四株不同动物来源弓形虫感染小鼠和鸡免疫病理变化的比较研究
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摘要
弓形虫病(Toxoplasmosis)是由刚地弓形虫(Toxoplasma gondii)引起的一种危害严重的人兽共患寄生虫病,在世界上分布广泛,大约有25%-50%的人受到感染。弓形虫的宿主非常广泛,猫科动物是其唯一的终末宿主,绝大多数温血动物均可作为该病原的中间宿主,然而不同宿主对弓形虫的易感性及转归均有不同。小鼠对其极为敏感,可引起急性的致死性感染因而常常作为弓形虫急性感染的动物模型；而鸡由于对弓形虫的感染不表现任何临床症状,被认为是不敏感的中间宿主。为了探寻这两种动物感染弓形虫后免疫病理学变化的差异,同时针对同一宿主对不同动物来源的弓形虫虫株感染后的免疫病理变化进行比较研究,特进行了如下工作：
1.猫源弓形虫虫株的分离及其与鸡源、猪源和人源虫株基因型的鉴定
对江苏南京地区11只家猫进行弓形虫抗体IgG的检测,筛选抗体阳性猫进行虫株的分离。利用盐酸-胃蛋白酶消化法处理阳性猫的心、脑、舌等组织,制成组织悬液腹腔接种小鼠,通过连续传代,分离到2株弓形虫虫株,分别命名为CAT2和CAT3。进而利用PCR-RFLP方法,对分离到的猫源虫株以及实验室保存的鸡源(JS)、猪源(CN)和人源(RH)共5株弓形虫虫株进行了基因型的鉴定,通过对7个等位基因5'-SAG2,3'-SAG2, SAG3, BTUB, GRA6, cB21-4和L358的扩增和酶切,证明此5株弓形虫虫株均为基因Ⅰ型。
2.四种不同来源弓形虫虫株对小鼠和鸡致病力的比较
小鼠对弓形虫非常敏感,而鸡通常不敏感。本研究对四种不同来源的5个虫株RH, CN, JS, CAT2和CAT3对鸡和小鼠的致病力分别进行比较,同时建立弓形虫感染雏鸡的动物模型。210只10日龄雏鸡分为21个组,每组10只,5个虫株RH,CN,JS,CAT2和CAT3按照5×108,1×108,1×107,和1×106不同剂量腹腔感染10日龄雏鸡,同时设阴性对照组,仅注射生理盐水；感染后每日观察实验鸡的临床症状,逐只测量直肠温度,记录每组鸡的死亡情况；利用PCR方法对53天未死亡的鸡进行检测,对急性死亡和53天未死亡的鸡进行病理组织切片,观察病理变化。对小鼠致病力的对比试验选用腹腔感染和灌胃感染两种途径,分别选用260只ICR小鼠,随机分为26个组,每组10只,按照不同的虫株选择1×105,1×104,1×103,1×102和1×101剂量进行感染,记录每只小鼠的存活时间；根据实验动物的存活时间对5个虫株的致病力进行比较。结果发现RH,CN, CAT2和CAT3四个虫株对小鼠和鸡的致病力无显著差异,而JS株对小鼠的致病力较弱,但对鸡的致病力较强,这说明虫株的来源对弓形虫的致病性具有重要的影响。同时发现1×107剂量的速殖子腹腔感染10日龄雏鸡,既能产生适度的临床症状,又能够使实验动物避免死亡,可作为弓形虫体内感染雏鸡的动物模型。综合考虑小鼠的感染率、存活时间以及感染过程中的偶然因素,发现1×102腹腔感染和1×104灌胃感染是小鼠模型的最佳感染剂量。
3.四种不同来源弓形虫虫株腹腔感染小鼠免疫病理变化的比较
本实验将JS、CAT、CN和RH弓形虫虫株腹腔感染小鼠,对小鼠感染弓形虫后的免疫病理变化进行比较。200只小鼠(18。22g)随机分成5个组,每组40只,分别命名为JS, CAT, CN, RH和阴性对照组,四个虫株JS、CAT、CN和RH的速殖子按1×102的剂量腹腔感染小鼠,阴性对照组仅注射PBS。感染后分别在第0天,3天,6天和8天采血和脾脏用于分离血清和脾脏淋巴细胞,每组10只。弓形虫循环抗原和特异性抗体(IgA,IgG, IgM和IgG的亚型IgGl、IgG2a、IgG2b和IgG3)利用ELISA方法进行检测；脾脏淋巴细胞中CD4+、CD8+T细胞和NK细胞以及MHC Ⅰ和MHC Ⅱ类分子的变化利用流式技术进行检测；细胞因子IFN-γ, IL-12, IL-4, IL-10和IL-17利用ELISA方法进行检测；血清铁、血清中NO和iNOS的活性利用比色法进行检测。感染后第6天能够检测到IgM并持续至第8天；感染后第8天能检测到IgA,而IgG及其亚型均未检测到；CD4+, CD8+T和NK细胞分别在第6天、第3天和第3天显著上升,均在第8天时显著下降,在此时间点仅CN组CD4+T细胞显著高于阴性对照组,4个感染组CD8+T细胞虽下降但仍显著高于阴性对照组,RH、CN和CAT组NK细胞显著高于阴性对照组；MHC Ⅰ分子第6天显著上升但在第8天时下降,仅CAT组显著高于阴性对照组；MHC Ⅱ分子从第3天显著下降并持续至第8天仍显著低于阴性对照组；IFN-γ和IL-12在第6天显著上升均在第8天时下降,4个感染组IFN-γ在第8天仍显著高于阴性对照组,但JS组IL-12与阴性对照组无差异；IL-10和IL-4在第3天显著上升均在第6天时显著下降,4个感染组IL-10仍显著高于阴性对照组,但IL-4与阴性对照组无差异；IL-17在第6天显著上升并持续至第8天仍高于阴性对照组；感染后第3天可检测到高浓度的NO、血清铁以及高活力的iNOS,均在第6天达到最高峰而后下降,第8天时,仅CAT组NO显著高于阴性对照组,4个感染组的iNOS与阴性对照组之间差异不显著,但血清铁仍显著高于阴性对照组。这些结果反应了小鼠抗弓形虫腹腔感染而引起的免疫病理学变化,而不同来源虫株之间存在的差异可能与虫株的生物学特性有关,说明虫株的来源对弓形虫免疫病理变化也具有重要的影响。
4.四种不同来源弓形虫虫株灌胃感染小鼠免疫病理变化的比较
本实验将JS、CAT、CN和RH弓形虫虫株灌胃感染小鼠,对小鼠感染弓形虫后的免疫病理变化进行比较。250只小鼠(18-22g)随机分成5个组,每组50只,分别命名为JS、CAT、CN、RH和阴性对照组,四个虫株JS、XAT、CN和RH的速殖子按1×104的剂量灌胃感染小鼠,阴性对照组仅灌服等量PBS。感染后分别在第0天,3天,6天,8天和10天采血和脾脏用于分离血清和脾脏淋巴细胞,每组10只。弓形虫循环抗原和特异性抗体(IgA、IgG、IgM和IgG的亚型IgG1、IgG2a、IgG2b和IgG3)利用ELISA方法进行检测；脾脏淋巴细胞中CD4+、CD8+T细胞和NK细胞以及MHCI和MHCⅡ类分子的变化利用流式技术进行检测；细胞因子IFN-γ， IL-12, IL-4, IL-10和IL-17利用ELISA方法进行检测；血清铁、血清中NO和iNOS的活性利用比色法进行检测。感染后第6天TCA阳性并持续至第10天；第10天时IgG显著上升并以IgG2a和IgG2b为主；IgA和IgM第6天时显著上升并持续至第10天；CD4+和CD8+T细胞第6天时开始显著上升,第8天达到高峰,各组CD4+T细胞在第10天下降,与阴性对照组无差异,而CD8+T细胞虽下降,但CN、CAT和JS仍显著高于阴性对照组；弓形虫感染后第3天,JS和CAT组NK细胞水平显著上升,第8天时,四个感染组均上升并持续至第10天；CAT组MHCI水平第3天显著上升,其余三个感染组无显著变化,第8天,四个感染组均显著上升,第10天时开始下降,但除JS组外,其余三个感染组仍显著高于阴性对照组；MHC Ⅱ分子在第3天显著下降并持续至第10天；感染后第6天,JS和CAT感染组组IFN-γ显著上升,第8天时,RH、CN和JS三个组显著上升,但CAT组下降,第10天时4个感染组均下降与阴性对照组无差异；RH和CAT组IL-12在感染后第3天显著上升,第6天时四个感染组均显著上升并持续至第8天,第10天时开始下降仅CAT组显著高于阴性对照组；RH和CAT组IL-4仅在第6天时显著上升；CN、JS和CAT组IL-17在第8天时显著上升而后开始下降,第10天时仅JS组显著高于阴性对照组；NO、血清铁和iNOS勺活力均在第3天开始显著上升并持续至第8天,第10天时下降与阴性对照组之间无差异。这些结果反应了小鼠弓形虫灌胃感染所引起的免疫病理变化。与腹腔感染小鼠相比,较晚出现的TCA,较早出现并且较高滴度的IgA以及产生的IgG说明腹腔感染和灌胃感染两种不同的感染途径影响免疫病理变化的产生。
