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RpoN (sigma factor 54) contributes to bacterial fitness during tracheal colonization of Bordetella bronchiseptica RpoN(sigma factor 54)有助于支气管败血波氏杆菌气管定植过程中的细菌适应性
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-12-17 DOI: 10.1111/1348-0421.13109
Xingyan Ma, Dendi K. Nugraha, Yukihiro Hiramatsu, Yasuhiko Horiguchi

The Gram-negative pathogenic bacterium Bordetella bronchiseptica is a respiratory pathogen closely related to Bordetella pertussis, the causative agent of whooping cough. Despite sharing homologous virulence factors, B. bronchiseptica infects a broad range of mammalian hosts, including some experimental animals, whereas B. pertussis is strictly adapted to humans. Therefore, B. bronchiseptica is often used as a representative model to explore the pathogenicity of Bordetella in infection experiments with laboratory animals. Although Bordetella virulence factors, including toxins and adhesins have been studied well, our recent study implied that unknown virulence factors are involved in tracheal colonization and infection. Here, we investigated bacterial genes contributing to tracheal colonization by high-throughput transposon sequencing (Tn-seq). After the screening, we picked up 151 candidate genes of various functions and found that a rpoN-deficient mutant strain was defective in tracheal colonization when co-inoculated with the wild-type strain. rpoN encodes σ54, a sigma factor that regulates the transcription of various genes, implying its contribution to various bacterial activities. In fact, we found RpoN of B. bronchiseptica is involved in bacterial motility and initial biofilm formation. From these results, we propose that RpoN supports bacterial colonization by regulating various bacteriological functions.

革兰氏阴性致病细菌支气管败血波氏杆菌是一种呼吸道病原体,与百日咳的病原体百日咳波氏杆菌密切相关。尽管具有相同的致病因子,支气管败血波氏杆菌可感染多种哺乳动物宿主,包括一些实验动物,而百日咳波氏杆菌则严格适应于人类。因此,支气管败血波氏杆菌经常被用作实验动物感染实验中探索博德特氏菌致病性的代表性模型。尽管包括毒素和粘附素在内的博德特氏菌毒力因子已被深入研究,但我们最近的研究表明,未知的毒力因子参与了气管定植和感染。在此,我们通过高通量转座子测序(Tn-seq)研究了导致气管定植的细菌基因。经过筛选,我们发现了151个具有不同功能的候选基因,并发现rpoN缺失突变株与野生型菌株共同接种时,气管定殖功能存在缺陷。事实上,我们发现支气管败血波氏杆菌的 RpoN 参与了细菌的运动和初始生物膜的形成。根据这些结果,我们认为 RpoN 通过调节各种细菌功能来支持细菌的定植。
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引用次数: 0
HPV vaccines induce trained immunity and modulate pro-inflammatory cytokine expression in response to secondary Toll-like receptor stimulations 人乳头瘤病毒疫苗诱导训练有素的免疫力,并在继发性 Toll 样受体刺激下调节促炎细胞因子的表达
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-12-17 DOI: 10.1111/1348-0421.13108
Mako Yamaguchi, Yohana S. Mtali, Hitomi Sonokawa, Ken Takashima, Yoshimi Fukushima, Takahisa Kouwaki, Hiroyuki Oshiumi

Cervical cancer is caused mostly by human papillomavirus (HPV), and several HPV vaccines have been developed to prevent its onset. Vaccines include antigens as well as adjuvants, with adjuvants playing an important role in activating the innate immune responses necessary for inducing adaptive immunological responses. Recent research has shown the presence of trained immunity inside the innate immune system. However, trained immunity conferred by HPV vaccinations is not well understood. In this work, we explored the innate immune responses and trained immunity caused by two HPV vaccines, Cervarix and Gardasil. Cervarix includes monophosphoryl lipid A and an aluminum adjuvant, and it significantly increased the expression of IL-6 and IFN-β mRNAs in RAW264.7 cells. On the contrary, Gardasil, which only includes an aluminum adjuvant, exhibited little cytokine expression but increased the expression of TLRs. Furthermore, Cervarix significantly increased IL-1β secretion from mouse macrophages, while Gardasil only mildly induced IL-1β secretion. Interestingly, initial stimulation with Gardasil enhanced the expression of IL-6 and TNF-α mRNAs upon secondary stimulation with TLR ligands, indicating that Gardasil induced trained immunity in macrophages. Moreover, Gardasil injection into mice resulted in enhanced TNF-α production in sera following secondary TLR stimulation. Our findings suggest that HPV vaccinations have the ability to induce trained immunity that modulate TLR ligand responses.

