A群链球菌CovRS双组份系统致病机制研究
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摘要
A群链球菌(Group A Streptococcus, GAS)是引起人类细菌感染的最重要病原之一。据2011年数据显示,全球每年大概有7亿例GAS引起的轻微、局部感染病例,其中约65万例转化为严重侵袭性感染(严重全身性感染),最后导致约四分之一的感染者死亡。A群链球菌感染可以引起相对轻微感染,主要有咽喉炎、急性扁桃体炎、猩红热、皮肤软组织感染、脓包病。它也可导致严重的侵袭性感染,如中毒性休克综合征和坏死性筋膜炎。该菌也可能造成非化脓性后遗症,如风湿性心脏病和急性肾小球肾炎。
由于GAS血清型的复杂性以及疫苗的安全性问题,目前尚无针对GAS的商业化疫苗。近年来由GAS引起的猩红热和严重全身性感染的发病率有所增长,引起了人们对该类细菌感染的更多关注。尽管研究者围绕GAS的毒力因子及致病机制已开展了大量研究工作,但目前对GAS导致侵袭性感染的致病机理和局部感染向侵袭性感染转化的分子机制尚不清楚。因此,进一步研究GAS在侵袭性感染过程中的固有免疫逃逸机制和了解GAS如何从局部感染转化为侵袭性感染的分子机制将有利于发现新的抗感染靶点和建立侵袭性感染早期诊断方法,对于有效预防和控制严重侵袭性感染具有重要意义。
本研究使用从A群链球菌中毒性休克综合征和坏死性筋膜炎等危及生命的感染病例中分离频率最高的M1T1血清型代表菌株进行侵袭性感染致病机制研究。第一,发现GAS可以通过CovRS双组份调控系统抑制中性粒细胞向感染部位募集以增强其侵袭能力,也解释了侵袭性感染临床分离株MGAS5005中covS基因的天然无义突变是导致该菌株中性粒细胞募集抑制能力、侵袭能力和毒力增强的主要原因。第二,用侵袭性感染模型评估了三个受CovRS双组份系统调控的中性粒细胞募集抑制因子在侵袭性感染过程中的重要性。第三,发现中性粒细胞在M1T1血清型GAS引起的局部感染转化为侵袭性感染的过程中发挥重要作用。第四,进一步完善M1T1血清型GAS引起的局部感染转化为侵袭性感染的分子模型。主要研究内容如下：
1.建立M1T1血清型GAS侵袭性感染模型。
本研究首先用临床分离的侵袭性感染代表菌株MGAS5005和咽炎感染代表菌株MGAS2221通过皮下接种的方式感染小鼠,建立侵袭性感染研究模型。在该模型中,与咽炎感染代表菌株MGAS2221相比,侵袭性感染代表菌株MGAS5005具有较强的毒力和软组织侵袭能力,并且感染部位缺少中性粒细胞。该表型与严重侵袭性感染——坏死性筋膜炎感染部位缺少中性粒细胞的临床表现一致,表明该动物模型成功模拟了侵袭性感染的临床表型,为侵袭性感染致病机制的研究奠定了基础。
2.M1T1血清型GAS通过CovRS双组份系统抑制中性粒细胞向感染部位募集以增强其侵袭能力和毒力。
本实验室首先通过同源重组的方法将野生型covSwt基因置换MGAS5005基因组中天然无义突变的covS△1bp基因,构建MGAS5005wtcovS回复菌株。动物实验表明MGAS5005wtcovS显著降低了毒力和侵袭能力,并且在感染区域募集了大量中性粒细胞,中性粒细胞含量与咽炎感染代表菌株MGAS2221感染部位募集的中性粒细胞水平相当。相反,MGAS2221△covS突变株毒力和侵袭能力显著增强,感染部位募集的中性粒细胞含量降低至MGAS5005相似的水平。该结果表明,GAS通过CovRS双组份系统抑制中性粒细胞向感染部位募集,并因此增强侵袭能力和毒力。上述结果也解释了侵袭性感染分离菌株MGAS5005中covS基因的天然无义突变是导致其抑制中性粒细胞募集能力和毒力增强的主要原因。通过检测患者感染部位分离菌株的covRS基因是否发生突变,或许可以成为一种侵袭性感染的辅助预测方法。
3.链球菌分泌性酯酶(SsE)是侵袭性感染中重要的中性粒细胞募集抑制因子和毒力因子。
上述研究结果证明在GAS侵袭性感染过程中,CovRS双组份系统参与抑制中性粒细胞向感染部位募集。CovRS双组份系统需要通过调控下游基因实现抑制中性粒细胞募集的功能。白介素-8蛋白酶(SpyCEP)、C5a肽酶(ScpA)和分泌性酯酶(SsE)是受CovRS负调控的中性粒细胞募集抑制因子。为了分析和比较中性粒细胞募集抑制因子SpyCEP、ScpA和SsE在侵袭性感染过程中的重要性,本研究以侵袭性感染代表菌株MGAS5005为亲本菌株,通过同源重组的方法分别构建这三个基因的单基因缺失突变株,双基因缺失突变株△spyCEP△scpA,△scpA△sse,△spyCEP△sse和三基因缺失突变株△spyCEP△scpA△sse。通过侵袭性感染模型,对单基因缺失突变株、双基因缺失突变株和三基因缺失突变株一共7个突变株同时进行比较发现：凡是缺失了sse基因的突变株(包括单基因、双基因和三基因缺失突变株),中性粒细胞募集抑制能力和毒力都显著降低；然而,spyCEP和scpA这两个基因的单基因和双基因缺失突变株的中性粒细胞募集抑制能力和毒力与野生株相比没有显著变化；并且三个因子之间没有协同增强中性粒细胞募集抑制能力和毒力的效应。以上结果证明SsE不仅是GAS侵袭性感染过程中抑制中性粒细胞募集的重要因子,而且是GAS侵袭性感染过程中的重要的毒力因子。通过开发针对该毒力因子的药物或者治疗性单克隆抗体,有希望用于治疗侵袭性感染。将该毒力因子的表达水平与GAS侵袭性感染严重程度相关联,有潜力发展为疾病严重程度的评判指标。
4.中性粒细胞在咽炎感染代表菌株转化成强侵袭性菌株的过程中发挥重要作用。
有研究报道,某些GAS菌株在小鼠体内传代后,covRS基因可能发生突变。covRS基因突变的菌株不能分泌广谱半胱氨酸蛋白酶(SpeB),因此本文将该类菌株简称为SpeB阴性菌株(SpeB-菌株)。本研究将咽炎代表菌株MGAS2221(SpeB阳性菌株)进行皮下感染,发现随着感染时间的延长,从感染部位分离到的SpeB阴性突变菌株(SpeB-菌株)比例越来越高,具有体内生存优势。体外生长曲线和体内竞争感染实验共同表明SpeB-菌株在体内的生存优势并不是生长速率导致的,而是因为SpeB-菌株在感染部位具有更强的抵抗炎症细胞清除能力。通过RT-PCR方法发现,与MGAS2221相比,SpeB-菌株中spyCEP、hasA和sse等基因的表达水平均显著升高。在小鼠软组织感染模型中证明,与亲本菌株MGAS2221相比,SpeB-菌株具有更强的毒力、中性粒细胞募集抑制能力和侵袭能力。以上结果表明在小鼠体内传代,可以诱导咽炎感染代表菌株MGAS2221“转化”成为具有强中性粒细胞募集抑制能力、强侵袭能力和强毒力的SpeB-菌株。