5.四种不同来源弓形虫虫株腹腔感染鸡免疫病理变化的比较
本实验将JS、CAT、CN和RH弓形虫虫株腹腔感染雏鸡,对鸡感染弓形虫后的免疫病理变化进行比较。300只10日龄雏鸡随机分成5个组,每组60只,分别命名为JS,CAT, CN, RH和阴性对照组,JS、CAT、CN和RH的速殖子按1×107的剂量腹腔感染雏鸡,阴性对照组仅注射PBS。感染后分别在第0天,4天,11天,25天,39天和53天采血和脾脏,分离血清和脾脏淋巴细胞,每组取10只。弓形虫循环抗原和特异性的抗体(IgA,IgG和IgM)利用ELISA方法进行检测；脾脏淋巴细胞中CD4+,CD8+以及MHC Ⅰ和MHC Ⅱ类分子的变化利用流式技术进行检测；细胞因子IFN-γ,IL-12,IL-4,IL-10和IL-17利用ELISA方法进行检测；血清铁、血清中NO和iNOS的活性利用比色法进行检测；血细胞包括中性粒细胞、单核细胞和淋巴细胞利用血细胞分析仪直接测定。感染组高水平的IgM,IgG和IgA分别在感染后第4天,第11天和第11天出现,并持续至39、53和39天；不同感染组CD4+T细胞分别在第4天和第11天显著上升,至53天时与阴性对照组无显著差异；CD8+T细胞和MHC Ⅰ类分子在第4天显著上升,至53天时,CD8+T细胞仍显著高于阴性对照组,而MHC Ⅰ类分子在39天时与阴性对照组差异不显著；MHC Ⅱ类分子在第4天显著上升又在25天时显著下降,至53天时与阴性对照组差异不显著；IFN-γ, IL-12, IL-10和IL-17分别在感染后第4天显著上升,25天时,感染组IFN-γ和IL-10与阴性对照组差异不显著,而感染组IL-12至53天时仍显著高于阴性对照组,IL-17则无显著差异；4个感染组IL-4自始至终均无显著变化；感染组NO,血清铁以及iNOS的活力在第4天显著上升,又在第39天后与阴性对照组无显著差异。这些都反应了鸡感染弓形虫后的免疫病理学变化。与另外三个感染组相比,JS组具有更高水平的CD4+, CD8+T细胞,IFN-γ, IL-12, IL-10,NO和更高活力的iNOS,这说明其差异可能与虫株的来源有关。与腹腔感染小鼠的结果相比,IgG抗体的产生,感染早期显著上升的MHC Ⅱ,较早产生的IFN-γ, IL-12和IL-17以及无显著变化的IL-4有可能是造成鸡和小鼠对弓形虫易感性差异的原因,其确切机制仍需进一步研究。
Toxoplasmosis is a globally spread zoonosis which is caused by Toxoplasma gondii. It is estimated that around25%to50%of the world human population is carrying the parasite. T. gondii is remarkably known to have a wide range of hosts. Domestic cats and other felids are the definitive hosts, and virtually all warm blooded animals, including humans, are the intermediate hosts. The pathogenicity of T. gondii infection to most animals varies widely, ranging from inapparent infection to fatal disease conditions. It is well-known that mice are most susceptible to T. gondii and always act as an animal model of acute infection. While chickens were found to display the chronic type of infection without apparent clinical signs to toxoplasmosis, and considered to be a quite resistant intermediate host to T. gondii. To study the immunopathological changes of these two hosts trying to find why chickens are resistant to T. gondii, this research mainly focuses on the following:
1. Isolation of Toxoplasma gondii from cats in Jiangsu Province and identification of the genotype for the different original isolates by PCR-RFLP.
In this research,11cats from Nanjing Jiangsu Province were tested for IgG against Toxoplasma gondii. Positive cats were killed humanlly and hearts, brains and tongues of each cat were bioassayed for Toxoplasma gondii individually. Tissues of each cat were mixed with five volumes of acidic pepsin. After that, the samples were centrifuged, neutralized with1.2%sodium bicarbonate (pH8.3), mixed with antibiotics (ampicillin and gentamycin sulfate). And then lml of tissue homogenate was inoculated intraperitoneally into each of six mice. At the third blind passages of the survived mice, two strains of T. gondii were isolated from cats No.2and No.3and named CAT2and CAT3. These two isolates and other three chicken (named JS), swine (named CN) and human (named RH) original Toxoplasma gondii isolates were identified by PCR-RFLP method. Seven genetic markers (5'-SAG2,3'-SAG2, SAG3, cB21-4, L358, BTUB and GRA6) of the five isolates were obtained by PCR. Digestion of these seven loci with appropriate endonucleases revealed that these isolates had the common haplotype to the type I lineage.