宫颈癌主要由人类乳头瘤病毒(HPV)引起,目前已开发出多种 HPV 疫苗来预防宫颈癌的发生。疫苗包括抗原和佐剂,其中佐剂在激活先天性免疫反应以诱导适应性免疫反应方面发挥着重要作用。最近的研究表明,先天性免疫系统中存在训练有素的免疫力。然而,人们对接种人乳头瘤病毒疫苗所产生的训练有素的免疫并不十分了解。在这项研究中,我们探讨了两种 HPV 疫苗(Cervarix 和 Gardasil)引起的先天性免疫反应和训练有素的免疫力。Cervarix 包括单磷脂 A 和铝佐剂,能显著增加 RAW264.7 细胞中 IL-6 和 IFN-β mRNA 的表达。相反,仅含有铝佐剂的加卫苗几乎没有细胞因子表达,但增加了 TLRs 的表达。此外,Cervarix 能显著增加小鼠巨噬细胞中 IL-1β 的分泌,而 Gardasil 只能轻微诱导 IL-1β 的分泌。有趣的是,加德西的初始刺激增强了TLR配体二次刺激时IL-6和TNF-α mRNA的表达,这表明加德西能诱导巨噬细胞产生训练有素的免疫力。此外,给小鼠注射加德西后,血清中的 TNF-α 在继发性 TLR 刺激下产生增加。我们的研究结果表明,HPV 疫苗有能力诱导训练有素的免疫,从而调节 TLR 配体反应。
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引用次数: 0
Development of recombinant rotavirus carrying herpes simplex virus 2 glycoprotein D gene based on reverse genetics technology 基于反向遗传学技术开发携带单纯疱疹病毒 2 糖蛋白 D 基因的重组轮状病毒
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-12-14 DOI: 10.1111/1348-0421.13107
Yoshiki Kawamura, Satoshi Komoto, Saori Fukuda, Masanori Kugita, Shuang Tang, Amita Patel, Julianna R. Pieknik, Shizuko Nagao, Koki Taniguchi, Philip R. Krause, Tetsushi Yoshikawa

Vaccine development for herpes simplex virus 2 (HSV-2) has been attempted, but no vaccines are yet available. A plasmid-based reverse genetics system for Rotavirus (RV), which can cause gastroenteritis, allows the generation of recombinant RV containing foreign genes. In this study, we sought to develop simian RV (SA11) as a vector to express HSV-2 glycoprotein D (gD2) and evaluated its immunogenicity in mice. We generated the recombinant SA11-gD2 virus (rSA11-gD2) and confirmed its ability to express gD2 in vitro. The virus was orally inoculated into suckling BALB/c mice and into 8-week-old mice. Serum IgG and IgA titers against RV and gD2 were measured by ELISA. In the 8-week-old mice inoculated with rSA11-gD2, significant increases in not only antibodies against RV but also IgG against gD2 were demonstrated. In the suckling mice, antibodies against RV were induced, but gD2 antibody was not detected. Diarrhea observed after the first inoculation of rSA11-gD2 in suckling mice was similar to that induced by the parent virus. A gD2 expressing simian RV recombinant, which was orally inoculated, induced IgG against gD2. This strategy holds possibility for genital herpes vaccine development.