为了研究宿主中性粒细胞在该“转化”过程中发挥的作用,本研究采用缺乏中性粒细胞的小鼠进行实验。首先,分别通过抗Gr-1和抗Ly6G的两种单克隆抗体消除正常小鼠感染部位中性粒细胞,两种抗体处理的结果均表明中性粒细胞在该“转化”过程中发挥重要作用。其次,使用中性粒细胞杀伤能力有缺陷的gp91phox-/-基因缺陷型小鼠再次确定中性粒细胞在该“转化”过程中起到重要作用。此外,为了排除炎症单核细胞在该过程中产生的影响,本研究使用炎症单核细胞不能从骨髓进入血液的CCR2-/-基因缺陷型小鼠进行试验,结果表明炎症单核细胞并未对“转化”过程产生影响。
5.本研究进一步完善了M1T1血清型GAS引起的局部感染向侵袭性感染转化的理论模型。
(1)在建立感染之初,GAS不仅需要正常的CovRS双组份系统来感应环境变化并迅速调控下游基因表达,同时需要分泌广谱半胱氨酸蛋白酶(SpeB)来破坏机体的第一道屏障(如咽喉或皮肤上皮细胞)。(2)当GAS突破第一道屏障之后,机体在感染部位募集大量中性粒细胞来清除GAS,此时GAS将通过各种免疫逃逸机制来抵抗免疫系统的清除。(3)其中,covRS基因发生突变将使得免疫逃逸相关的因子能够大量表达,因此具有较强的固有免疫逃逸能力,获得了体内生存优势。(4)成功免疫逃逸的GAS进入血液全身性扩散进而导致侵袭性感染发生。
Group A Streptococcus (GAS) is one of the most important human bacterial pathogens. According to the data in2011, it shows that700million of mild, local infection cases occurred worldwide each year, in which650,000cases turn into serious invasive infections (severe systemic infection). One quarter of these invasive infection cases eventually lead to death. GAS can cause relatively mild infections including pharyngitis, acute tonsillitis, scarlet fever, skin infections and impetigo. It can also cause life-threatening invasive infections, such as toxic shock syndrome (TSS) and necrotizing fasciitis. Besides, GAS is also responsible for apyogenous sequelae, such as rheumatic heart disease and acute glomerulonephritis.
There is currently no commercial vaccine against GAS because of its diverse serotype complexity and vaccine safety concerning. In recent years, there is an increase in cases of scarlet fever and severe systemic infections caused by GAS, which aroused greater concern for streptococcal infections. Despite there have been a lot of researches on virulence factors and pathogenesis of GAS, the pathogenic mechanism of GAS invasive infections and the molecular mechanism how local infections transit to invasive infections are still unclear. Therefore, further study on the mechanism of innate immunity evasion during invasive infections and the phase-switching mechanism could help to discover new anti-infection targets and establish early-stage diagnostic methods of invasive diseases. These progresses will be helpful to prevent and control severe invasive diseases.
In this study, we selected representative strains of MIT1serotype to elucidate the pathogenesis of invasive infections. M1T1is the serotype which is mostly related with life-threatening conditions, such as streptococcal toxic shock syndrome and necrotizing fasciitis. First, our study found that GAS could inhibit the recruitment of neutrophils to infection sites via regulating the two-component system CovRS, in which way GAS increases the invasive capacity. This explains natural null