2. The pathogenicity of four isolates of T. gondii from different animals in chickens and mice
The pathogenicity of T. gondii infection to mice and chickens varies widely. Mice are susceptible while chickens are not. In this study, five isolates (RH, CN, JS, CAT2and CAT3) of T. gondii which well conserved in liquid nitrogen in Laboratory of Veterinary Molecular and Immunological Parasitology, Nanjing Agricultural University, China were used to study the pathogenicity on chickens and mice, respectively, and to construct the animal model which infected on the broiler chickens. Two-hundred and ten chickens aging10-day-old were allocated into21groups of10chickens each. The chickens were infected intraperitoneally with these five isolates with different dosages (5×108,1×108,1×107and1×106). The negative control (-Ve) group was mockly inoculated with physiological saline alone. After that, clinical symptoms and the rectal temperatures of the chickens were checked every day. The died cases during acute phage were checked for T.gondii tachyzoites by making wet smears after necropsy. And the living cases were detected for the infection situation of T. gondii at day53by PCR method. Histopathological sections were used to observe the pathological changes in the died chickens during acute phage and the living animals at day53. For the study of pathogenicity in mice, two routes of infection were used. For one route,260ICR mice were allocated into26groups of10mice each. The mice were infected intraperitoneally and intragastrically with the tachyzoites of these five isolates, respectively. The infection doses were1×105,1×104,1×103,1×102and1×101, respectively. The survival time of each mouse was recorded post inoculation. Results show that no significant differences of pathogenicity were found in chickens and mice among the RH, CN, CAT2and CAT3isolates while the pathogenicity of JS isolate was weak to the mice but comparatively strong to the chicken. These findings suggested that the differences might be related to the sources of the isolate origin. However, the exact mechanisms of them need to be further investigated. Meanwhile, inoculation intraperitoneally at the dosage of1×107tachyzoites on the ten days old chickens can effectively infect the chickens, making them display moderate clinical signs and at the same time stimulate a proper immunopathological changes beside avoidance of losing them during the experiment suggesting that it is a suitable model to study the in vivo infection of T. gondii on chickens. Considering the infection rate, survival time and the causal factors during the infection of mice, it was found that1×102intraperitoneally injected and1×104intragastrically delievered were the suitable dosages to experimentally infect the mice model in this study.
