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Genetic insight into the relationship between inflammatory bowel disease and Clostridioides difficile infection. 从基因角度洞察炎症性肠病与艰难梭菌感染之间的关系。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-22 DOI: 10.1128/msphere.00567-24
Kelly C Cushing-Damm, Yanhua Chen, Xiaomeng Du, Annapurna Kuppa, Chinmay Raut, Antonino Oliveri, Vincent L Chen, Brett Vanderwerff, Matt Zawistowski, Krishna Rao, Peter Higgins, Elizabeth K Speliotes

Patients with inflammatory bowel disease (IBD) are at increased risk of Clostridioides difficile infection (CDI). Herein, we aimed to determine if genetic risk contributes to this observed association. We carried out a genome-wide association study (GWAS) analysis in the Michigan Genomics Initiative and the United Kingdom Biobank for CDI based on ICD codes and meta-analyzed these results with similar publicly accessible GWAS summary statistics from Finngen. Conditional and joint multi-SNP analyses were used to identify independent associations. Imputation of the human leukocyte antigen (HLA) region with fine mapping was used to try to identify causal HLA allele groups. Two-sample bidirectional Mendelian randomization (MR) was implemented to determine causal relationships between IBD and CDI. A total of 3,500 cases of CDI and 674,323 controls were meta-analyzed, revealing one genome-wide significant variant for CDI, HLA-C;LINC02571-rs3134745-C (P = 4.27E-08), which annotated to the major histocompatibility complex on chromosome 6. While fine mapping did not identify a statistically significant HLA allele group, there was a suggestive signal for HLA-B*35:01 (P = 4.74e-04). Using two-sample MR, genetically predicted IBD was associated with increased risk of CDI (MR Egger [odds ratio {OR} 1.16, 95% confidence interval {CI} 1.02-1.31]). Subset analysis revealed that risk was primarily driven by genetically predicted ulcerative colitis (MR Egger [OR 1.22, 95% CI 1.05-1.41]). These results highlight the importance of the host immune response in CDI pathogenesis, help explain the observed relationship between IBD and CDI, and open new avenues for targeted treatment of CDI in IBD.IMPORTANCEData from this paper (i) provide reproducible evidence that susceptibility CDI is genetically mediated, (ii) highlight genetic risk as a mechanism for the increased risk of CDI in patients with inflammatory bowel disease, and (iii) point toward anti-interleukin-23 therapy as a common therapeutic strategy.

炎症性肠病(IBD)患者感染艰难梭菌(CDI)的风险增加。在此,我们旨在确定遗传风险是否导致了这种观察到的关联。我们在密歇根基因组学倡议(Michigan Genomics Initiative)和英国生物库(United Kingdom Biobank)中根据 ICD 编码对 CDI 进行了全基因组关联研究(GWAS)分析,并将这些结果与芬根(Finngen)类似的可公开获取的 GWAS 统计摘要进行了元分析。使用条件分析和多SNP联合分析来确定独立关联。对人类白细胞抗原(HLA)区域进行了精细图谱推算,以尝试确定因果关系的 HLA 等位基因组。采用双样本双向孟德尔随机化(MR)来确定 IBD 和 CDI 之间的因果关系。共对 3,500 例 CDI 病例和 674,323 例对照进行了荟萃分析,发现了一个对 CDI 有显著影响的全基因组变异,即 HLA-C;LINC02571-rs3134745-C(P = 4.27E-08),该变异注释于 6 号染色体上的主要组织相容性复合体。虽然精细图谱没有发现具有统计学意义的 HLA 等位基因组,但 HLA-B*35:01 (P = 4.74e-04)是一个提示性信号。利用双样本 MR,遗传预测的 IBD 与 CDI 风险增加有关(MR Egger [几率比{OR} 1.16,95% 置信区间{CI} 1.02-1.31])。子集分析显示,风险主要是由遗传预测的溃疡性结肠炎引起的(MR Egger [OR 1.22, 95% CI 1.05-1.41])。这些结果凸显了宿主免疫反应在 CDI 发病机制中的重要性,有助于解释所观察到的 IBD 与 CDI 之间的关系,并为 IBD 患者 CDI 的靶向治疗开辟了新途径。本文的数据(i)提供了 CDI 易感性由遗传介导的可重复证据;(ii)强调了遗传风险是炎症性肠病患者 CDI 风险增加的机制;(iii)指出抗白细胞介素-23 治疗是一种常见的治疗策略。
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引用次数: 0
Expanded geographic distribution for two Legionella pneumophila sequence types of clinical concern. 扩大两种临床关注的嗜肺军团菌序列类型的地理分布。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-28 DOI: 10.1128/msphere.00756-23
Jennafer A P Hamlin, Natalia A Kozak-Muiznieks, Jeffrey W Mercante, Lavanya Rishishwar, Emily T Norris, Anna B Gaines, Maliha K Ishaq, Jonas M Winchell, Melisa J Willby

