副溶血性弧菌（Vibrio parahaemolyticus，V.parahaemolyticus）是一种重要的食源性致病菌，在全球范围内流行，属于革兰氏阴性细菌。副溶血性弧菌在胃肠道中的感染通常会引起腹泻、发热、呕吐等临床症状，严重时可导致败血症的发生。细菌的Ⅲ型分泌系统（Type Ⅲ secretion system，T3SS）横跨三种生物膜，是一种将细菌中的效应蛋白递送到宿主细胞中从而产生作用的精密菌体结构，在细菌的致病过程中占据重要地位。副溶血性弧菌中具有两套T3SS（T3SS1与T3SS2），其中T3SS1主要介导副溶血性弧菌感染中细胞毒性的产生，T3SS1也是副溶血性弧菌引发败血症的原因之一。鉴于副溶血性弧菌危害的广泛程度，研究其毒力因子及其作用机制有助于开发更有效的检测靶点并制定相关的防控策略。此前研究表明，副溶血性弧菌至少存在四种能够通过T3SS1易位至宿主细胞中的蛋白，分别是VopQ、VopS、VpA0450以及VopR。有研究发现VopR通过自身存在的细菌磷酸肌醇结构域（Bacterial phosphoinositide domain， BPD），在易位到宿主细胞后定位在宿主细胞膜上，但是VopR作为T3SS1效应蛋白，在副溶血性弧菌感染过程中的存在的具体功能仍待解析。
本研究通过探索T3SS1效应蛋白VopR在副溶血性弧菌感染中到的功能，阐明VopR在副溶血性弧菌感染中的分子作用机制, 以期为开发新型抗菌策略及病原检测方法提供理论依据。主要研究结果如下：
1.VopR的细胞感染生物学特性分析
利用同源重组技术，在副溶血性弧菌RIMD的衍生菌株POR3（T3SS2^-, tdh^-）中构建vopR基因缺失株POR3-ΔvopR与回补株POR3-CvopR，同时为了排除其它T3SS1效应蛋白的功能冗余，本次研究还构建了vopQ、vopS、vpA0450以及vopR 共同缺失的菌株POR3-ΔE4以及vopR基因回补株POR3-ΔE4-CvopR。通过PCR以及RT-qPCR试验，验证本次研究所需菌株构建成功；同时检测了基因组中vopR上下游基因的转录情况，结果表明vopR基因的缺失不明显影响其上下游基因表达，另外生长曲线显示，POR3-ΔvopR与野生株生长速率无显著差异，证明构建菌株的表型变化主要源于VopR的功能表现，这些菌株可用于对VopR的功能研究。随后，为进一步发掘VopR在V.parahaemolyticus细胞毒性产生的影响，通过体外细胞感染检测V.parahaemolyticus感染期间LDH的释放。结果表明，在V.parahaemolyticus感染90 min后，VopR能够显著抑制LDH的释放。细胞凋亡/坏死染色显示，在V.parahaemolyticus感染后的90 min，VopR可显著减少受感染HeLa细胞中的坏死细胞以及凋亡相关细胞的比例。与此同时，通过对VopR的易位检测发现，VopR在细菌感染的90 min已产生明显易位。综上，VopR在易位进入宿主细胞后能够显著抑制V.parahaemolyticus感染过程中细胞毒性的产生。
2. VopR在副溶血性弧菌感染中对宿主细胞基因转录的调控
为进一步了解VopR在副溶血性弧菌感染中具体对宿主产生的影响，本研究利用能够较快产生细胞毒性差异HeLa细胞进行研究，通过RNAseq探索了感染POR3、POR3-ΔvopR后45和90 min时引起的宿主基因转录变化， 结果发现：POR3感染相对于未感染组产生了66个差异表达基因，而ΔvopR感染则产生了117个差异表达基因；时序表达模式分析显示，两组差异基因在45与90 min呈现不同的动态表达模式。随后的比较分析发现，与POR3感染组相比，vopR基因缺失后特异性诱导了促炎性细胞因子基因如IL-6、IL-8、CXCL2/3以及FOS/JUN家族基因转录的上调，这种上调Caco-2细胞和THP-1巨噬细胞中也同样存在。这些结果显示出了效应蛋白VopR在感染过程中对宿主促炎性反应的抑制作用，并且这种抑制作用广泛存在于不同类型的细胞中。KEGG通路富集分析显示，VopR在副溶血性弧菌的感染中可能涉及对MAPK信号通路的调控；随后对MAPK p38以及Erk1/2在感染中的激活情况进行了调查，发现POR3以及POR3-ΔE4感染中均诱导了p38以及Erk1/2的磷酸化程度上调，而vopR基因的缺失在副溶血性弧菌感染90 min时虽然并未引起p38磷酸化的明显变化，但是MAPK-Erk1/2的磷酸化水平却在vopR基因回补后进一步增强了，提示VopR在感染中激活了宿主MAPK-Erk1/2。为了解这种对MAPK-Erk1/2的激活在VopR抑制宿主免疫功能中的影响，利用MAPK-Erk1/2活化抑制剂U0126对HeLa细胞预处理后再进行vopR基因缺失/回补菌株进行感染，检测发现VopR诱导的对IL6、JUN以及FOS转录的抑制作用在U0126处理后消失，因此VopR对促炎性因子IL6的转录抑制依赖于MAPK-Erk1/2激活。因此，VopR在副溶血性弧菌感染宿主细胞的过程中，通过激活MAPK-Erk1/2来抑制宿主细胞的促炎反应。
3. VopR通过Rac1-ERK1/2信号介导对宿主的免疫应答
为继续探索VopR在宿主细胞内的具体作用机制，本研究将VopR在真核细胞中进行过表达，间接免疫荧光显示，VopR定位于真核细胞细胞质膜周边。将VopR作为诱饵蛋白，通过免疫共沉淀试验下拉HeLa细胞中潜在与VopR具有相互作用的宿主蛋白，筛选VopR作用靶点。经质谱分析，总共得到361个潜在与VopR相互作用的宿主蛋白，经细胞亚定位筛选及
Co-IP、激光共聚焦验证，确认宿主小GTPase Rac1与VopR产生特异性结合。使用CRISPR/Cas9技术，通过慢病毒包装构建RAC1^-/- HeLa细胞。感染90 min后发现：WT细胞中POR3-ΔE4-CvopR较POR3-ΔE4产生了更低的LDH释放，而在RAC1^-/- HeLa中，vopR基因的回补并未对感染后LDH的释放产生影响；另外，VopR对MAPK-Erk1/2的激活作用在RAC1基因敲除后消失；与此同时，RT-qPCR证实RAC1^-/- HeLa细胞中，VopR在HeLa细胞中对IL-8转录的抑制作用也被减弱。综上，VopR需要通过Rac1激活Erk1/2通路以实现对宿主细胞的免疫抑制功能，以此减轻副溶血性弧菌感染中对细胞的损伤。
4. VopR对机体的免疫抑制有助于副溶血性弧菌的全身感染
此前，肠外感染模型已确认了T3SS1在副溶血性弧菌全身感染中的关键作用，于是，为了确定VopR在副溶血性弧菌全身感染中是否存在作用，本研究采用BALB/c小鼠腹腔感染模型，评估了POR3-ΔE4和POR3-ΔE4-CvopR在全身感染中的作用差异，结果显示，缺失了所有效应蛋白的POR3-ΔE4在感染中并不致小鼠死亡，但是POR3-ΔE4-CvopR感染后小鼠死亡率较ΔE4显著升高。随后，通过检测感染POR3-ΔE4和POR3-ΔE4-CvopR 6h后的小鼠腹腔肝、脾以及胸腔心脏中的细菌载量发现，POR3-ΔE4-CvopR较POR3-ΔE4在不同的组织中都存在更高的细菌数量；H&E染色病理切片显示感染后6 h，POR3-ΔE4-CvopR组对小鼠的脾脏造成了严重的出血，显示出了明显的败血症；利用RT-qPCR试验检测小鼠肝、脾以及心脏组织中促炎性细胞因子的转录情况，发现POR3-ΔE4-CvopR感染后，IL-1β、IL-6以及TNFα在心脏和肝脏中存在不同程度的转录抑制。综上，VopR通过抑制宿主炎性反应促进副溶血性弧菌系统性扩散，最终加剧全身感染导致宿主死亡。
综上，本研究通过构建vopR基因缺失/回补菌株，检验了vopR基因对副溶血性弧菌生物感染学特性，并利用转录组、质谱等方式明确了VopR在感染副溶血性弧菌中对宿主细胞基因的转录调控以及作用靶点，阐明了VopR对宿主细胞的免疫调节作用机制。此外，进行的小鼠体内试验还发现了VopR的免疫抑制加重了V.parahaemolyticus 的全身感染。研究结果有助于对T3SS1效应蛋白的致病机制有更深入的了解，为研发V.parahaemolyticus 新型抗菌制剂以及检测靶标提供研究基础。