3. Comparisons of immunopathological changes of four isolates of Toxoplasma gondii from different animals intraperitoneally infected in mice
A total of200,(18-22g) mice were allocated randomly into5groups which named JS, CAT, CN, RH and a negative control group (-Ve) with40mice in each group. Tachyzoites of four different T. gondii isolates JS, CAT, CN and RH were inoculated intraperitoneally with the dose of1×102in the four designed groups, respectively. The negative control (-Ve) group was mockly inoculated with PBS alone. Blood and spleen samples were obtained on the day of inoculation (day0) and at days3,6and8post-infection to screen the immune responses. Toxoplasma circulating antigens (TCA) and T. gondii specific antibodies (IgA, IgG, IgE, IgM and subsets of IgG) in the serum were detected by enzyme-linked immunosorbent assay (ELISA) method. Subsets of T-lymphocytes (CD4+and CD8+), NK cells and major histocompatibility complex (MHC) molecules (MHC-I and MHC-II) from spleen cells were analyzed by flow cytometric method. The kinetics of cytokines (IFN-y, IL-12, IL-4, IL-10and IL-17) were evaluated by ELISA method. Serum iron, serum nitric oxide (NO) and inducible nitric oxide synthase (iNOS) activity changes were detected by colorimetric technique. IgM specific antibody to T. gondii was first to be found at day6and this level was kept untill the end of the experiment, meanwhile IgA was first detected at day8. However, no specific IgG, subsets of IgG and IgE antibodies were found during the experiment. Flow cytometric analysis indicated that increases of CD4+, CD8+T lymphocytes and NK cells in the four infected groups at days6,3and3, respectively. Thereafter, all these three factors were dropped at day8. For CD4+T lymphocytes, only CN group was showed a significant increase compared to the negative control group, while RH, CN and CAT groups were significantly higher for NK cells.However, all these four infected groups were significantly higher than the negative control group for CD8+T lymphocytes at this timepoint. MHC class I increased in the four infected groups at day6and decreased at day8while MHC class II was down-regulated from day3to8in the four infected groups but no significant differences were shown among the four infected groups. Increases in expression of IFN-y and IL-12were detected in the four infected groups at day6and decreased at day8. However, the levels of IFN-y in the four infected groups were still higher than the negative control group but only RH, CN and CAT groups showed higher levels of IL-12. Notable increases of IL-10and IL-4in the infected groups were found at day3, but dropped at day6. At this time, the levels of IL-10were still higher than the negative control group but IL-4was not. Levels of IL-17were increased markedly at day6 and kept the high levels to the day8of the experiment. A significant increase in the concentration of NO, serum iron and the activity of iNOS were observed in the infected groups at day3, and reached the peaks at day6. After that, concentrations of serum iron in the four targeted groups and the concentration of NO in CAT group were significantly higher than the negative control group at day8. However, no significant differences regarding the activity of iNOS were found in these four infected groups. These findings might partially be explain the immunopathological changes through which T. gondii infect mice. Differences of the detected markers among the four isolates suggested that the bionomic characteristics of varied origin isolates might be present variance when infected the certain host.