mutation of CovRS in hypervirulent GAS strain MGAS5005is responsible for the enhancement of its invasiveness and virulence. Second, the importance of three reported factors, which are regulated by CovRS and involved in the inhibition of neutrophil recruitment, in the course of invasive infections are evaluated in invasive infection model. Third, neutrophils play an important role during the course, in which local infections caused by M1T1strains transit to invasive infections. Fourth, the molecular model of local invasive infections caused by M1T1serotype strains switching to invasive infections is further established. The main contents are as follows:
1. Infection model of invasive infection caused by M1T1GAS strains is established.
In this study, mice were subcutaneously infected with clinical isolates of invasive representative strain MGAS5005and pharyngitis representative strain MGAS2221to establish the infection model of invasive infection. Compared with pharyngitis representative strain MGAS2221, invasive representative strain MGAS5005displays more virulence and invasive capacity in soft tissue. In addition, the infection sites of MGAS5005was severely lack of recruited neutrophils, which is consistent with clinical manifestation that in cases of severe invasive infections-necrotizing fasciitis, infection sites also lacks of neutrophil. This indicates that the animal model successfully simulates the process of invasive infections, thus it laid the foundation for the study of pathogenesis of invasive infections.
2. M1T1GAS strains inhibit the neutrophil recruitment to infection sites to increase the invasive ability and virulence via regulation of two-component system CovRS.
Homologous replacement of natural null covS△1bp in MGAS5005with wild-type covS resulted in MGAS5005wtcovS. In animal infection experiments, MGAS5005wtcovS showed reduced virulence as well as invasive ability. Besides, it enhanced neutrophil ingress to infection sites, where the level of neutrophils was similar to that at MGAS2221sites. On the contrary, MGAS2221△covS mutant showed greatly enhanced virulence and invasion capacity. The level of neutrophils at MGAS2221△covS sites was similar to that at MGAS5005infection sites. Therefore, these results indicate that GAS employs the two-component system CovRS to inhibit neutrophil recruitment in infection sites, in which way increases invasive capacity and virulence. It also explains that covS null mutation is responsible for the enhancement of the inhibition of neutrophil recruitment and virulence in invasive strain MGAS5005. Detecting the mutation state of covRS in patients'infection sites is promising to develop into an auxiliary prediction method of invasive infections.