Legionella pneumophila serogroup 1 sequence types (ST) 213 and 222, a single-locus variant of ST213, were first detected in the early 1990s in the Midwest United States (U.S.) and the late 1990s in the Northeast U.S. and Canada. Since 1992, these STs have increasingly been implicated in community-acquired sporadic and outbreak-associated Legionnaires' disease (LD) cases. We were interested in understanding the change in LD frequency due to these STs and identifying genetic features that differentiate these STs from one another. For the geographic area examined here (Mountain West to Northeast) and over the study period (1992-2020), ST213/222-associated LD cases identified by the Centers for Disease Control and Prevention increased by 0.15 cases per year, with ST213/222-associated LD cases concentrated in four states: Michigan (26%), New York (18%), Minnesota (16%), and Ohio (10%). Additionally, between 2002 and 2021, ST222 caused at least five LD outbreaks in the U.S.; no known outbreaks due to ST213 occurred in the U.S. during this time. We compared the genomes of 230 ST213/222 isolates and found that the mean of the average nucleotide identity (ANI) within each ST was high (99.92% for ST222 and 99.92% for ST213), with a minimum between ST ANI of 99.50% and a maximum of 99.87%, indicating low genetic diversity within and between these STs. While genomic features were identified (e.g., plasmids and CRISPR-Cas systems), no association explained the increasing geographic distribution and prevalence of ST213 and ST222. Yet, we provide evidence of the expanded geographical distribution of ST213 and ST222 in the U.S.IMPORTANCESince the 1990s, cases of Legionnaires' disease (LD) attributed to a pair of closely related Legionella pneumophila variants, ST213 and ST222, have increased in the U.S. Furthermore, between 2002 and 2021, ST222 caused at least five outbreaks of LD in the U.S., while ST213 has not been linked to any U.S. outbreak. We wanted to understand how the rate of LD cases attributed to these variants has changed over time and compare the genetic features of the two variants. Between 1992 and 2020, we determined an increase of 0.15 LD cases ascribed to ST213/222 per year in the geographic region studied. Our research shows that these STs are spreading within the U.S., yet most of the cases occurred in four states: Michigan, New York, Minnesota, and Ohio. Additionally, we found little genetic diversity within and between these STs nor could specific genetic features explain their geographic spread.

嗜肺军团菌第 1 血清群序列类型(ST)213 和 222(ST213 的单病灶变异型)分别于 20 世纪 90 年代初和 20 世纪 90 年代末首次在美国中西部和美国东北部及加拿大发现。自 1992 年以来,这些 STs 越来越多地与社区获得性散发性和爆发性军团病(LD)病例有关。我们有兴趣了解这些 ST 导致的退伍军人病症频率的变化,并找出区分这些 ST 的遗传特征。在本文研究的地理区域(西部山区到东北部)和研究期间(1992-2020 年),美国疾病控制和预防中心确定的 ST213/222 相关 LD 病例每年增加 0.15 例,ST213/222 相关 LD 病例主要集中在四个州:密歇根州(26%)、纽约州(18%)、明尼苏达州(16%)和俄亥俄州(10%)。此外,在 2002 年至 2021 年期间,ST222 在美国至少引起了五次 LD 病例暴发;在此期间,美国没有发生过已知的 ST213 导致的病例暴发。我们比较了 230 个 ST213/222 分离物的基因组,发现每个 ST 内部的平均核苷酸同一性(ANI)很高(ST222 为 99.92%,ST213 为 99.92%),ST 之间的 ANI 最低为 99.50%,最高为 99.87%,表明这些 ST 内部和之间的遗传多样性很低。虽然确定了基因组特征(如质粒和 CRISPR-Cas 系统),但没有发现任何关联能解释 ST213 和 ST222 地理分布和流行率不断增加的原因。重要意义自 20 世纪 90 年代以来,由一对密切相关的嗜肺军团菌变种 ST213 和 ST222 引起的军团病(LD)病例在美国有所增加。我们希望了解这些变异体导致的 LD 病例发生率随着时间的推移发生了怎样的变化,并比较这两种变异体的遗传特征。从 1992 年到 2020 年,我们确定在所研究的地理区域内,ST213/222 导致的 LD 病例每年增加 0.15 例。我们的研究表明,这些 ST 变体正在美国蔓延,但大多数病例发生在四个州:密歇根州、纽约州、明尼苏达州和俄亥俄州。此外,我们发现这些 STs 内部和之间几乎没有遗传多样性,特定的遗传特征也无法解释其地理分布。
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引用次数: 0
A whole-cell pertussis vaccine engineered to elicit reduced reactogenicity protects baboons against pertussis challenge. 一种全细胞百日咳疫苗可降低反应性,保护狒狒免受百日咳挑战。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-23 DOI: 10.1128/msphere.00647-24
Parul Kapil, Yihui Wang, Kelsey Gregg, Lindsey Zimmerman, Damaris Molano, Jonatan Maldonado Villeda, Peter Sebo, Tod J Merkel

Whole-cell pertussis (wP) vaccines introduced in the 1940s led to a dramatic reduction of pertussis incidence and are still widely used in low- and middle-income countries (LMICs) worldwide. The reactogenicity of wP vaccines resulted in reduced public acceptance, which drove the development and introduction of acellular pertussis (aP) vaccines in high-income countries in the 1990s. Increased incidence of pertussis disease has been observed in high-income countries following the introduction of aP vaccines despite near universal rates of pediatric vaccination. These increases are attributed to the reduced protection against colonization, carriage, and transmission as well as reduced duration of immunity conferred by aP vaccines relative to the wP vaccines they replaced. A reduced reactogenicity whole-cell pertussis (RRwP) vaccine was recently developed with the goal of achieving the same protection as conferred by wP vaccination but with an improved safety profile, which may benefit countries in which wP vaccines are still in routine use. In this study, we tested the RRwP vaccine in a baboon model of pertussis infection. We found that the RRwP vaccine induced comparable cellular and humoral immune responses and comparable protection following challenge relative to the wP vaccine, while significantly reducing injection-site reactogenicity.IMPORTANCEThe World Health Organization (WHO) recommended in 2015 that countries administering wP vaccines in their national vaccine programs should continue to do so, and that switching to aP vaccines for primary infant immunization should only be considered if periodic booster vaccinations and/or maternal immunization could be assured and sustained in their national immunization schedules (WHO, Vaccine 34:1423-1425, 2016, https://doi.org/10.1016/j.vaccine.2015.10.136). Due to the considerably higher cost of aP vaccines and the larger number of doses required, most LMICs continue to use wP vaccines. The development and introduction of a wP vaccine that induces fewer adverse events without sacrificing protection would significantly benefit countries in which wP vaccines are still in routine use. The results of this study indicate this desirable goal may be achievable.