4. Comparisons of immunopathological changes of four isolates of Toxoplasma gondii from different animals intragastrically infected in mice
A total of250,(18-22g) mice were allocated randomly into5groups which named JS, CAT, CN, RH and a negative control group (-Ve) with50mice in each group. Tachyzoites of four different T. gondii isolates JS, CAT, CN and RH were inoculated intragastrically with the dose of1×104in the four designed groups, respectively. The negative control (-Ve) group was mockly inoculated with PBS alone. Blood and spleen samples were obtained on the day of inoculation (day0) and at days3,6,8and10post-infection to screen the immune responses. Toxoplasma circulating antigens (TCA) and T. gondii specific antibodies (IgA, IgG, IgE, IgM and subsets of IgG) in the serum were detected by ELISA method. Subsets of T-lymphocytes (CD4+and CD8+), NK cells and major histocompatibility complex (MHC) molecules (MHC-Ⅰ and MHC-Ⅱ) from spleen cells were analyzed by flow cytometric method. The kinetics of cytokines (IFN-y, IL-12, IL-4, IL-10and IL-17) were evaluated by ELISA method. Serum iron, serum nitric oxide (NO) and inducible nitric oxide synthase (iNOS) activity changes were detected by colorimetric technique. All the animals in the four infected groups were positive in TCA at day6and the high levels were kept untill the end of the experiment. IgG specific antibody to T. gondii was first to be detected at day10and the subsets IgG2a and IgG2b were both found while IgGl and IgG3were not. IgA and IgM antibodies were first to be found at day6and kept the high levels till day10without any significant differences among the four infected groups. Flow cytometric analysis indicated that increases of CD4+and CD8+T lymphocytes in the four infected groups at day6and they reached the peaks at day8. At day10, the levels of CD4+in the four infected groups were decreased without any significant differences compared to the negative control group. However, the levels of CD8+in CN, CAT and JS groups were still higher than the control negative. At day3, only JS and CAT groups were showed a markedly increase in NK cells while all the four infected groups were significantly higher than the negative control group from day8to10. Similar with NK cells, MHC class I molecules of CAT group were increased notablely at day3while all the four infected groups got the higher levels at day8. At day10, all the targeted groups except JS were still higher than the control negative. However, MHC class II molecules were down-regulated from day3to10without any significant differences among the four infected groups. Increases in expression of IFN-y were detected in the different infected groups at days6and8, respectively, and dropped to the level of negative control group at day10. For IL-12, levels of RH and CAT groups were started to increase at day3. However, at day6all the infected groups showed a significant increase. Except of CAT group, at day10, the levels of IL-12were dropped and showed no significance compared with the negative control group. For IL-4, only RH and CAT groups showed the significant increase at day6. IL-17of CN, JS and CAT groups was increased at day8and level declined at day10except JS group. A noteably increase in the concentrations of NO, serum iron and the activity of iNOS were observed in the infected groups at day3and kept the levels to day8. While no significant differences were found at day10when compared to the negative control group. These findings might partially explain the immunopathological changes through which T. gondii infect mice. When compared with the results of intraperitoneally infected mice, positive response of IgG antibody, higher titres and early expressed of IgA and delayed TCA might be present variance when using different routes to establish an infection with T. gondii.
5. Comparisons of the immunopathological changes with four different isolates of Toxoplasma gondii in chickens
In this study,4isolates (JS, CAT, CN and RH) were used to compare the immunopathological changes in chickens and to investigate whether the origins of T. gondii could play some roles in the pathogenicities of T. gondii and the susceptibilities of different animals. A total of300,10-day-old chickens were allocated randomly into five groups which named JS, CAT, CN, RH and a negative control group (-Ve) with sixty birds in each group. Tachyzoites of JS, CAT, CN and RH were inoculated intraperitoneally with the dose of1×107in the four designed groups, respectively. The negative control (-Ve) group was mockly inoculated with PBS alone. Blood and spleen samples were obtained on the day of inoculation (day O) and at days4,11,25,39and53post-infection to screen the immunopathological changes. Toxoplasma gondii circulating antigens (TCA) and T. gondii specific antibodies (IgA, IgG and IgM) in the serum were detected by ELISA method. Subsets of T-lymphocytes (CD4+and CD8+) and major histocompatibility complex (MHC) molecules (MHC-Ⅰ and MHC-Ⅱ) from spleen cells were analyzed by flow cytometric method. The kinetics of cytokines (IFN-y, IL-12, IL-4, IL-10and IL-17), serum iron, serum nitric oxide (NO) and inducible nitric oxide synthase (iNOS) activity changes were evaluated by ELISA method. Differential cell counts including neutrophils, lymphocytes and monocytes in the peripheral blood were carried out with an automated electronic cell Coulter counter. Higher levels of specifc IgA, IgG and IgM antibodies were detected in the targated groups. Increased CD4+and CD8+T cells, highly expressed MHC I molecules and up-regulated MHC Ⅱ molecules were noticed during the early stages of infection. However, MHC Ⅱ molecules was down-regulated after the the early stages. High concentrations of IFN-y, IL-12, IL-10and IL-17were also observed. Higher concentrations of NO, iron and high activity of iNOS were also noticed in the infected groups. These findings might partially explain the resistance to T. gondii infection in chickens. Compared to the other3isolates, JS group showed significant high levels of CD4+and CD8+T cells, high levels of IFN-y, IL-12, IL-10, high concentrations of NO and high activity of iNOS. These might be related to the sources of the isolates origins. When compared with the results of mice, positive response of IgG antibody, up-regulated MHC II molecules at the early stage of infection and early expressed of IFN-y and IL-12might be the reasons for the sensitive differences of chicken and mouse when infected with T. gondii.