Vibrio parahaemolyticus (V.parahaemolyticus) is an important foodborne pathogen, which is prevalent worldwide and belongs to gram-negative bacteria. The infection of Vibrio parahaemolyticus in the gastrointestinal tract usually causes diarrhea, fever, vomiting, and other clinical symptoms, which can lead to sepsis in severe cases. The type III secretion system (T3SS) of bacteria spans three kinds of biofilms. It is a precise "nanomachine" that delivers effector proteins in bacteria to host cells to produce effects. It plays an important role in the pathogenic process of bacteria. There are two sets of T3SS (T3SS1 and T3SS2) in Vibrio parahaemolyticus, of which T3SS1 mainly mediates the generation of cytotoxicity and sepsis during infection. Given the extensive harm of Vibrio parahaemolyticus, studying its virulence factors and its action mechanism will help develop more effective detection targets and formulate relevant prevention and control strategies. Previous studies have shown that Vibrio parahaemolyticus has at least four effectors that can translocate to host cells through T3SS1, namely VopQ, VopS, VpA0450, and VopR. Studies have found that VopR is localized on the host cell membrane after translocation to the host cell through its bacterial phosphoinositide domain (BPD). However, the specific function of VopR as a putative T3SS1 effector protein in the process of Vibrio parahaemolyticus infection remains to be resolved.
This study explored the role of VopR, an effector of Vibrio parahaemolyticus T3SS1, in its infection, and elucidated the molecular mechanism of VopR function in Vibrio parahaemolyticus infection, to provide a theoretical basis for the development of new antibacterial strategies and pathogen detection methods. The main research results are as follows:

1. Analysis of biological characteristics of VopR in Vibrio parahaemolyticus infection in cells

Using homologous recombination technology, POR3-ΔvopR and POR3-CvopR were constructed in POR3 (T3SS2^-, tdh^-), a derivative strain of Vibrio parahaemolyticus RIMD. At the same time, to rule out the functional redundancy of other T3SS1 effector proteins, POR3-ΔE4 and POR3-ΔE4-CvopR, which were both deleted by vopQ, vopS, vpa0450 and vopR, and POR3-ΔE4-CvopR, which was complemented by vopR gene, were also constructed in this study. Through PCR and RT-qPCR tests, it was verified that the strains needed for this study were successfully constructed; At the same time, the transcription of the upstream and downstream genes of vopR in the genome was detected. The results showed that the deletion of vopR gene did not significantly affect the expression of its upstream and downstream genes. In addition, the growth curve showed that there was no significant difference in the growth rate between POR3-ΔvopR and the wild strain, which proved that the phenotypic changes of the constructed strains mainly originated from the functional performance of VopR. These strains can be used for the functional study of vopR. Subsequently, to further explore the influence of VopR on V.parahaemolyticus cytotoxicity, LDH release during V.parahaemolyticus infection was detected by in-cell infection. The results showed that VopR could significantly inhibit the release of LDH after V.parahaemolyticus infection for 90 min. Apoptosis/necrosis staining showed that VopR could significantly reduce the proportion of necrotic and apoptosis-related cells in infected HeLa cells at 90 min after V.parahaemolyticus infection. At the same time, through the translocation detection of vopR, it was found that VopR had produced obvious translocation at 90 min of bacterial infection. In conclusion, VopR can significantly inhibit the generation of cytotoxicity during V.parahaemolyticus infection after translocation into host cells.

2. regulation of VopR on host cell gene transcription in Vibrio parahaemolyticus infection

To further understand the specific impact of VopR on the host in Vibrio parahaemolyticus infection, this study used HeLa cells that can rapidly produce cytotoxic differences. RNAseq was used to explore the transcriptional changes of host genes caused by POR3 and POR3- ΔvopR infection at 45 and 90 min after infection. The results showed that POR3 infection produced 66 differentially expressed genes compared with the uninfected group, while ΔvopR infection produced 117 differentially expressed genes; Temporal expression pattern analysis showed that the two groups of differential genes showed different dynamic expression patterns at 45 and 90 min. The subsequent comparative analysis found that compared with the POR3 infection group, the deletion of vopR gene specifically induced the upregulation of host proinflammatory cytokine genes IL-6, IL-8, CXCL2/3, and FOS/JUN family gene transcription. This upregulation also existed in Caco-2 cells and THP-1 macrophages, showing the inhibitory effect of effector protein VopR on host proinflammatory cytokine transcription during infection, and this inhibitory effect widely exists in different types of cells. KEGG pathway enrichment analysis showed that VopR may be involved in the regulation of the MAPK signaling pathway in the infection of Vibrio parahaemolyticus; Subsequently, the activation of MAPK p38 and Erk1/2 in infection was investigated. It was found that both POR3 and POR3-ΔE4 infection induced the upregulation of phosphorylation of p38 and Erk1/2. Although the deletion of vopR gene did not cause obvious changes in p38 phosphorylation at 90 min after Vibrio parahaemolyticus infection, the phosphorylation level of MAPK-Erk1/2 was further enhanced after vopr gene complementation, suggesting that vopr activated host MAPK-Erk1/2 in infection. To understand the effect of MAPK-Erk1/2 activation on the immunosuppressive function of VopR, HeLa cells were pretreated with MAPK-Erk1/2 activation inhibitor U0126 and then infected with the vopR gene deletion/complementation strain. It was found that the inhibition of IL6, JUN, and FOS transcription induced by VopR disappeared after U0126 treatment, so the transcriptional inhibition of proinflammatory factor IL6 by VopR depended on MAPK-Erk1/2 activation. Therefore, in the process of Vibrio parahaemolyticus infection of host cells, VopR inhibits the pro-inflammatory response of host cells by activating MAPK-Erk1/2.