20 世纪 40 年代引入的全细胞百日咳(wP)疫苗使百日咳发病率大幅下降,目前仍在全球中低收入国家广泛使用。wP 疫苗的致反应性降低了公众的接受度,这推动了 20 世纪 90 年代无细胞百日咳 (aP) 疫苗在高收入国家的开发和引入。尽管儿科疫苗接种率接近普及,但在引入 aP 疫苗后,高收入国家的百日咳发病率仍有所上升。发病率上升的原因是 aP 疫苗对定植、携带和传播的保护能力降低,而且相对于被其取代的 wP 疫苗,aP 疫苗的免疫持续时间缩短。最近开发出了一种致病反应性降低的全细胞百日咳疫苗(RRwP),其目标是实现与 wP 疫苗相同的保护效果,但安全性有所提高,这可能会使仍在常规使用 wP 疫苗的国家受益。在这项研究中,我们在百日咳狒狒感染模型中测试了 RRwP 疫苗。我们发现,与 wP 疫苗相比,RRwP 疫苗可诱导相似的细胞和体液免疫反应,并在挑战后产生相似的保护作用,同时显著降低了注射部位的致反应性。重要意义世界卫生组织(WHO)于2015年建议,在国家疫苗计划中接种wP疫苗的国家应继续接种wP疫苗,只有在国家免疫计划中能确保和维持定期加强免疫和/或母体免疫接种的情况下,才应考虑改用aP疫苗进行婴儿初次免疫接种(WHO,Vaccine 34:1423-1425,2016,https://doi.org/10.1016/j.vaccine.2015.10.136).由于 aP 疫苗的成本远高于 aP 疫苗,且所需剂量较大,大多数低收入国家仍在使用 wP 疫苗。开发和引入一种可在不牺牲保护作用的前提下减少不良反应的 wP 疫苗将使仍在常规使用 wP 疫苗的国家受益匪浅。本研究的结果表明这一理想目标是可以实现的。
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引用次数: 0
Mice colonized with the defined microbial community OMM19.1 are susceptible to Clostridioides difficile infection without prior antibiotic treatment. 定植了定义微生物群落 OMM19.1 的小鼠在未接受抗生素治疗的情况下容易感染艰难梭菌。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-29 DOI: 10.1128/msphere.00718-24
Michelle Chua, James Collins

Diverse gut microorganisms present in humans and mice are essential for the prevention of microbial pathogen colonization. However, antibiotic-induced dysbiosis of the gut microbiome reduces microbial diversity and allows Clostridioides difficile (C. difficile) to colonize the intestine. The Oligo-Mouse-Microbiota 19.1 (OMM19.1) is a synthetic community that consists of bacteria that are taxonomically and functionally designed to mimic the specific pathogen-free mouse gut microbiota. Here, we examined the susceptibility of OMM19.1 colonized mice to C. difficile infection (CDI) at a range of infectious doses (103, 105, and 107 spores) without prior antibiotic treatment. We found that mice colonized with OMM19.1 were susceptible to CDI regardless of the dose. The clinical scores increased with increasing C. difficile dosage. Infection with C. difficile was correlated with a significant increase in Ligilactobacillus murinus and Escherichia coli, while the relative abundance of Bacteroides caecimuris, Akkermansia muciniphila, Extibacter muris, and Turicimonas muris was significantly decreased following CDI. Our results demonstrate that the OMM19.1 community requires additional bacteria to enable C. difficile colonization resistance.IMPORTANCEThe human gut microbiota consists of a wide range of microorganisms whose composition and function vary according to their location and have a significant impact on health and disease. The ability to generate and test the defined microbiota within gnotobiotic animal models is essential for determining the mechanisms responsible for colonization resistance. The exact mechanism(s) by which healthy microbiota prevents Clostridioides difficile infection is unknown, although competition for nutrients, active antagonism, production of inhibitory metabolites (such as secondary bile acids), and microbial manipulation of the immune system are all thought to play a role. Here, we colonized germ-free C57BL/6 mice with a synthetic bacterial community (OMM19.1) that mimics the specific pathogen-free mouse microbiota. Following breeding, to enable immune system development, F1 mice were infected with three different doses of C. difficile. Our research suggests that there are additional essential microbial functions that are absent from the current OMM19.1 model.