1.猫源弓形虫虫株的分离及其与鸡源、猪源和人源虫株基因型的鉴定
对江苏南京地区11只家猫进行弓形虫抗体IgG的检测,筛选抗体阳性猫进行虫株的分离。利用盐酸-胃蛋白酶消化法处理阳性猫的心、脑、舌等组织,制成组织悬液腹腔接种小鼠,通过连续传代,分离到2株弓形虫虫株,分别命名为CAT2和CAT3。进而利用PCR-RFLP方法,对分离到的猫源虫株以及实验室保存的鸡源(JS)、猪源(CN)和人源(RH)共5株弓形虫虫株进行了基因型的鉴定,通过对7个等位基因5'-SAG2,3'-SAG2, SAG3, BTUB, GRA6, cB21-4和L358的扩增和酶切,证明此5株弓形虫虫株均为基因Ⅰ型。
2.四种不同来源弓形虫虫株对小鼠和鸡致病力的比较
小鼠对弓形虫非常敏感,而鸡通常不敏感。本研究对四种不同来源的5个虫株RH, CN, JS, CAT2和CAT3对鸡和小鼠的致病力分别进行比较,同时建立弓形虫感染雏鸡的动物模型。210只10日龄雏鸡分为21个组,每组10只,5个虫株RH,CN,JS,CAT2和CAT3按照5×108,1×108,1×107,和1×106不同剂量腹腔感染10日龄雏鸡,同时设阴性对照组,仅注射生理盐水；感染后每日观察实验鸡的临床症状,逐只测量直肠温度,记录每组鸡的死亡情况；利用PCR方法对53天未死亡的鸡进行检测,对急性死亡和53天未死亡的鸡进行病理组织切片,观察病理变化。对小鼠致病力的对比试验选用腹腔感染和灌胃感染两种途径,分别选用260只ICR小鼠,随机分为26个组,每组10只,按照不同的虫株选择1×105,1×104,1×103,1×102和1×101剂量进行感染,记录每只小鼠的存活时间；根据实验动物的存活时间对5个虫株的致病力进行比较。结果发现RH,CN, CAT2和CAT3四个虫株对小鼠和鸡的致病力无显著差异,而JS株对小鼠的致病力较弱,但对鸡的致病力较强,这说明虫株的来源对弓形虫的致病性具有重要的影响。同时发现1×107剂量的速殖子腹腔感染10日龄雏鸡,既能产生适度的临床症状,又能够使实验动物避免死亡,可作为弓形虫体内感染雏鸡的动物模型。综合考虑小鼠的感染率、存活时间以及感染过程中的偶然因素,发现1×102腹腔感染和1×104灌胃感染是小鼠模型的最佳感染剂量。
3.四种不同来源弓形虫虫株腹腔感染小鼠免疫病理变化的比较
本实验将JS、CAT、CN和RH弓形虫虫株腹腔感染小鼠,对小鼠感染弓形虫后的免疫病理变化进行比较。200只小鼠(18。22g)随机分成5个组,每组40只,分别命名为JS, CAT, CN, RH和阴性对照组,四个虫株JS、CAT、CN和RH的速殖子按1×102的剂量腹腔感染小鼠,阴性对照组仅注射PBS。感染后分别在第0天,3天,6天和8天采血和脾脏用于分离血清和脾脏淋巴细胞,每组10只。弓形虫循环抗原和特异性抗体(IgA,IgG, IgM和IgG的亚型IgGl、IgG2a、IgG2b和IgG3)利用ELISA方法进行检测；脾脏淋巴细胞中CD4+、CD8+T细胞和NK细胞以及MHC Ⅰ和MHC Ⅱ类分子的变化利用流式技术进行检测；细胞因子IFN-γ, IL-12, IL-4, IL-10和IL-17利用ELISA方法进行检测；血清铁、血清中NO和iNOS的活性利用比色法进行检测。感染后第6天能够检测到IgM并持续至第8天；感染后第8天能检测到IgA,而IgG及其亚型均未检测到；CD4+, CD8+T和NK细胞分别在第6天、第3天和第3天显著上升,均在第8天时显著下降,在此时间点仅CN组CD4+T细胞显著高于阴性对照组,4个感染组CD8+T细胞虽下降但仍显著高于阴性对照组,RH、CN和CAT组NK细胞显著高于阴性对照组；MHC Ⅰ分子第6天显著上升但在第8天时下降,仅CAT组显著高于阴性对照组；MHC Ⅱ分子从第3天显著下降并持续至第8天仍显著低于阴性对照组；IFN-γ和IL-12在第6天显著上升均在第8天时下降,4个感染组IFN-γ在第8天仍显著高于阴性对照组,但JS组IL-12与阴性对照组无差异；IL-10和IL-4在第3天显著上升均在第6天时显著下降,4个感染组IL-10仍显著高于阴性对照组,但IL-4与阴性对照组无差异；IL-17在第6天显著上升并持续至第8天仍高于阴性对照组；感染后第3天可检测到高浓度的NO、血清铁以及高活力的iNOS,均在第6天达到最高峰而后下降,第8天时,仅CAT组NO显著高于阴性对照组,4个感染组的iNOS与阴性对照组之间差异不显著,但血清铁仍显著高于阴性对照组。这些结果反应了小鼠抗弓形虫腹腔感染而引起的免疫病理学变化,而不同来源虫株之间存在的差异可能与虫株的生物学特性有关,说明虫株的来源对弓形虫免疫病理变化也具有重要的影响。
4.四种不同来源弓形虫虫株灌胃感染小鼠免疫病理变化的比较
本实验将JS、CAT、CN和RH弓形虫虫株灌胃感染小鼠,对小鼠感染弓形虫后的免疫病理变化进行比较。250只小鼠(18-22g)随机分成5个组,每组50只,分别命名为JS、CAT、CN、RH和阴性对照组,四个虫株JS、XAT、CN和RH的速殖子按1×104的剂量灌胃感染小鼠,阴性对照组仅灌服等量PBS。感染后分别在第0天,3天,6天,8天和10天采血和脾脏用于分离血清和脾脏淋巴细胞,每组10只。弓形虫循环抗原和特异性抗体(IgA、IgG、IgM和IgG的亚型IgG1、IgG2a、IgG2b和IgG3)利用ELISA方法进行检测；脾脏淋巴细胞中CD4+、CD8+T细胞和NK细胞以及MHCI和MHCⅡ类分子的变化利用流式技术进行检测；细胞因子IFN-γ， IL-12, IL-4, IL-10和IL-17利用ELISA方法进行检测；血清铁、血清中NO和iNOS的活性利用比色法进行检测。