针对单纯疱疹病毒 2(HSV-2)的疫苗开发工作已经开始,但目前还没有疫苗问世。轮状病毒(Rotavirus,RV)可引起肠胃炎,而基于质粒的反向遗传学系统可产生含有外来基因的重组 RV。在本研究中,我们试图开发猿猴 RV(SA11)作为表达 HSV-2 糖蛋白 D(gD2)的载体,并在小鼠体内评估其免疫原性。我们生成了重组 SA11-gD2 病毒(rSA11-gD2),并在体外证实了其表达 gD2 的能力。我们将病毒口服接种到哺乳的 BALB/c 小鼠和 8 周大的小鼠体内。用酶联免疫吸附法测定血清中针对 RV 和 gD2 的 IgG 和 IgA 滴度。在接种了 rSA11-gD2 的 8 周龄小鼠中,不仅针对 RV 的抗体显著增加,而且针对 gD2 的 IgG 也显著增加。在乳鼠中,RV抗体被诱导出来,但没有检测到gD2抗体。乳鼠首次接种 rSA11-gD2 后观察到的腹泻与母体病毒诱导的腹泻相似。口服表达 gD2 的猿 RV 重组病毒可诱导出针对 gD2 的 IgG。这一策略为生殖器疱疹疫苗的开发提供了可能。
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引用次数: 0
Azithromycin regulates bacterial virulence and immune response in a murine model of ceftazidime-treated Pseudomonas aeruginosa acute pneumonia 阿奇霉素在头孢他啶治疗铜绿假单胞菌急性肺炎小鼠模型中调节细菌毒力和免疫反应
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-12-10 DOI: 10.1111/1348-0421.13106
A.-G. Leroy, J. Caillon, A. Broquet, V. Lemabecque, S. Delanou, N. Caroff, K. Asehnoune, A. Roquilly, L. Crémet

Pseudomonas aeruginosa (PA) remains one of the leading causes of nosocomial acute pneumonia. The array of virulence factors expressed by PA and the intense immune response associated with PA pneumonia play a major role in the severity of these infections. New therapeutic approaches are needed to overcome the high resistance of PA to antibiotics and to reduce the direct damage to host tissues. Through its immunomodulatory and anti-virulence effects, azithromycin (AZM) has demonstrated clinical benefits in patients with chronic PA respiratory infections. However, there is relatively little evidence in PA acute pneumonia. We investigated the effects of AZM, as an adjunctive therapy combined with ceftazidime (CAZ), in a murine model of PA acute pneumonia. We observed that the combined therapy (i) reduces the weight loss of mice 24 h post-infection (hpi), (ii) decreases neutrophil influx into the lungs at 6 and 24 hpi, while this effect is absent in a LPS-induced pneumonia or when PA is pretreated with antibiotics and mice do not receive any antibiotics, and that (iii) AZM, alone or with CAZ, modulates the expression of PA quorum sensing regulators and virulence factors (LasI, LasA, PqsE, PhzM, ExoS). Our findings support beneficial effects of AZM with CAZ on PA acute pneumonia by both bacterial virulence and immune response modulations. Further investigations are needed to clarify the exact underlying mechanisms responsible for the reduction of the neutrophils influx and to better discriminate between direct immunomodulatory properties of AZM, and indirect effects on neutrophilia resulting from bacterial virulence modulation.