人类和小鼠肠道微生物的多样性对于防止微生物病原体定植至关重要。然而,抗生素引起的肠道微生物群失调降低了微生物的多样性,使艰难梭菌(C. difficile)得以在肠道内定植。低聚小鼠微生物群 19.1(OMM19.1)是一种合成群落,由细菌组成,这些细菌在分类和功能上都是为了模仿特定的无病原体小鼠肠道微生物群而设计的。在此,我们研究了定植了 OMM19.1 的小鼠在一系列感染剂量(103、105 和 107 个孢子)下对艰难梭菌感染(CDI)的易感性,而事先并未进行抗生素治疗。我们发现,定植了 OMM19.1 的小鼠对 CDI 易感,与感染剂量无关。随着艰难梭菌剂量的增加,小鼠的临床评分也会增加。感染艰难梭菌后,鼠乳杆菌(Ligilactobacillus murinus)和大肠埃希氏菌(Escherichia coli)的数量显著增加,而粪肠杆菌(Bacteroides caecimuris)、粘液杆菌(Akkermansia muciniphila)、鼠埃希氏杆菌(Extibacter muris)和鼠弧菌(Turicimonas muris)的相对数量则显著减少。我们的研究结果表明,OMM19.1 群落需要更多的细菌来实现艰难梭菌定植抗性。重要意义人类肠道微生物群由多种微生物组成,其组成和功能因位置而异,对健康和疾病有重大影响。在非生物动物模型中生成和测试确定的微生物群的能力对于确定耐定植性的机制至关重要。健康微生物群预防艰难梭菌感染的确切机制尚不清楚,但营养竞争、主动拮抗、抑制性代谢产物(如次生胆汁酸)的产生以及微生物对免疫系统的操纵都被认为在其中发挥了作用。在这里,我们用模拟特定无病原体小鼠微生物群的合成细菌群落(OMM19.1)定植无菌 C57BL/6 小鼠。繁殖后,为了使免疫系统发育,F1小鼠感染了三种不同剂量的艰难梭菌。我们的研究表明,目前的 OMM19.1 模型还不具备其他基本的微生物功能。
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引用次数: 0
Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance in Plasmodium falciparum. 增强细胞应激反应和蛋白质降解能力是恶性疟原虫产生青蒿素抗药性的原因。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-22 DOI: 10.1128/msphere.00371-24
Melissa R Rosenthal, Sukhithasri Vijayrajratnam, Tessa M Firestone, Caroline L Ng

Malaria remains a global health burden, killing over half a million people each year. Decreased therapeutic efficacy to artemisinin, the most efficacious antimalarial, has been detected in sub-Saharan Africa, a worrying fact given that over 90% of deaths occur on this continent. Mutations in Kelch13 are the most well-established molecular marker for artemisinin resistance, but these do not explain all artemisinin-resistant isolates. Understanding the biological underpinnings of drug resistance is key to curbing the emergence and spread of artemisinin resistance. Artemisinin-mediated non-specific alkylation leads to the accumulation of misfolded and damaged proteins and activation of the parasite unfolded protein response (UPR). In addition, the parasite proteasome is vital to artemisinin resistance, as we have previously shown that chemical inhibition of the proteasome or mutations in the β2 proteasome subunit increase parasite susceptibility to dihydroartemisinin (DHA), the active metabolite of artemisinins. Here, we investigate parasites with mutations at the Kelch13 and/or 19S and 20S proteasome subunits with regard to UPR regulation and proteasome activity in the context of artemisinin resistance. Our data show that perturbing parasite proteostasis kills parasites, early parasite UPR signaling dictates DHA survival outcomes, and DHA susceptibility correlates with impairment of proteasome-mediated protein degradation. Importantly, we show that functional proteasomes are required for artemisinin resistance in a Kelch13-independent manner, and compound-selective proteasome inhibition demonstrates why artemisinin-resistant Kelch13 mutants remain susceptible to the related antimalarial peroxide OZ439. These data provide further evidence for targeting the parasite proteasome and UPR to overcome existing artemisinin resistance.IMPORTANCEDecreased therapeutic efficacy represents a major barrier to malaria treatment control strategies. The malaria proteasome and accompanying unfolded protein response are crucial to artemisinin resistance, revealing novel antimalarial therapeutic strategies.

疟疾仍然是全球健康的负担,每年造成 50 多万人死亡。在撒哈拉以南非洲地区发现,对青蒿素(最有效的抗疟药物)的疗效有所下降,这是一个令人担忧的事实,因为超过 90% 的死亡发生在该大陆。Kelch13 基因突变是青蒿素抗药性最成熟的分子标记,但这并不能解释所有青蒿素抗药性分离株。了解耐药性的生物学基础是遏制青蒿素耐药性出现和蔓延的关键。青蒿素介导的非特异性烷基化会导致错误折叠和受损蛋白质的积累,并激活寄生虫的未折叠蛋白反应(UPR)。此外,寄生虫蛋白酶体对青蒿素抗性也至关重要,因为我们之前已经证明,对蛋白酶体的化学抑制或蛋白酶体β2亚基的突变会增加寄生虫对青蒿素的活性代谢产物双氢青蒿素(DHA)的敏感性。在这里,我们研究了 Kelch13 和/或 19S 和 20S 蛋白酶体亚基发生突变的寄生虫在青蒿素抗性背景下的 UPR 调节和蛋白酶体活性。我们的数据表明,扰乱寄生虫蛋白稳态会杀死寄生虫,寄生虫的早期 UPR 信号决定了 DHA 的存活结果,而 DHA 易感性与蛋白酶体介导的蛋白质降解受损有关。重要的是,我们发现功能性蛋白酶体是青蒿素抗性所必需的,而青蒿素抗性不依赖于 Kelch13,化合物选择性蛋白酶体抑制证明了为什么青蒿素抗性 Kelch13 突变体仍然对相关的抗疟过氧化物 OZ439 敏感。这些数据为以寄生虫蛋白酶体和 UPR 为靶点克服现有的青蒿素抗药性提供了进一步的证据。重要意义疗效降低是疟疾治疗控制策略的主要障碍。疟疾蛋白酶体和伴随的未折叠蛋白反应对青蒿素抗药性至关重要,揭示了新型抗疟疾治疗策略。
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引用次数: 0
In vivo RNA sequencing reveals a crucial role of Fus3-Kss1 MAPK pathway in Candida glabrata pathogenicity. 体内 RNA 测序揭示了 Fus3-Kss1 MAPK 通路在念珠菌致病性中的关键作用。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-30 DOI: 10.1128/msphere.00715-24
Xinreng Mo, Xiangtai Yu, Hao Cui, Kang Xiong, Shan Yang, Chang Su, Yang Lu

