筛选表明，新的小分子DPA-3具有有效的抗真菌活性，而不会诱导哺乳动物细胞毒性。此外，DPA-3显著减少白色念珠菌ATCC 10231菌株的菌丝和生物膜形成，优于FDA批准的两种抗真菌药物。我们的研究结果表明，DPA-3作为一种抗真菌药物具有进一步开发的潜力。

引用次数: 0

Vitamin D-induced LL-37 modulates innate immune responses of human primary macrophages during DENV-2 infection. 维生素d诱导的LL-37在DENV-2感染期间调节人原代巨噬细胞的先天免疫反应。

IF 3.3 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-05-05 DOI: 10.1093/femspd/ftac014

J. Castillo, Diana M Giraldo, J. Smit, Izabela A. Rodenhuis-Zybert, S. Urcuqui-Inchima

Epidemics of dengue, an acute and potentially severe disease caused by mosquito-borne dengue virus (DENV), pose a major challenge to clinicians and health care services across the sub(tropics). Severe disease onset is associated with a dysregulated inflammatory response to the virus and there are currently no drugs to alleviate disease symptoms. LL-37 is a potent antimicrobial peptide with a wide range of immunoregulatory properties. In this study, we assessed the effect of LL-37 on DENV-2-induced responses in human monocyte-derived macrophages (MDMs). We show that simultaneous exposure of exogenous LL-37 and DENV-2 resulted in reduced replication of the virus in MDMs, while the addition of LL-37 post-exposure to DENV-2 did not. Interestingly, the latter condition reduced the production of IL-6 and increased the expression of genes involved in virus sensing and antiviral response. Finally, we demonstrate that low endogenous levels and limited production of LL-37 in MDMs in response to DENV-2 infection can be increased by differentiating MDMs in the presence of Vitamin D (VitD3). Taken together, this study demonstrates that in addition to its antimicrobial properties, LL-37 has immunomodulatory properties in the curse of DENV infection and its production can be increased by VitD3.

登革热是一种由蚊媒登革热病毒(DENV)引起的急性和可能严重的疾病，登革热的流行对整个亚热带地区的临床医生和卫生保健服务构成了重大挑战。严重的疾病发作与对病毒的炎症反应失调有关，目前没有药物可以减轻疾病症状。LL-37是一种有效的抗菌肽，具有广泛的免疫调节特性。在这项研究中，我们评估了LL-37对人单核细胞源性巨噬细胞(MDMs)中denv -2诱导反应的影响。我们发现，同时暴露于外源的LL-37和DENV-2导致病毒在MDMs中的复制减少，而暴露于DENV-2后添加LL-37则没有。有趣的是，后一种情况减少了IL-6的产生，增加了参与病毒感知和抗病毒反应的基因的表达。最后，我们证明了在DENV-2感染的MDMs中，低内源性的LL-37水平和有限的LL-37的产生可以通过在维生素D (VitD3)的存在下分化MDMs而增加。综上所述，本研究表明，LL-37除了具有抗菌特性外，还具有DENV感染的免疫调节特性，并且VitD3可以增加其产量。

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引用次数: 6

Inhibition of infection-induced vascular permeability modulates host leukocyte recruitment to Mycobacterium marinum granulomas in zebrafish. 抑制感染诱导的血管通透性可调节斑马鱼体内马氏分枝杆菌肉芽肿的宿主白细胞募集。

IF 2.7 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-04-29 DOI: 10.1093/femspd/ftac009

Julia Y Kam, Tina Cheng, Danielle C Garland, Warwick J Britton, David M Tobin, Stefan H Oehlers

Mycobacterial granuloma formation involves significant stromal remodeling including the growth of leaky, granuloma-associated vasculature. These permeable blood vessels aid mycobacterial growth, as antiangiogenic or vascular normalizing therapies are beneficial host-directed therapies in preclinical models of tuberculosis across host-mycobacterial pairings. Using the zebrafish-Mycobacterium marinum infection model, we demonstrate that vascular normalization by inhibition of vascular endothelial protein tyrosine phosphatase (VE-PTP) decreases granuloma hypoxia, the opposite effect of hypoxia-inducing antiangiogenic therapy. Inhibition of VE-PTP decreased neutrophil recruitment to granulomas in adult and larval zebrafish, and decreased the proportion of neutrophils that extravasated distal to granulomas. Furthermore, VE-PTP inhibition increased the accumulation of T cells at M. marinum granulomas. Our study provides evidence that, similar to the effect in solid tumors, vascular normalization during mycobacterial infection increases the T cell:neutrophil ratio in lesions which may be correlates of protective immunity.