铜绿假单胞菌(Pseudomonas aeruginosa,PA)仍然是引起医院内急性肺炎的主要原因之一。铜绿假单胞菌表达的一系列毒力因子以及与铜绿假单胞菌肺炎相关的强烈免疫反应对这些感染的严重程度起着重要作用。需要新的治疗方法来克服 PA 对抗生素的高度耐药性,并减少对宿主组织的直接损害。通过免疫调节和抗病毒作用,阿奇霉素(AZM)已在慢性 PA 呼吸道感染患者中显示出临床疗效。然而,有关 PA 急性肺炎的证据相对较少。我们在 PA 急性肺炎小鼠模型中研究了 AZM 与头孢他啶(CAZ)联合辅助治疗的效果。我们观察到,联合疗法(i)减少了小鼠感染后 24 小时(hpi)的体重下降,(ii)减少了中性粒细胞在感染后 6 小时和 24 小时涌入肺部、(iii)AZM单独或与CAZ一起可调节PA法定量感应调节因子和毒力因子(LasI、LasA、PqsE、PhzM、ExoS)的表达。我们的研究结果表明,AZM 联合 CAZ 可通过调节细菌毒力和免疫反应对 PA 急性肺炎产生有益影响。还需要进一步研究,以明确减少中性粒细胞流入的确切机制,并更好地区分 AZM 的直接免疫调节特性和细菌毒力调节对中性粒细胞增多的间接影响。
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引用次数: 0
Issue Information – Cover 发行资料-封面
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-12-07 DOI: 10.1111/1348-0421.13010

Cover photograph: illustrates the analysis of the known 2VSM.PDB complex, which consists of the G protein and Ephrin B2 receptor. The stability of the complex was evaluated using the covariance of the residue index. Microbiol Immunol: 67:501-513. Article link here

封面图片:说明了对已知2VSM的分析。PDB复合物,由G蛋白和Ephrin B2受体组成。利用残留指数的协方差评价配合物的稳定性。中国生物医学工程学报(英文版):57 - 61。文章链接
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引用次数: 0
List of reviewers 审稿人列表。
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-12-07 DOI: 10.1111/1348-0421.13105
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引用次数: 0
Association of ATG16L1 and ATG5 gene polymorphisms with susceptibility to hepatitis B virus infection and progression to HCC in central China 中国中部地区ATG16L1和ATG5基因多态性与乙型肝炎病毒感染易感性和HCC进展的关系
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-11-22 DOI: 10.1111/1348-0421.13104
Qiaoyu Wu, Yaoling Ouyang

Hepatitis B virus (HBV) infection is a severe public health problem worldwide. The relationship between polymorphisms of autophagy-related 16-like 1 gene (ATG16L1) and autophagy-related gene 5 (ATG5) with susceptibility to the stage of HBV infection has been reported in different populations. Nevertheless, this association is not seen in the population of central China. This study recruited 452 participants, including 246 HBV-infected patients (139 chronically infected HBV without hepatocellular carcinoma [HCC] and 107 HBV-related HCC patients) and 206 healthy controls. Genotyping of ATG16L1 rs2241880 and ATG5 rs688810 were performed using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism, respectively. Our results indicated that the G allele of ATG16L1 rs2241880 was more frequent in healthy controls than in patients with chronicHBV infection. After adjusting for age and sex, an association between the ATG16L1 rs2241880 polymorphism and HBV infection was significant under the dominant and allele models (p = 0.009 and 0.003, respectively). However, no association between the ATG5 polymorphisms and HBV infection was observed. We also did not find a significant association between ATG16L1 and ATG5 polymorphisms and the progression of HBV-related HCC. Therefore, the genetic polymorphism of ATG16L1 rs2241880 may be associated with susceptibility to HBV infection in the population of central China.

乙型肝炎病毒(HBV)感染是世界范围内严重的公共卫生问题。自噬相关16-样1基因(ATG16L1)和自噬相关基因5 (ATG5)多态性与HBV感染阶段易感性的关系在不同人群中已有报道。然而,这种关联在中国中部人群中未见。该研究招募了452名参与者,包括246名HBV感染患者(139名慢性HBV感染无肝细胞癌[HCC]和107名HBV相关HCC患者)和206名健康对照。ATG16L1 rs2241880和ATG5 rs688810分别采用Sanger测序和聚合酶链反应-限制性片段长度多态性进行基因分型。我们的研究结果表明,ATG16L1 rs2241880的G等位基因在健康对照中比在慢性乙型肝炎感染患者中更常见。在调整年龄和性别后,在显性和等位基因模型下,ATG16L1 rs2241880多态性与HBV感染之间存在显著关联(p分别= 0.009和0.003)。然而,ATG5多态性与HBV感染之间没有关联。我们也没有发现ATG16L1和ATG5多态性与hbv相关HCC进展之间的显著关联。因此,ATG16L1 rs2241880基因多态性可能与中国中部人群对HBV感染的易感性有关。
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引用次数: 0
Biological characteristics and pathogenicity of a Staphylococcus aureus strain with an incomplete hemolytic phenotype isolated from bovine milk 牛乳中分离的一株不完全溶血性金黄色葡萄球菌的生物学特性和致病性。
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-11-20 DOI: 10.1111/1348-0421.13102
Xiuhua Xu, Tingting Zhou, Xueyao Fang, Longhua Hu, Jin Zhu, Feng Zheng