3. Streptococcal secreted esterase (SsE) is the critical neutrophil recruitment inhibitor and virulence factor during invasive infections.
Previous results demonstrated two-component system CovRS is closely related to inhibition of neutrophil recruitment in invasive infections. CovRS functions via regulating down-stream effectors. Interleukin-8/CXC chemokine peptidase (SpyCEP), C5a peptidase (ScpA), and streptococcal secreted esterase (SsE) are reported to be negatively regulated by CovRS and involved in inhibition of neutrophil recruitment during GAS infections. To evaluate and compare the importance of these factors during the invasive infection process, we constructed single mutants, double mutant AspyCEPAscpA, AscpAAsse, AspyCEPAsse and triple mutant△spyCEPAscpAAsse of invasive representative strain MGAS5005. In invasive infection model, comparing the single, double and triple mutants, a total of seven mutants we found that:all of the mutants with sse deletion (including single, double and triple mutants) decreased inhibition capacity of neutrophil recruitment and virulence; on the contrary, AspyCEP, AscpA and AspyCEPAscpA lead to similar overall pathology with parent strain MGAS5005; these three factors have no synergistic effect on inhibition of neutrophil infiltration and virulence enhancement. These results demonstrate that SsE is not only the key factor required for GAS inhibition of neutrophil infiltration during invasive infections, but also an important virulence factor of GAS. Development of drug and therapeutic monoclonal antibodies against SsE is promising for the treatment of invasive infections. Besides, association the expression level of SsE with the invasive infection severity has the potential to develop as an evaluation indicator of disease severity.
4. Neutrophil plays a critical role during the phase of GAS in vivo transition from pharyngitis strain to invasive strain.
Some studies reported that covRS spontaneously mutates in some mouse-passaged derivatives, which could not secret streptococcal pyrogenic exotoxin (SpeB). In this study, we refer these strains as SpeB negative (SpeB-) strains. Mice were subcutaneously infected with pharyngitis infection representative strain MGAS2221(SpeB positive). It was discovered that SpeB negative (SpeB-) mutants recovered from infection sites increased with the passage of time, which indicates that SpeB-mutants have survival advantage in infection sites compared to MGAS2221. Based on the result of in vitro growth curve and in vivo competitive growth assay, the survival advantage of SpeB-is not due to a growth advantage but the increasing resistance against inflammatory cells-mediated clearance. By RT-PCR analysis, we found the expression of important factors, such as spyCEP, hasA and sse, increased in SpeB-strains. Compared with MGAS2221, SpeB-strain showed enhanced virulence, capacity of neutrophil recruitment inhibition and invasiveness in mice soft tissue infection model. These results indicate that passage in mice could induce the pharyngitis representative strain MGAS2221to transit into SpeB strain with enhanced capacity of neutrophil recruitment inhibition, invasiveness and virulenc.
To find the selective pressure favoring the phase-switching, mice model lacking neutrophil is used in this study. First, anti-Gr-1and anti-Ly6G monoclonal antibodies are used to deplete neutrophils in mice infection sites. The results verified that neutrophil involves in the phase-switching process. Second, the results with gp91phox-/-deficient mice, which are defective in neutrophil-mediated killing, further support that neutrophil plays a critical role during the phase of GAS in vivo transition. Besides, to exclude the effect exerted by inflammatory monocytes, CCR2-/-deficient mice, in which inflammatory monocytes could not emigrate to bloodstream from bone marrow, was used. The results showed that inflammatory monocytes didn't contribute critically to this process.
5. This study improved the theoretical model of local infections caused by M1T1switching to invasive infections
(1) At the beginning of infection establishment, GAS needs wild type CovRS two-component system to sense environmental change and regulate downstream gene expression, as well as SpeB to destroy the host first barrier (such as the throat or skin epithelial cells).(2) After bacteria break through the first barrier, host will recruit a large number of neutrophils to the infection sites to clear the bacteria. In responding, GAS employs multiple mechanisms to evade from immunity clearance.(3) Partial bacteria mutated in covRS, which leads to increasing expression of.immunity evasion factors. These strains with enhanced capacity of innate immunity evasion take survival advantage in vivo.(4) GAS which succeeds in immunity evasion diffuses into the blood and cause invasive disease.