分枝杆菌肉芽肿的形成涉及严重的基质重塑，包括渗漏、肉芽肿相关血管的生长。这些可渗透的血管有助于分枝杆菌的生长，因为在宿主与分枝杆菌配对的结核病临床前模型中，抗血管生成或血管正常化疗法是有益的宿主导向疗法。我们利用斑马鱼-马氏分枝杆菌感染模型证明，通过抑制血管内皮蛋白酪氨酸磷酸酶（VE-PTP）使血管正常化可减少肉芽肿缺氧，这与缺氧诱导型抗血管生成疗法的效果相反。抑制 VE-PTP 可减少中性粒细胞招募到成体斑马鱼和幼体斑马鱼的肉芽肿，并降低肉芽肿远端外渗的中性粒细胞比例。此外，VE-PTP抑制增加了T细胞在M. marinum肉芽肿中的聚集。我们的研究提供的证据表明，与实体瘤中的效果类似，分枝杆菌感染期间血管正常化会增加病灶中T细胞与中性粒细胞的比例，这可能与保护性免疫有关。

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引用次数: 0

Tannerella forsythia strains differentially induce interferon gamma-induced protein 10 (IP-10) expression in macrophages due to lipopolysaccharide heterogeneity. 由于脂多糖的异质性，单宁菌在巨噬细胞中诱导干扰素γ诱导蛋白10 (IP-10)的表达存在差异。

IF 3.3 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-04-29 DOI: 10.1093/femspd/ftac008

Sreedevi Chinthamani, Rajendra P Settem, Kiyonobu Honma, Graham P Stafford, Ashu Sharma

Tannerella forsythia is strongly implicated in the development of periodontitis, an inflammatory disease that destroys the bone and soft tissues supporting the tooth. To date, the knowledge of the virulence attributes of T. forsythia species has mainly come from studies with a laboratory adapted strain (ATCC 43037). In this study, we focused on two T. forsythia clinical isolates, UB4 and UB20, in relation to their ability to activate macrophages. We found that these clinical isolates differentially induced proinflammatory cytokine expression in macrophages. Prominently, the expression of the chemokine protein IP-10 (CXCL10) was highly induced by UB20 as compared to UB4 and the laboratory strain ATCC 43037. Our study focused on the lipopolysaccharide component (LPS) of these strains and found that UB20 expressed a smooth-type LPS, unlike UB4 and ATCC 43037 each of which expressed a rough-type LPS. The LPS from UB20, via activation of TLR4, was found to be a highly potent inducer of IP-10 expression via signaling through STAT1 (signal transducer and activator of transcription-1). These data suggest that pathogenicity of T. forsythia species could be strain dependent and the LPS heterogeneity associated with the clinical strains might be responsible for their pathogenic potential and severity of periodontitis.

连翘Tannerella与牙周炎的发展密切相关，牙周炎是一种破坏支撑牙齿的骨骼和软组织的炎症性疾病。迄今为止，对连翘物种毒力特性的了解主要来自对实验室适应菌株(ATCC 43037)的研究。在这项研究中，我们重点研究了两种连翘临床分离物UB4和UB20对巨噬细胞的激活能力。我们发现这些临床分离株在巨噬细胞中诱导促炎细胞因子的表达存在差异。值得注意的是，与UB4和实验室菌株ATCC 43037相比，UB20高度诱导趋化因子蛋白IP-10 (CXCL10)的表达。我们的研究重点是这些菌株的脂多糖成分(LPS)，发现UB20表达的是光滑型LPS，而UB4和ATCC 43037表达的是粗糙型LPS。来自UB20的LPS通过激活TLR4，通过STAT1(信号转换器和转录激活器-1)信号传导，被发现是IP-10表达的高效诱导剂。这些数据表明，连翘的致病力可能是菌株依赖的，与临床菌株相关的LPS异质性可能是其致病潜力和牙周炎严重程度的原因。

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引用次数: 2

Polymicrobial interaction in biofilm: mechanistic Insights. 生物膜中的多微生物相互作用：机理见解。

IF 3.3 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-04-27 DOI: 10.1093/femspd/ftac010

Pratima Gupta, Anmol Kulshrestha

Polymicrobial biofilm formation during multi-species infection is a serious threat growing worldwide. According to CDC, the microbial biofilm infection covers more than 65% of total infection. In many diseases, their natural habitat does not have one causative agent because most of the species exist in co-aggregation (such as CF, OM, Dental Caries) leading to polymicrobial biofilm. Polymicrobial biofilm is a big problem in bacterio-fungal and inter-species bacterial diseases developed during chronic illness and created a major health burden globally. This review focused on various aspects of polymicrobial biofilms such as why they are forming polymicrobial biofilm arrangements, the significance of studying these biofilms, the interaction between causative microbes. Also, we reviewed how these interactions and polymicrobial formations make the biofilm more recalcitrant towards the treatment. Understanding the mechanistic process behind these biofilm formations gives an insight into specific molecules, proteins responsible for their polymicrobial nature are likely to be very helpful in anti-microbial researches.