感染后第6天TCA阳性并持续至第10天；第10天时IgG显著上升并以IgG2a和IgG2b为主；IgA和IgM第6天时显著上升并持续至第10天；CD4+和CD8+T细胞第6天时开始显著上升,第8天达到高峰,各组CD4+T细胞在第10天下降,与阴性对照组无差异,而CD8+T细胞虽下降,但CN、CAT和JS仍显著高于阴性对照组；弓形虫感染后第3天,JS和CAT组NK细胞水平显著上升,第8天时,四个感染组均上升并持续至第10天；CAT组MHCI水平第3天显著上升,其余三个感染组无显著变化,第8天,四个感染组均显著上升,第10天时开始下降,但除JS组外,其余三个感染组仍显著高于阴性对照组；MHC Ⅱ分子在第3天显著下降并持续至第10天；感染后第6天,JS和CAT感染组组IFN-γ显著上升,第8天时,RH、CN和JS三个组显著上升,但CAT组下降,第10天时4个感染组均下降与阴性对照组无差异；RH和CAT组IL-12在感染后第3天显著上升,第6天时四个感染组均显著上升并持续至第8天,第10天时开始下降仅CAT组显著高于阴性对照组；RH和CAT组IL-4仅在第6天时显著上升；CN、JS和CAT组IL-17在第8天时显著上升而后开始下降,第10天时仅JS组显著高于阴性对照组；NO、血清铁和iNOS勺活力均在第3天开始显著上升并持续至第8天,第10天时下降与阴性对照组之间无差异。这些结果反应了小鼠弓形虫灌胃感染所引起的免疫病理变化。与腹腔感染小鼠相比,较晚出现的TCA,较早出现并且较高滴度的IgA以及产生的IgG说明腹腔感染和灌胃感染两种不同的感染途径影响免疫病理变化的产生。
5.四种不同来源弓形虫虫株腹腔感染鸡免疫病理变化的比较
本实验将JS、CAT、CN和RH弓形虫虫株腹腔感染雏鸡,对鸡感染弓形虫后的免疫病理变化进行比较。300只10日龄雏鸡随机分成5个组,每组60只,分别命名为JS,CAT, CN, RH和阴性对照组,JS、CAT、CN和RH的速殖子按1×107的剂量腹腔感染雏鸡,阴性对照组仅注射PBS。感染后分别在第0天,4天,11天,25天,39天和53天采血和脾脏,分离血清和脾脏淋巴细胞,每组取10只。弓形虫循环抗原和特异性的抗体(IgA,IgG和IgM)利用ELISA方法进行检测；脾脏淋巴细胞中CD4+,CD8+以及MHC Ⅰ和MHC Ⅱ类分子的变化利用流式技术进行检测；细胞因子IFN-γ,IL-12,IL-4,IL-10和IL-17利用ELISA方法进行检测；血清铁、血清中NO和iNOS的活性利用比色法进行检测；血细胞包括中性粒细胞、单核细胞和淋巴细胞利用血细胞分析仪直接测定。感染组高水平的IgM,IgG和IgA分别在感染后第4天,第11天和第11天出现,并持续至39、53和39天；不同感染组CD4+T细胞分别在第4天和第11天显著上升,至53天时与阴性对照组无显著差异；CD8+T细胞和MHC Ⅰ类分子在第4天显著上升,至53天时,CD8+T细胞仍显著高于阴性对照组,而MHC Ⅰ类分子在39天时与阴性对照组差异不显著；MHC Ⅱ类分子在第4天显著上升又在25天时显著下降,至53天时与阴性对照组差异不显著；IFN-γ, IL-12, IL-10和IL-17分别在感染后第4天显著上升,25天时,感染组IFN-γ和IL-10与阴性对照组差异不显著,而感染组IL-12至53天时仍显著高于阴性对照组,IL-17则无显著差异；4个感染组IL-4自始至终均无显著变化；感染组NO,血清铁以及iNOS的活力在第4天显著上升,又在第39天后与阴性对照组无显著差异。这些都反应了鸡感染弓形虫后的免疫病理学变化。与另外三个感染组相比,JS组具有更高水平的CD4+, CD8+T细胞,IFN-γ, IL-12, IL-10,NO和更高活力的iNOS,这说明其差异可能与虫株的来源有关。与腹腔感染小鼠的结果相比,IgG抗体的产生,感染早期显著上升的MHC Ⅱ,较早产生的IFN-γ, IL-12和IL-17以及无显著变化的IL-4有可能是造成鸡和小鼠对弓形虫易感性差异的原因,其确切机制仍需进一步研究。
Toxoplasmosis is a globally spread zoonosis which is caused by Toxoplasma gondii. It is estimated that around25%to50%of the world human population is carrying the parasite. T. gondii is remarkably known to have a wide range of hosts. Domestic cats and other felids are the definitive hosts, and virtually all warm blooded animals, including humans, are the intermediate hosts. The pathogenicity of T. gondii infection to most animals varies widely, ranging from inapparent infection to fatal disease conditions. It is well-known that mice are most susceptible to T. gondii and always act as an animal model of acute infection. While chickens were found to display the chronic type of infection without apparent clinical signs to toxoplasmosis, and considered to be a quite resistant intermediate host to T. gondii. To study the immunopathological changes of these two hosts trying to find why chickens are resistant to T. gondii, this research mainly focuses on the following:
1. Isolation of Toxoplasma gondii from cats in Jiangsu Province and identification of the genotype for the different original isolates by PCR-RFLP.