Candida glabrata is an important and increasingly common pathogen of humans, particularly in immunocompromised hosts. Despite this, little is known about how this fungus causes disease. Here, we applied RNA sequencing and an in vivo invasive infection model to identify the attributes that allow this organism to infect hosts. Fungal transcriptomes show a dramatic increase in the expression of Fus3 and Kss1, two mitogen-activated protein kinases (MAPKs), during invasive infection. We further demonstrate that they are both highly induced under a combination of serum and high CO2 conditions. Deletion of both FUS3 and KSS1, but neither gene alone, results in a reduced fungal burden in organs, as well as in the gastrointestinal tract in the DSS (Dextran Sulfate Sodium)-induced colitis model. Similarly, the defect in persistence in macrophages and attenuated adhesion to epithelial cells are observed when FUS3 and KSS1 are both disrupted. The fus3 kss1 double mutant also displays defects in the induction of virulence attributes such as genes required for iron acquisition and adhesion and in the anti-fungal drug tolerance. The putative downstream transcription factors Ste12 (1), Ste12 (2), Tec1, and Tec2 are found to be involved in the regulation of these virulence attributes. Collectively, our study indicates that an evolutionary conserved MAPK pathway, which regulates mating and filamentous growth in Saccharomyces cerevisiae, is critical for C. glabrata pathogenicity.

Importance: The MAPK signaling pathway, mediated by closely related kinases Fus3 and Kss1, is crucial for controlling mating and filamentous growth in Saccharomyces cerevisiae, but this pathway does not significantly impact hyphal development and pathogenicity in Candida albicans, a commensal-pathogenic fungus of humans. Furthermore, deletion of Cpk1, the ortholog of Fus3 in pathogenic fungus Cryptococcus neoformans, has no effect on virulence. Here, we demonstrate that the MAPK pathway is crucial for the pathogenicity of Candida glabrata, a fungus that causes approximately one-third of cases of hematogenously disseminated candidiasis in the United States. This pathway regulates multiple virulence attributes including the induction of iron acquisition genes and adhesins, as well as persistence in macrophages and organs. Our work provides insights into C. glabrata pathogenesis and highlights an example in which regulatory rewiring of a conserved pathway confers a virulent phenotype in a pathogen.

光滑念珠菌是一种重要的人类病原体,而且越来越常见,尤其是在免疫力低下的宿主中。尽管如此,人们对这种真菌如何致病却知之甚少。在这里,我们应用 RNA 测序和体内侵袭感染模型来确定这种真菌感染宿主的属性。真菌转录组显示,在入侵感染过程中,两种丝裂原活化蛋白激酶(MAPK)Fus3 和 Kss1 的表达量急剧增加。我们进一步证明,在血清和高二氧化碳条件下,这两种酶都会被高度诱导。在右旋糖酐硫酸钠(DSS)诱导的结肠炎模型中,同时缺失 FUS3 和 KSS1(而非单独缺失这两个基因)会导致器官以及胃肠道中的真菌负担减轻。同样,当 FUS3 和 KSS1 同时被破坏时,巨噬细胞中的持久性缺陷和对上皮细胞的粘附力也会减弱。fus3 kss1 双突变体在诱导毒力属性(如铁获取和粘附所需的基因)和抗真菌药物耐受性方面也表现出缺陷。推测的下游转录因子 Ste12 (1)、Ste12 (2)、Tec1 和 Tec2 参与了这些毒力属性的调控。总之,我们的研究表明,进化保守的 MAPK 通路(调节酿酒酵母的交配和丝状生长)对 C. glabrata 的致病性至关重要:由密切相关的激酶 Fus3 和 Kss1 介导的 MAPK 信号通路对控制酿酒酵母的交配和丝状生长至关重要,但这一通路对白色念珠菌(一种人类共生致病真菌)的菌丝发育和致病性并无显著影响。此外,致病真菌新生隐球菌中 Fus3 的直向同源物 Cpk1 的缺失对致病性也没有影响。在这里,我们证明了 MAPK 通路对于光滑念珠菌的致病性至关重要,这种真菌导致了美国约三分之一的血源性播散念珠菌病病例。该途径调节多种致病性属性,包括诱导铁获取基因和粘附蛋白,以及在巨噬细胞和器官中的持久性。我们的研究深入了解了玻璃样念珠菌的致病机理,并突出展示了一个实例,即保守通路的调控重构赋予病原体一种毒性表型。
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引用次数: 0
A novel antibody treatment reduces deformed wing virus loads in the western honey bee (Apis mellifera). 一种新型抗体疗法可减少西方蜜蜂(Apis mellifera)的畸形翅病毒载量。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-30 DOI: 10.1128/msphere.00497-24
N J J MacMillan, B M Hause, T Nordseth, A Felden, J W Baty, J L Pitman, P J Lester

The deformed wing virus (Iflavirus aladeformis) (DWV) is a key driver of colony loss in the western honey bee (Apis mellifera). Here, we demonstrate that orally delivered anti-DWV antibodies can act systemically to reduce DWV loads in naturally infected honey bees. Immunoglobulin Y (IgY) was produced in adult chickens against two DWV proteins, harvested from their eggs, and fed to bees in a sucrose solution. An enzyme-linked immunosorbent assay demonstrated that orally delivered anti-DWV IgY migrated to the hemolymph. We next assessed the ability of orally delivered anti-DWV IgY to reduce DWV viral loads in naturally infected bees using qPCR. An antibody treatment resulted in a significant eightfold viral load reduction in DWV-infected bees. Our findings demonstrate the potential for antibody treatments to help mitigate the losses attributed to DWV in A. mellifera.