由于GAS血清型的复杂性以及疫苗的安全性问题,目前尚无针对GAS的商业化疫苗。近年来由GAS引起的猩红热和严重全身性感染的发病率有所增长,引起了人们对该类细菌感染的更多关注。尽管研究者围绕GAS的毒力因子及致病机制已开展了大量研究工作,但目前对GAS导致侵袭性感染的致病机理和局部感染向侵袭性感染转化的分子机制尚不清楚。因此,进一步研究GAS在侵袭性感染过程中的固有免疫逃逸机制和了解GAS如何从局部感染转化为侵袭性感染的分子机制将有利于发现新的抗感染靶点和建立侵袭性感染早期诊断方法,对于有效预防和控制严重侵袭性感染具有重要意义。
本研究使用从A群链球菌中毒性休克综合征和坏死性筋膜炎等危及生命的感染病例中分离频率最高的M1T1血清型代表菌株进行侵袭性感染致病机制研究。第一,发现GAS可以通过CovRS双组份调控系统抑制中性粒细胞向感染部位募集以增强其侵袭能力,也解释了侵袭性感染临床分离株MGAS5005中covS基因的天然无义突变是导致该菌株中性粒细胞募集抑制能力、侵袭能力和毒力增强的主要原因。第二,用侵袭性感染模型评估了三个受CovRS双组份系统调控的中性粒细胞募集抑制因子在侵袭性感染过程中的重要性。第三,发现中性粒细胞在M1T1血清型GAS引起的局部感染转化为侵袭性感染的过程中发挥重要作用。第四,进一步完善M1T1血清型GAS引起的局部感染转化为侵袭性感染的分子模型。主要研究内容如下：
1.建立M1T1血清型GAS侵袭性感染模型。
本研究首先用临床分离的侵袭性感染代表菌株MGAS5005和咽炎感染代表菌株MGAS2221通过皮下接种的方式感染小鼠,建立侵袭性感染研究模型。在该模型中,与咽炎感染代表菌株MGAS2221相比,侵袭性感染代表菌株MGAS5005具有较强的毒力和软组织侵袭能力,并且感染部位缺少中性粒细胞。该表型与严重侵袭性感染——坏死性筋膜炎感染部位缺少中性粒细胞的临床表现一致,表明该动物模型成功模拟了侵袭性感染的临床表型,为侵袭性感染致病机制的研究奠定了基础。
2.M1T1血清型GAS通过CovRS双组份系统抑制中性粒细胞向感染部位募集以增强其侵袭能力和毒力。
本实验室首先通过同源重组的方法将野生型covSwt基因置换MGAS5005基因组中天然无义突变的covS△1bp基因,构建MGAS5005wtcovS回复菌株。动物实验表明MGAS5005wtcovS显著降低了毒力和侵袭能力,并且在感染区域募集了大量中性粒细胞,中性粒细胞含量与咽炎感染代表菌株MGAS2221感染部位募集的中性粒细胞水平相当。相反,MGAS2221△covS突变株毒力和侵袭能力显著增强,感染部位募集的中性粒细胞含量降低至MGAS5005相似的水平。该结果表明,GAS通过CovRS双组份系统抑制中性粒细胞向感染部位募集,并因此增强侵袭能力和毒力。上述结果也解释了侵袭性感染分离菌株MGAS5005中covS基因的天然无义突变是导致其抑制中性粒细胞募集能力和毒力增强的主要原因。通过检测患者感染部位分离菌株的covRS基因是否发生突变,或许可以成为一种侵袭性感染的辅助预测方法。
3.链球菌分泌性酯酶(SsE)是侵袭性感染中重要的中性粒细胞募集抑制因子和毒力因子。
上述研究结果证明在GAS侵袭性感染过程中,CovRS双组份系统参与抑制中性粒细胞向感染部位募集。CovRS双组份系统需要通过调控下游基因实现抑制中性粒细胞募集的功能。白介素-8蛋白酶(SpyCEP)、C5a肽酶(ScpA)和分泌性酯酶(SsE)是受CovRS负调控的中性粒细胞募集抑制因子。为了分析和比较中性粒细胞募集抑制因子SpyCEP、ScpA和SsE在侵袭性感染过程中的重要性,本研究以侵袭性感染代表菌株MGAS5005为亲本菌株,通过同源重组的方法分别构建这三个基因的单基因缺失突变株,双基因缺失突变株△spyCEP△scpA,△scpA△sse,△spyCEP△sse和三基因缺失突变株△spyCEP△scpA△sse。通过侵袭性感染模型,对单基因缺失突变株、双基因缺失突变株和三基因缺失突变株一共7个突变株同时进行比较发现：凡是缺失了sse基因的突变株(包括单基因、双基因和三基因缺失突变株),中性粒细胞募集抑制能力和毒力都显著降低；然而,spyCEP和scpA这两个基因的单基因和双基因缺失突变株的中性粒细胞募集抑制能力和毒力与野生株相比没有显著变化；并且三个因子之间没有协同增强中性粒细胞募集抑制能力和毒力的效应。以上结果证明SsE不仅是GAS侵袭性感染过程中抑制中性粒细胞募集的重要因子,而且是GAS侵袭性感染过程中的重要的毒力因子。通过开发针对该毒力因子的药物或者治疗性单克隆抗体,有希望用于治疗侵袭性感染。将该毒力因子的表达水平与GAS侵袭性感染严重程度相关联,有潜力发展为疾病严重程度的评判指标。