多物种感染过程中多微生物生物膜的形成是一个日益严重的威胁。根据美国疾病控制与预防中心的数据，微生物生物膜感染占总感染的65%以上。在许多疾病中，它们的自然栖息地没有一个病原体，因为大多数物种以共聚集的形式存在（如CF、OM、龋齿），导致多微生物生物膜。多微生物生物膜是慢性病期间发生的细菌-真菌和物种间细菌疾病中的一个大问题，并在全球范围内造成了重大的健康负担。这篇综述集中在多微生物生物膜的各个方面，如它们为什么形成多微生物生物薄膜排列，研究这些生物膜的意义，致病微生物之间的相互作用。此外，我们还回顾了这些相互作用和多微生物的形成是如何使生物膜对治疗更加顽固的。了解这些生物膜形成背后的机制过程，可以深入了解特定的分子，负责其多微生物性质的蛋白质可能对抗微生物研究非常有帮助。

引用次数: 10

Invasive candidiasis in Africa, what is the current picture? 侵袭性念珠菌病在非洲的现状如何?

IF 3.3 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-04-22 DOI: 10.1093/femspd/ftac012

C. A. Okoye, E. Nweze, C. Ibe

Invasive candidiasis is a serious, progressive, and potentially deadly infection that can affect the brain, heart, bones, eyes, and other parts of the body. It is associated with risk factors such as the use of indwelling medical devices and prolonged hospital stay, and broad-spectrum antibiotics use. It is especially seen in immunocompromised individuals such as patients with prolonged hospital stay, gastrointestinal surgery, haematological malignancies, and respiratory diseases. We have conducted a systematic search of literature using a select group of database and appropriate search words and found that in Africa, there are 18,293 documented/reported cases of invasive candidiasis in the last few decades (1976-2021) and 16,636(91%) were cases of candidaemia. South Africa had the highest number of reported cases - 15,002(82%), which may be due to underreporting of cases in other countries. HIV positive persons with invasive candidiasis in Africa accounted for 1,052(5.8%). C. albicans was the most frequently isolated species 6,328(32.6%), followed by Candida parapsilosis 5,910(30.4%), and Candida auris 1,505(7.8%). Due to the affordability and availability of blood culture, it was used for diagnosis in most of the studies examined, while a few studies combined other techniques and just 3 studies from 2 countries used serological tests. Echinocandins are recommended as first-line therapy but are only available in 12 countries and are highly priced. The use of fluconazole because of its availability and relatively inexpensive nature has led to increased resistance of Candida species to the drug.

侵袭性念珠菌病是一种严重、进行性和潜在致命的感染，可影响大脑、心脏、骨骼、眼睛和身体其他部位。它与诸如使用留置医疗器械和延长住院时间以及使用广谱抗生素等风险因素有关。尤其见于免疫功能低下的个体，如住院时间延长、胃肠手术、血液恶性肿瘤和呼吸系统疾病患者。我们使用精选的数据库组和适当的检索词对文献进行了系统检索，发现在非洲，过去几十年(1976-2021)有18293例侵袭性念珠菌病记录/报告病例，16636例(91%)为念珠菌血症病例。南非报告的病例数最多，为15,002例(82%)，这可能是由于其他国家少报病例所致。非洲感染侵袭性念珠菌病的HIV阳性患者占1052例(5.8%)。分离最多的菌种为白色念珠菌6328株(32.6%)，其次为假丝酵母菌5910株(30.4%)，耳念珠菌1505株(7.8%)。由于血培养的可负担性和可获得性，在大多数被检查的研究中，它被用于诊断，而少数研究结合了其他技术，来自两个国家的只有3项研究使用了血清学检测。棘白菌素被推荐为一线治疗药物，但仅在12个国家可获得，且价格高昂。氟康唑的使用，由于其可获得性和相对便宜的性质，导致念珠菌物种对药物的耐药性增加。

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引用次数: 2

A framework for educating and empowering students by teaching about history and consequences of bias in STEM 通过教授STEM中偏见的历史和后果来教育和增强学生能力的框架

IF 3.3 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-04-07 DOI: 10.1093/femspd/ftac006