Importance: Deformed wing virus (DWV) is considered to be a key component of declining honey bee health which threatens global food production. The virus can result in significantly shortened lifespan, deformities in developing bees, and impaired cognition. There is currently no method to directly control the virus. The virus can be indirectly controlled with acaricidal treatments that target a key vector, the parasitic varroa mite (Varroa destructor). But acaricide resistance and a lack of effective alternatives for the control of both Varroa and DWV are major threats to beekeeping and the wider agricultural industry. Our research presents a significant development in the ability to reduce DWV burden in honey bees using IgY antibodies. Moreover, immunoglobulin Y has the potential to be more broadly established as a new treatment modality to combat other pathogens and parasites in A. mellifera.

畸形翅病毒(Iflavirus aladeformis)(DWV)是造成西方蜜蜂(Apis mellifera)蜂群损失的主要原因。在这里,我们证明了口服抗 DWV 抗体可在自然感染的蜜蜂中发挥系统性作用,减少 DWV 的负荷。我们在成年鸡体内产生了抗两种DWV蛋白的免疫球蛋白Y(IgY),从它们的卵中提取,并用蔗糖溶液喂给蜜蜂。酶联免疫吸附试验表明,口服抗DWV IgY可迁移到血淋巴中。接下来,我们使用 qPCR 评估了口服抗 DWV IgY 降低自然感染蜜蜂体内 DWV 病毒载量的能力。经抗体处理后,受 DWV 感染的蜜蜂体内的病毒载量明显降低了 8 倍。我们的研究结果表明,抗体疗法有可能帮助减轻畸形翼病毒给 A. mellifera 造成的损失:畸形翅病毒(DWV)被认为是蜜蜂健康状况下降的一个关键因素,它威胁着全球的粮食生产。该病毒可导致蜜蜂寿命明显缩短、发育中的蜜蜂畸形以及认知能力受损。目前还没有直接控制这种病毒的方法。病毒可以通过杀螨剂来间接控制,杀螨剂针对的是一种关键的媒介--寄生变节螨(Varroa destructor)。但是,杀螨剂的抗药性以及缺乏有效的替代品来控制变螨和 DWV,是养蜂业和更广泛的农业产业面临的主要威胁。我们的研究在利用 IgY 抗体减少蜜蜂 DWV 负担方面取得了重大进展。此外,免疫球蛋白 Y 有可能被更广泛地确立为一种新的治疗方式,用于防治蜜蜂体内的其他病原体和寄生虫。
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引用次数: 0
Detection of Hepatovirus A (HAV) in wastewater indicates widespread national distribution and association with socioeconomic indicators of vulnerability. 在废水中检测到甲型肝炎病毒(HAV)表明该病毒在全国广泛分布,并与易感性的社会经济指标有关。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-30 DOI: 10.1128/msphere.00645-24
Alessandro Zulli, Elana M G Chan, Alexandria B Boehm

Wastewater-based epidemiology, which seeks to assess disease occurrence in communities through measurements of infectious disease biomarkers in wastewater, may represent a valuable tool for understanding the occurrence of hepatitis A infections in communities. In this study, we measured concentrations of Hepatovirus A (HAV) RNA, in samples from 191 wastewater treatment plants spanning 40 US states and the District of Columbia from September 2023 to June 2024 and compared the measurements with traditional measures of disease occurrence. Nationally, 13.76% of the 21,079 wastewater samples were positive for HAV RNA, and both concentrations and positivity rates were associated with NNDSS hepatitis A case data nationally (Kendall rank correlation coefficient = 0.20, concentrations; and 0.33, positivity rate; both P < 0.05). We further demonstrated that higher rates of wastewater HAV detection were positively associated with socioeconomic indicators of vulnerability including homelessness and drug overdose deaths (both P < 0.0001). Areas with above average levels of homelessness were 48% more likely to have HAV wastewater detections, while areas with above average levels of drug overdose deaths were 14% more likely to have HAV wastewater detections. Using more granular case data, we present a case study in the state of Maine that reinforces these results and suggests a potential lead time for wastewater over clinical case detection and exposure events. The ability to detect HAV RNA in wastewater before clinical cases emerge could allow public health officials to implement targeted interventions like vaccination campaigns.IMPORTANCEDespite the existence of a highly effective vaccine for hepatitis A, outbreaks in vulnerable populations remain common. The disease can be asymptomatic or subclinical, and disproportionately impacts populations with inadequate access to healthcare, leading to a severe underestimation of the occurrence of this viral infection. This study investigates the potential for wastewater measurements of biomarkers of the causative agent of hepatitis A (HAV RNA) to provide insights into disease occurrence. Results highlight the potential for wastewater-based epidemiology to be a complementary tool to traditional surveillance for monitoring and controlling HAV transmission.