Staphylococcus aureus is a common pathogen capable of infecting both humans and animals and causing various severe diseases. Here, we aimed to determine the biological features and pathogenicity of S. aureus strain Sa9, of the incomplete hemolysis phenotype, isolated from bovine milk. Sa9 was classified as ST97 by multilocus sequence typing, and it showed increased β-hemolysin expression and lower Hla and Hld expression levels compared with that in the S. aureus USA300 strain LAC. RT-PCR and ELISA results showed that the expression levels of inflammatory cytokines were higher in Sa9-induced mouse primary peritoneal macrophages compared with those induced by the LAC strain. However, the Sa9 strain also mediated anti-inflammatory effects by upregulating IL-10 and IFN-β in macrophages, which were not apparently induced by S. aureus culture supernatants. Phagocytosis and whole-blood survival assays were also performed to assess the in vitro survival of bacteria, and the virulence was evaluated in mice. Although the Sa9 strain showed lower ability of intracellular survival in macrophages than LAC, similar multiplication in human whole blood and pathogenicity toward mice were observed. Taken together, we report that the distinctive immune response induced by the S. aureus strain with an incomplete hemolysis phenotype occurs in cattle, and its potential pathogenicity and risk of transmission to humans require attention.

金黄色葡萄球菌是一种常见的病原体,能够感染人和动物,引起各种严重疾病。在这里,我们旨在确定从牛乳中分离的不完全溶血表型金黄色葡萄球菌Sa9菌株的生物学特性和致病性。通过多位点序列分型将Sa9归为ST97,与金黄色葡萄球菌USA300菌株LAC相比,Sa9 β-溶血素表达升高,Hla和Hld表达水平降低。RT-PCR和ELISA结果显示,sa9诱导的小鼠原代腹腔巨噬细胞中炎症因子的表达水平高于LAC诱导的小鼠。然而,Sa9菌株也通过上调巨噬细胞中的IL-10和IFN-β介导抗炎作用,而金黄色葡萄球菌培养上清液对这一作用的诱导作用并不明显。通过吞噬和全血存活试验评估细菌的体外存活,并对小鼠进行毒力评估。虽然Sa9菌株在巨噬细胞中的细胞内存活能力低于LAC,但在人全血中的增殖和对小鼠的致病性相似。综上所述,我们报告了由具有不完全溶血表型的金黄色葡萄球菌菌株诱导的独特免疫反应发生在牛身上,其潜在的致病性和传播给人类的风险需要引起注意。
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引用次数: 0
Pneumococcus downregulates the molecular weight of the extracellular domain of the epidermal growth factor receptor of alveolar epithelial cells 肺炎球菌下调肺泡上皮细胞表皮生长因子受体胞外结构域的分子量。
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-11-17 DOI: 10.1111/1348-0421.13103
Toshihito Isono, Satoru Hirayama, Hisanori Domon, Yutaka Terao

Pneumococcus is themajor cause of bacterial and invasive pneumococcal infections. Disrupting the alveolarepithelial barrier is an important step in the pathogenesis of invasivepneumococcal infections. The epidermal growth factor receptor (EGFR) maintainsthe integrity of the alveolar epithelial barrier. In this study, we showed that secretory pneumococcal molecules decrease the molecular weight of EGFR without peptide degradation and inhibit alveolar epithelial cell proliferation via EGFR.