C. Moreau, Andrea M. Darby, A. Demery, Lina M Arcila Hernández, Clara L. Meaders

Abstract Racism and bias are pervasive in society—and science, technology, engineering, and mathematics (STEM) fields are not immune to these issues. It is imperative that we educate ourselves and our students about the history and consequences of this bias in STEM, investigate the research showing bias toward marginalized groups, understand how to interpret misuses of science in perpetuating bias, and identify advances and solutions to overcome racism and bias throughout our professional and personal lives. Here, we present one model for teaching a universal course for participants of all professional stages to address these issues and initiate solutions. As very few institutions require students to enroll in courses on racism and bias in STEM or even offer such courses, our curriculum could be used as a blueprint for implementation across institutions. Ultimately, institutions and academic disciplines can incorporate this important material with more region and/or discipline specific studies of bias.

种族主义和偏见在社会中普遍存在，科学、技术、工程和数学(STEM)领域也不能幸免。我们必须让自己和学生了解STEM中这种偏见的历史和后果，调查显示对边缘群体的偏见的研究，了解如何解释滥用科学使偏见永久化，并在我们的职业和个人生活中找到克服种族主义和偏见的进步和解决方案。在这里，我们提出了一种模式，为所有专业阶段的参与者教授一门通用课程，以解决这些问题并提出解决方案。由于很少有机构要求学生参加STEM领域的种族主义和偏见课程，甚至提供此类课程，我们的课程可以作为跨机构实施的蓝图。最终，机构和学科可以将这些重要的材料与更多地区和/或学科特定的偏见研究结合起来。

引用次数: 0

Expression and structure of the Chlamydia trachomatis DksA ortholog 沙眼衣原体DksA同源基因的表达和结构

IF 3.3 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-04-07 DOI: 10.1093/femspd/ftac007

Cameron Mandel, Hong Yang, G. W. Buchko, J. Abendroth, N. Grieshaber, Travis Chiarelli, S. Grieshaber, Anders Omsland

Abstract Chlamydia trachomatis is a bacterial obligate intracellular parasite and a significant cause of human disease, including sexually transmitted infections and trachoma. The bacterial RNA polymerase-binding protein DksA is a transcription factor integral to the multicomponent bacterial stress response pathway known as the stringent response. The genome of C. trachomatis encodes a DksA ortholog (DksACt) that is maximally expressed at 15–20 h post infection, a time frame correlating with the onset of transition between the replicative reticulate body (RB) and infectious elementary body (EB) forms of the pathogen. Ectopic overexpression of DksACt in C. trachomatis prior to RB–EB transitions during infection of HeLa cells resulted in a 39.3% reduction in overall replication (yield) and a 49.6% reduction in recovered EBs. While the overall domain organization of DksACt is similar to the DksA ortholog of Escherichia coli (DksAEc), DksACt did not functionally complement DksAEc. Transcription of dksACt is regulated by tandem promoters, one of which also controls expression of nrdR, encoding a negative regulator of deoxyribonucleotide biosynthesis. The phenotype resulting from ectopic expression of DksACt and the correlation between dksACt and nrdR expression is consistent with a role for DksACt in the C. trachomatis developmental cycle.

沙眼衣原体是一种细菌专性细胞内寄生虫，是人类疾病的重要原因，包括性传播感染和沙眼。细菌RNA聚合酶结合蛋白DksA是多组分细菌应激反应途径中不可或缺的转录因子，称为严格反应。沙眼衣原体基因组编码DksA同源物(DksACt)，该同源物在感染后15-20小时表达最多，这一时间框架与病原体在复制网状体(RB)和感染性初级体(EB)形式之间转变的开始相关。在感染HeLa细胞期间，在RB-EB转换之前，沙眼衣原体中的DksACt异位过表达导致总复制(产量)减少39.3%，恢复的EBs减少49.6%。虽然DksACt的整体结构域组织与大肠杆菌(DksAEc)的DksA同源物相似，但DksACt在功能上不与DksAEc互补。dksACt的转录受串联启动子调控，其中一个启动子还控制nrdR的表达，编码脱氧核糖核苷酸生物合成的负调控因子。DksACt异位表达导致的表型以及DksACt与nrdR表达的相关性与DksACt在沙眼衣原体发育周期中的作用一致。

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引用次数: 1

Retraction to: mitogen-activated protein kinases regulate mycobacterium avium-induced tumor necrosis factor-α release from macrophages. 缩回:丝裂原活化蛋白激酶调节巨噬细胞中巨噬杆菌诱导的肿瘤坏死因子-α的释放。

IF 3.3 4区医学 Q3 IMMUNOLOGY

Pathogens and disease

Pub Date : 2022-02-09 DOI: 10.1093/femspd/ftac041

引用次数: 0

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