基于废水的流行病学旨在通过测量废水中的传染病生物标志物来评估社区中的疾病发生情况,它可能是了解社区中甲型肝炎感染发生情况的重要工具。在这项研究中,我们测量了 2023 年 9 月至 2024 年 6 月期间来自美国 40 个州和哥伦比亚特区的 191 家污水处理厂样本中甲型肝炎病毒 (HAV) RNA 的浓度,并将测量结果与传统的疾病发生率测量方法进行了比较。从全国范围来看,21,079 份废水样本中有 13.76% 呈 HAV RNA 阳性,浓度和阳性率均与全国 NNDSS 甲型肝炎病例数据相关(浓度方面的 Kendall 秩相关系数 = 0.20;阳性率方面的 Kendall 秩相关系数 = 0.33;P 均小于 0.05)。我们进一步证明,较高的废水甲型肝炎病毒检测率与无家可归者和吸毒过量死亡等社会经济弱势指标呈正相关(均 P < 0.0001)。无家可归人数高于平均水平的地区检测到 HAV 废水的可能性要高出 48%,而吸毒过量死亡人数高于平均水平的地区检测到 HAV 废水的可能性要高出 14%。通过使用更精细的病例数据,我们介绍了缅因州的一个案例研究,该研究证实了这些结果,并表明废水可能比临床病例检测和暴露事件更早出现。在临床病例出现之前检测废水中甲型肝炎病毒 RNA 的能力可以让公共卫生官员实施有针对性的干预措施,如开展疫苗接种活动。这种疾病可能没有症状或处于亚临床状态,对无法获得充分医疗保健服务的人群的影响尤为严重,导致对这种病毒感染发生率的严重低估。本研究调查了废水中甲型肝炎致病因子(HAV RNA)生物标志物的测量潜力,以便深入了解疾病的发生情况。研究结果突出表明,基于废水的流行病学有可能成为传统监测的补充工具,用于监测和控制甲型肝炎病毒的传播。
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引用次数: 0
Layer segmented filamentous bacteria colonize and impact gut health of broiler chickens. 层段丝状菌定植并影响肉鸡肠道健康。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-18 DOI: 10.1128/msphere.00492-24
Jared Meinen-Jochum, Caleb J Skow, Melha Mellata

In commercial poultry farms, chicks hatch away from their progenitors from which they acquire key host-specific microbiota, like segmented filamentous bacteria (SFB) involved in gut maturation in early life. This study investigated whether providing chicken SFB to newly hatched broilers would increase their gut maturation and resistance to bacteria relevant to broiler and human health. One-day-old Ross308 broilers were orally treated with either phosphate-buffered saline (CON) or layer-derived SFB (D-SFB). On days 5, 10, 17, and 24, feces were collected to detect and enumerate SFB and Enterobacteriaceae. On days 8, 15, 22, and 29, birds were euthanized, intestinal samples were collected to detect and enumerate SFB through quantitative PCR (qPCR) and microscopy and expression of genes associated with gut immune function through reverse transcription-qPCR. This study showed that, despite their host specificity, layer SFB can colonize their genetically distinct relative broilers. Ileal SFB colonization was accelerated by a week with the SFB treatment and covered the proximal, medial, and distal sections of the ileum. Colonization of the ileum by SFB in early life highly activated gene expression of intestinal barrier proteins and cytokines, e.g., IL-10 and IFNγ but not IL-17. SFB treatment reduced the level of Enterobacteriaceae in the gut and provided superior resistance to intestinal and extraintestinal pathogens as tested in vitro. Overall, early gut colonization of SFB is imperative for the maturation of the gut immune system and the establishment of a homeostatic gut environment. Improving our understanding of gut immune maturation in food-producing animals is crucial for both human and animal health.IMPORTANCEIn commercial farms, newly hatched chicks may lack host-specific microbiota that help mature their gut immune system for lifelong health benefits. Here, introducing an avian segmented filamentous bacteria (SFB) to commercially sourced chickens orally at hatch accelerated SFB colonization of the ileum. Remarkably, SFB from layers were able to colonize broilers and enhance gut immune maturation, and this immunomodulation impacted the ability to increase intestinal and extraintestinal resistance to bacteria relevant to poultry and human health. With the antibiotic restrictions in animal production, strategies that will help mitigate infections are urgently needed. In summary, we developed a live prophylactic for newly hatched chicks to improve animal health and food safety. Due to the host specificity of SFB, our data highlight the importance of investigating the molecular mechanism of SFB interaction in their own host.