3. VopR mediates immunosuppression to the host through Rac1-Erk1/2 signaling

To continue to explore the specific mechanism of VopR in host cells, this study overexpressed VopR in eukaryotic cells. Indirect immunofluorescence showed that VopR was localized at the periphery of the eukaryotic cell plasma membrane. Using VopR as bait, the potential host proteins interacting with VopR in HeLa cells were pulled down by Co-Immunoprecipitation assay to screen the targets of VopR. After mass spectrometry analysis, a total of 361 host proteins potentially interacting with VopR were obtained. After cell sublocalization screening and Co-IP, laser confocal verification, it was confirmed that the host small GTPase Rac1 specifically binds to VopR. RAC1^-/- HeLa cells were constructed by lentiviral packaging using CRISPR/cas9 technology. After 90 min of infection, it was found that POR3-ΔE4-CvopR produced lower LDH release than POR3-ΔE4 in WT cells, while in RAC1^-/- HeLa, the recruitment of vopR gene did not affect the release of LDH after infection; In addition, the activating effect of VopR on MAPK-Erk1/2 disappeared after RAC1 gene knockdown; At the same time, RT-qPCR confirmed that the inhibitory effect of VopR on IL-8 transcription was also attenuated in RAC1^-/- HeLa cells. In conclusion, VopR needs to activate the Erk1/2 pathway through Rac1 to achieve immunosuppressive function on host cells, to reduce the damage to cells in Vibrio parahaemolyticus infection.

4. Immunosuppression of VopR enhances systemic infection with V. parahaemolyticus

Previously, the parenteral infection model has confirmed the key role of T3SS1 in the systemic infection of Vibrio parahaemolyticus. Therefore, to determine whether there is a role for VopR in the systemic infection of Vibrio parahaemolyticus, we used the intraperitoneal infection model of Balb/c mice to evaluate the difference in the role of POR3-ΔE4 and POR3-ΔE4-CvopR in the systemic infection. The results showed that POR3-ΔE4 without all T3SS1 effectors did not cause the death of mice in the infection, but the mortality of POR3-ΔE4-CvopR was significantly higher than that of ΔE4. Subsequently, by detecting the bacterial load in the abdominal liver, spleen and thoracic heart of mice infected with POR3-ΔE4 and POR3-ΔE4-CvopR for 6h, it was found that POR3-ΔE4-CvopR had higher bacterial number in different tissues than POR3-ΔE4; HE stained pathological sections showed that 6 h after infection, the POR3-ΔE4-CvopR group caused severe bleeding to the spleen of mice, showing obvious sepsis; RT-qPCR was used to detect the transcription of pro-inflammatory cytokines in liver, spleen and heart tissues of mice. It was found that IL-1β, IL-6, and TNFα were transcriptionally inhibited in the heart and liver after POR3-ΔE4-CvopR infection. In conclusion, VopR promotes the systemic spread of Vibrio parahaemolyticus by inhibiting the host inflammatory response and ultimately exacerbates systemic infection leading to host death.
In conclusion, this study examined the biological infective characteristics of the vopR gene against Vibrio parahaemolyticus by constructing a vopR deletion/complementation strain and identified the transcriptional regulation and functional targets of vopR on host cell genes in Vibrio parahaemolyticus infection by transcriptome and mass spectrometry, and clarified the immune regulatory mechanism of VopR on host cells. In addition, the in vivo test in mice also found that the immunosuppression of VopR aggravated the systemic infection of V.parahaemolyticus. The research results help to have a deeper understanding of the pathogenic mechanism of the T3SS1 effector and provide a research basis for the development of new antibacterial agents and detection targets of V.parahaemolyticus.

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