4.中性粒细胞在咽炎感染代表菌株转化成强侵袭性菌株的过程中发挥重要作用。
有研究报道,某些GAS菌株在小鼠体内传代后,covRS基因可能发生突变。covRS基因突变的菌株不能分泌广谱半胱氨酸蛋白酶(SpeB),因此本文将该类菌株简称为SpeB阴性菌株(SpeB-菌株)。本研究将咽炎代表菌株MGAS2221(SpeB阳性菌株)进行皮下感染,发现随着感染时间的延长,从感染部位分离到的SpeB阴性突变菌株(SpeB-菌株)比例越来越高,具有体内生存优势。体外生长曲线和体内竞争感染实验共同表明SpeB-菌株在体内的生存优势并不是生长速率导致的,而是因为SpeB-菌株在感染部位具有更强的抵抗炎症细胞清除能力。通过RT-PCR方法发现,与MGAS2221相比,SpeB-菌株中spyCEP、hasA和sse等基因的表达水平均显著升高。在小鼠软组织感染模型中证明,与亲本菌株MGAS2221相比,SpeB-菌株具有更强的毒力、中性粒细胞募集抑制能力和侵袭能力。以上结果表明在小鼠体内传代,可以诱导咽炎感染代表菌株MGAS2221“转化”成为具有强中性粒细胞募集抑制能力、强侵袭能力和强毒力的SpeB-菌株。
为了研究宿主中性粒细胞在该“转化”过程中发挥的作用,本研究采用缺乏中性粒细胞的小鼠进行实验。首先,分别通过抗Gr-1和抗Ly6G的两种单克隆抗体消除正常小鼠感染部位中性粒细胞,两种抗体处理的结果均表明中性粒细胞在该“转化”过程中发挥重要作用。其次,使用中性粒细胞杀伤能力有缺陷的gp91phox-/-基因缺陷型小鼠再次确定中性粒细胞在该“转化”过程中起到重要作用。此外,为了排除炎症单核细胞在该过程中产生的影响,本研究使用炎症单核细胞不能从骨髓进入血液的CCR2-/-基因缺陷型小鼠进行试验,结果表明炎症单核细胞并未对“转化”过程产生影响。
5.本研究进一步完善了M1T1血清型GAS引起的局部感染向侵袭性感染转化的理论模型。
(1)在建立感染之初,GAS不仅需要正常的CovRS双组份系统来感应环境变化并迅速调控下游基因表达,同时需要分泌广谱半胱氨酸蛋白酶(SpeB)来破坏机体的第一道屏障(如咽喉或皮肤上皮细胞)。(2)当GAS突破第一道屏障之后,机体在感染部位募集大量中性粒细胞来清除GAS,此时GAS将通过各种免疫逃逸机制来抵抗免疫系统的清除。(3)其中,covRS基因发生突变将使得免疫逃逸相关的因子能够大量表达,因此具有较强的固有免疫逃逸能力,获得了体内生存优势。(4)成功免疫逃逸的GAS进入血液全身性扩散进而导致侵袭性感染发生。
Group A Streptococcus (GAS) is one of the most important human bacterial pathogens. According to the data in2011, it shows that700million of mild, local infection cases occurred worldwide each year, in which650,000cases turn into serious invasive infections (severe systemic infection). One quarter of these invasive infection cases eventually lead to death. GAS can cause relatively mild infections including pharyngitis, acute tonsillitis, scarlet fever, skin infections and impetigo. It can also cause life-threatening invasive infections, such as toxic shock syndrome (TSS) and necrotizing fasciitis. Besides, GAS is also responsible for apyogenous sequelae, such as rheumatic heart disease and acute glomerulonephritis.