在商业化家禽饲养场中,雏鸡在孵化过程中会远离其祖先,并从祖先那里获得关键的宿主特异性微生物群,如参与生命早期肠道成熟的分节丝状菌(SFB)。本研究调查了为刚孵化的肉鸡提供鸡分段丝状菌是否会提高它们的肠道成熟度以及对与肉鸡和人类健康有关的细菌的抵抗力。一天龄的 Ross308 肉鸡口服磷酸盐缓冲盐水(CON)或来源于蛋鸡的 SFB(D-SFB)。第 5、10、17 和 24 天,收集粪便以检测和计数 SFB 和肠杆菌科细菌。第 8、15、22 和 29 天,对鸟类实施安乐死,收集肠道样本,通过定量 PCR(qPCR)和显微镜检测和计数 SFB,并通过反转录-qPCR 检测与肠道免疫功能相关的基因表达。这项研究表明,尽管具有宿主特异性,但蛋鸡SFB可以在其基因不同的相对肉鸡中定植。经SFB处理一周后,回肠SFB定植速度加快,并覆盖了回肠的近端、内侧和远端。SFB早期在回肠的定植高度激活了肠道屏障蛋白和细胞因子的基因表达,如IL-10和IFNγ,但没有激活IL-17。在体外测试中,SFB 处理降低了肠道中肠杆菌的水平,并提供了对肠道和肠道外病原体的卓越抵抗力。总之,SFB 的早期肠道定植对于肠道免疫系统的成熟和肠道平衡环境的建立至关重要。重要意义在商业化养殖场中,新孵化的雏鸡可能缺乏宿主特异性微生物群,而宿主特异性微生物群有助于雏鸡肠道免疫系统的成熟,从而为雏鸡的终生健康带来益处。在这里,在孵化时通过口服向商业化饲养的鸡引入禽类分段丝状菌(SFB)可加速 SFB 在回肠的定植。值得注意的是,来自蛋鸡的 SFB 能够在肉鸡体内定植并增强肠道免疫成熟,这种免疫调节影响了增强肠道和肠道外对家禽和人类健康相关细菌的抵抗力的能力。随着动物生产中抗生素的限制,迫切需要有助于减轻感染的策略。总之,我们为新孵化的雏鸡开发了一种活疫苗,以改善动物健康和食品安全。由于 SFB 的宿主特异性,我们的数据强调了研究 SFB 在其宿主中相互作用的分子机制的重要性。
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引用次数: 0
Cell aggregation mediated by ACE2 deletion in Candida auris modulates fungal colonization and host immune responses in the skin. 白色念珠菌中 ACE2 缺失介导的细胞聚集调节真菌在皮肤中的定植和宿主免疫反应。
IF 3.7 2区 生物学 Q2 MICROBIOLOGY Pub Date : 2024-11-21 Epub Date: 2024-10-30 DOI: 10.1128/msphere.00734-24
Abishek Balakumar, Abigail Cox, Shankar Thangamani

Candida auris is an emerging multi-drug-resistant fungal pathogen that colonizes the skin and causes invasive infections in hospitalized patients. Multi-cellular aggregative phenotype is widely reported in the C. auris isolates, but its role in skin colonization and host immune response is not yet known. In this study, we generated aggregative phenotype by deleting the ACE2 gene in C. auris and determined the fungal colonization and host immune response using an intradermal mouse model of C. auris skin infection. Our results indicate that mice infected with ace2Δ strain had significantly lower fungal load after 3 and 14 days post-infections compared to the non-aggregative wild-type and the ACE2 reintegrated strain. The colonization of ace2Δ is associated with increased recruitment of CD11b+ Ly6G+ neutrophils and decreased accumulation of CD11b+ Ly6 Chi inflammatory monocytes and CD11b+ MHCII+ CD64+ macrophages. Furthermore, Th17 cells and type 3 innate lymphoid cells (ILCs) were significantly increased in the skin tissue of ace2Δ infected mice. Our findings suggest that aggregative phenotype mediated by ACE2 deletion in C. auris induces potent neutrophil and IL-17-mediated immune response and reduces fungal colonization in the skin.IMPORTANCEC. auris is a rapidly emerging fungal pathogen that can colonize hospitalized patients, especially in skin tissue, and cause invasive infections. C. auris isolates exhibit morphological heterogeneity, and the multicellular aggregative phenotype of C. auris is reported frequently in clinical settings. Understanding the role of fungal morphotypes in colonization, persistence, and immune response in the skin microenvironment will have potential applications in clinical diagnosis and novel preventive and therapeutic measures. Here, we utilized the murine model of intradermal infection and determined that the aggregative phenotype of C. auris as the result of ACE2 gene deletion elicits potential innate and adaptive immune responses in mice. These observations will help explain the differences in the skin colonization and immune responses of the aggregative morphotype of C. auris and open the door to developing novel antifungal therapeutics.

白色念珠菌(Candida auris)是一种新出现的多重耐药真菌病原体,可在皮肤上定植并导致住院病人的侵袭性感染。多细胞聚集表型在 C. auris 分离物中被广泛报道,但其在皮肤定植和宿主免疫反应中的作用尚不清楚。在本研究中,我们通过删除 C. auris 中的 ACE2 基因产生了聚集表型,并使用 C. auris 皮肤感染小鼠皮内模型测定了真菌定植和宿主免疫反应。我们的结果表明,与非聚集野生型和 ACE2 重整合株相比,感染 ace2Δ 株的小鼠在感染后 3 天和 14 天的真菌负荷量明显较低。ace2Δ的定植与CD11b+ Ly6G+中性粒细胞的招募增加以及CD11b+ Ly6 Chi炎性单核细胞和CD11b+ MHCII+ CD64+巨噬细胞的聚集减少有关。此外,ace2Δ感染小鼠皮肤组织中的Th17细胞和3型先天性淋巴细胞(ILCs)显著增加。我们的研究结果表明,ACE2缺失介导的C. auris聚集表型可诱导有效的中性粒细胞和IL-17介导的免疫反应,并减少真菌在皮肤中的定植。C. auris 分离物表现出形态异质性,临床上经常报告 C. auris 的多细胞聚集表型。了解真菌形态在皮肤微环境中的定植、持续存在和免疫反应中的作用将可能应用于临床诊断和新型预防与治疗措施。在这里,我们利用小鼠皮内感染模型,确定了由于 ACE2 基因缺失导致的 C. auris 的聚集表型会引起小鼠潜在的先天性和适应性免疫反应。这些观察结果将有助于解释C. auris聚集表型在皮肤定植和免疫反应方面的差异,并为开发新型抗真菌疗法打开大门。
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