肺炎球菌是细菌性和侵袭性肺炎球菌感染的主要原因。破坏肺泡上皮屏障是侵袭性肺炎球菌感染发病机制的重要步骤。表皮生长因子受体(EGFR)维持肺泡上皮屏障的完整性。在这项研究中,我们发现,分泌性肺炎球菌分子降低EGFR的分子量而不降解肽,并通过EGFR抑制肺泡上皮细胞的增殖。
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引用次数: 0
Modulatory effects of supplementation of Lentinula edodes mycelia extract and l-arginine on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice 补充香菇菌丝提取物和l-精氨酸对结肠癌小鼠免疫原性化疗疗效的调节作用。
IF 2.6 4区 医学 Q4 IMMUNOLOGY Pub Date : 2023-11-14 DOI: 10.1111/1348-0421.13101
Takahito Taniura, Kazunari Ishitobi, Masaaki Hidaka, Mamoru Harada

Some chemotherapeutic drugs can induce cancer cell death and enhance antitumor T-cell immunity in cancer-bearing hosts. Immunomodulatory reagents could augment such chemotherapy-induced effects. We previously reported that oral digestion of Lentinula edodes mycelia (L.E.M.) extract or l-arginine supplementation can augment antitumor T-cell responses in cancer-bearing mice. In this study, the effects of L.E.M. extract with or without l-arginine on the therapeutic efficacy of immunogenic chemotherapy by 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and/or cyclophosphamide (CP) are examined using two mouse colon cancer models. In MC38 and CT26 cancer models, therapy with 5-FU/L-OHP/CP significantly suppressed tumor growth, and supplementation with L.E.M. extract halved the tumor volumes. However, the modulatory effect of L.E.M. extract was not significant. In the CT26 cancer model, supplementation with L.E.M. extract and l-arginine had no clear effect on tumor growth. In contrast, their addition to chemotherapy halved the tumor volumes, although the effect was not significant. There was no difference in the cytotoxicity of tumor-specific cytotoxic T cells generated from CT26-cured mice treated by chemotherapy alone versus chemotherapy combined with L.E.M. extract/l-arginine. These results indicate that the antitumor effects of immunogenic chemotherapy were too strong to ascertain the effects of supplementation of L.E.M. extract and l-arginine, but these reagents nonetheless have immunomodulatory effects on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice.

一些化疗药物可以诱导癌细胞死亡,增强肿瘤宿主的抗肿瘤t细胞免疫。免疫调节试剂可以增强这种化疗诱导的效应。我们之前报道过,口服消化香菇菌丝体(L.E.M.)提取物或补充l-精氨酸可以增强患癌小鼠的抗肿瘤t细胞反应。本研究采用两种小鼠结肠癌模型,研究了加或不加l-精氨酸对5-氟尿嘧啶(5-FU)/奥沙利铂(L-OHP)和/或环磷酰胺(CP)免疫原性化疗疗效的影响。在MC38和CT26癌症模型中,5-FU/L-OHP/CP治疗可显著抑制肿瘤生长,补充leem提取物可使肿瘤体积减半。而枸杞提取物的调节作用不显著。在CT26肿瘤模型中,补充leem提取物和l-精氨酸对肿瘤生长无明显影响。相比之下,他们在化疗的基础上使肿瘤体积减半,尽管效果并不显著。单独化疗与化疗联合e.m.提取物/ l-精氨酸治疗ct26治愈小鼠产生的肿瘤特异性细胞毒性T细胞的细胞毒性没有差异。这些结果表明,免疫原性化疗的抗肿瘤作用太强,无法确定补充leemm提取物和l-精氨酸的效果,但这些试剂对免疫原性化疗对结肠癌小鼠的治疗效果具有免疫调节作用。
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引用次数: 0
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Microbiology and Immunology
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