There is currently no commercial vaccine against GAS because of its diverse serotype complexity and vaccine safety concerning. In recent years, there is an increase in cases of scarlet fever and severe systemic infections caused by GAS, which aroused greater concern for streptococcal infections. Despite there have been a lot of researches on virulence factors and pathogenesis of GAS, the pathogenic mechanism of GAS invasive infections and the molecular mechanism how local infections transit to invasive infections are still unclear. Therefore, further study on the mechanism of innate immunity evasion during invasive infections and the phase-switching mechanism could help to discover new anti-infection targets and establish early-stage diagnostic methods of invasive diseases. These progresses will be helpful to prevent and control severe invasive diseases.
In this study, we selected representative strains of MIT1serotype to elucidate the pathogenesis of invasive infections. M1T1is the serotype which is mostly related with life-threatening conditions, such as streptococcal toxic shock syndrome and necrotizing fasciitis. First, our study found that GAS could inhibit the recruitment of neutrophils to infection sites via regulating the two-component system CovRS, in which way GAS increases the invasive capacity. This explains natural null mutation of CovRS in hypervirulent GAS strain MGAS5005is responsible for the enhancement of its invasiveness and virulence. Second, the importance of three reported factors, which are regulated by CovRS and involved in the inhibition of neutrophil recruitment, in the course of invasive infections are evaluated in invasive infection model. Third, neutrophils play an important role during the course, in which local infections caused by M1T1strains transit to invasive infections. Fourth, the molecular model of local invasive infections caused by M1T1serotype strains switching to invasive infections is further established. The main contents are as follows:
1. Infection model of invasive infection caused by M1T1GAS strains is established.
In this study, mice were subcutaneously infected with clinical isolates of invasive representative strain MGAS5005and pharyngitis representative strain MGAS2221to establish the infection model of invasive infection. Compared with pharyngitis representative strain MGAS2221, invasive representative strain MGAS5005displays more virulence and invasive capacity in soft tissue. In addition, the infection sites of MGAS5005was severely lack of recruited neutrophils, which is consistent with clinical manifestation that in cases of severe invasive infections-necrotizing fasciitis, infection sites also lacks of neutrophil. This indicates that the animal model successfully simulates the process of invasive infections, thus it laid the foundation for the study of pathogenesis of invasive infections.
2. M1T1GAS strains inhibit the neutrophil recruitment to infection sites to increase the invasive ability and virulence via regulation of two-component system CovRS.
Homologous replacement of natural null covS△1bp in MGAS5005with wild-type covS resulted in MGAS5005wtcovS. In animal infection experiments, MGAS5005wtcovS showed reduced virulence as well as invasive ability. Besides, it enhanced neutrophil ingress to infection sites, where the level of neutrophils was similar to that at MGAS2221sites. On the contrary, MGAS2221△covS mutant showed greatly enhanced virulence and invasion capacity. The level of neutrophils at MGAS2221△covS sites was similar to that at MGAS5005infection sites. Therefore, these results indicate that GAS employs the two-component system CovRS to inhibit neutrophil recruitment in infection sites, in which way increases invasive capacity and virulence. It also explains that covS null mutation is responsible for the enhancement of the inhibition of neutrophil recruitment and virulence in invasive strain MGAS5005. Detecting the mutation state of covRS in patients'infection sites is promising to develop into an auxiliary prediction method of invasive infections.
3. Streptococcal secreted esterase (SsE) is the critical neutrophil recruitment inhibitor and virulence factor during invasive infections.
Previous results demonstrated two-component system CovRS is closely related to inhibition of neutrophil recruitment in invasive infections. CovRS functions via regulating down-stream effectors. Interleukin-8/CXC chemokine peptidase (SpyCEP), C5a peptidase (ScpA), and streptococcal secreted esterase (SsE) are reported to be negatively regulated by CovRS and involved in inhibition of neutrophil recruitment during GAS infections. To evaluate and compare the importance of these factors during the invasive infection process, we constructed single mutants, double mutant AspyCEPAscpA, AscpAAsse, AspyCEPAsse and triple mutant△spyCEPAscpAAsse of invasive representative strain MGAS5005. In invasive infection model, comparing the single, double and triple mutants, a total of seven mutants we found that:all of the mutants with sse deletion (including single, double and triple mutants) decreased inhibition capacity of neutrophil recruitment and virulence; on the contrary, AspyCEP, AscpA and AspyCEPAscpA lead to similar overall pathology with parent strain MGAS5005; these three factors have no synergistic effect on inhibition of neutrophil infiltration and virulence enhancement. These results demonstrate that SsE is not only the key factor required for GAS inhibition of neutrophil infiltration during invasive infections, but also an important virulence factor of GAS. Development of drug and therapeutic monoclonal antibodies against SsE is promising for the treatment of invasive infections. Besides, association the expression level of SsE with the invasive infection severity has the potential to develop as an evaluation indicator of disease severity.
4. Neutrophil plays a critical role during the phase of GAS in vivo transition from pharyngitis strain to invasive strain.
Some studies reported that covRS spontaneously mutates in some mouse-passaged derivatives, which could not secret streptococcal pyrogenic exotoxin (SpeB). In this study, we refer these strains as SpeB negative (SpeB-) strains. Mice were subcutaneously infected with pharyngitis infection representative strain MGAS2221(SpeB positive). It was discovered that SpeB negative (SpeB-) mutants recovered from infection sites increased with the passage of time, which indicates that SpeB-mutants have survival advantage in infection sites compared to MGAS2221. Based on the result of in vitro growth curve and in vivo competitive growth assay, the survival advantage of SpeB-is not due to a growth advantage but the increasing resistance against inflammatory cells-mediated clearance. By RT-PCR analysis, we found the expression of important factors, such as spyCEP, hasA and sse, increased in SpeB-strains. Compared with MGAS2221, SpeB-strain showed enhanced virulence, capacity of neutrophil recruitment inhibition and invasiveness in mice soft tissue infection model. These results indicate that passage in mice could induce the pharyngitis representative strain MGAS2221to transit into SpeB strain with enhanced capacity of neutrophil recruitment inhibition, invasiveness and virulenc.
To find the selective pressure favoring the phase-switching, mice model lacking neutrophil is used in this study. First, anti-Gr-1and anti-Ly6G monoclonal antibodies are used to deplete neutrophils in mice infection sites. The results verified that neutrophil involves in the phase-switching process. Second, the results with gp91phox-/-deficient mice, which are defective in neutrophil-mediated killing, further support that neutrophil plays a critical role during the phase of GAS in vivo transition. Besides, to exclude the effect exerted by inflammatory monocytes, CCR2-/-deficient mice, in which inflammatory monocytes could not emigrate to bloodstream from bone marrow, was used. The results showed that inflammatory monocytes didn't contribute critically to this process.
5. This study improved the theoretical model of local infections caused by M1T1switching to invasive infections
(1) At the beginning of infection establishment, GAS needs wild type CovRS two-component system to sense environmental change and regulate downstream gene expression, as well as SpeB to destroy the host first barrier (such as the throat or skin epithelial cells).(2) After bacteria break through the first barrier, host will recruit a large number of neutrophils to the infection sites to clear the bacteria. In responding, GAS employs multiple mechanisms to evade from immunity clearance.(3) Partial bacteria mutated in covRS, which leads to increasing expression of.immunity evasion factors. These strains with enhanced capacity of innate immunity evasion take survival advantage in vivo.(4) GAS which succeeds in immunity evasion diffuses into the blood and cause invasive disease.
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