In this research,11cats from Nanjing Jiangsu Province were tested for IgG against Toxoplasma gondii. Positive cats were killed humanlly and hearts, brains and tongues of each cat were bioassayed for Toxoplasma gondii individually. Tissues of each cat were mixed with five volumes of acidic pepsin. After that, the samples were centrifuged, neutralized with1.2%sodium bicarbonate (pH8.3), mixed with antibiotics (ampicillin and gentamycin sulfate). And then lml of tissue homogenate was inoculated intraperitoneally into each of six mice. At the third blind passages of the survived mice, two strains of T. gondii were isolated from cats No.2and No.3and named CAT2and CAT3. These two isolates and other three chicken (named JS), swine (named CN) and human (named RH) original Toxoplasma gondii isolates were identified by PCR-RFLP method. Seven genetic markers (5'-SAG2,3'-SAG2, SAG3, cB21-4, L358, BTUB and GRA6) of the five isolates were obtained by PCR. Digestion of these seven loci with appropriate endonucleases revealed that these isolates had the common haplotype to the type I lineage.
2. The pathogenicity of four isolates of T. gondii from different animals in chickens and mice
The pathogenicity of T. gondii infection to mice and chickens varies widely. Mice are susceptible while chickens are not. In this study, five isolates (RH, CN, JS, CAT2and CAT3) of T. gondii which well conserved in liquid nitrogen in Laboratory of Veterinary Molecular and Immunological Parasitology, Nanjing Agricultural University, China were used to study the pathogenicity on chickens and mice, respectively, and to construct the animal model which infected on the broiler chickens. Two-hundred and ten chickens aging10-day-old were allocated into21groups of10chickens each. The chickens were infected intraperitoneally with these five isolates with different dosages (5×108,1×108,1×107and1×106). The negative control (-Ve) group was mockly inoculated with physiological saline alone. After that, clinical symptoms and the rectal temperatures of the chickens were checked every day. The died cases during acute phage were checked for T.gondii tachyzoites by making wet smears after necropsy. And the living cases were detected for the infection situation of T. gondii at day53by PCR method. Histopathological sections were used to observe the pathological changes in the died chickens during acute phage and the living animals at day53. For the study of pathogenicity in mice, two routes of infection were used. For one route,260ICR mice were allocated into26groups of10mice each. The mice were infected intraperitoneally and intragastrically with the tachyzoites of these five isolates, respectively. The infection doses were1×105,1×104,1×103,1×102and1×101, respectively. The survival time of each mouse was recorded post inoculation. Results show that no significant differences of pathogenicity were found in chickens and mice among the RH, CN, CAT2and CAT3isolates while the pathogenicity of JS isolate was weak to the mice but comparatively strong to the chicken. These findings suggested that the differences might be related to the sources of the isolate origin. However, the exact mechanisms of them need to be further investigated. Meanwhile, inoculation intraperitoneally at the dosage of1×107tachyzoites on the ten days old chickens can effectively infect the chickens, making them display moderate clinical signs and at the same time stimulate a proper immunopathological changes beside avoidance of losing them during the experiment suggesting that it is a suitable model to study the in vivo infection of T. gondii on chickens. Considering the infection rate, survival time and the causal factors during the infection of mice, it was found that1×102intraperitoneally injected and1×104intragastrically delievered were the suitable dosages to experimentally infect the mice model in this study.
3. Comparisons of immunopathological changes of four isolates of Toxoplasma gondii from different animals intraperitoneally infected in mice
A total of200,(18-22g) mice were allocated randomly into5groups which named JS, CAT, CN, RH and a negative control group (-Ve) with40mice in each group. Tachyzoites of four different T. gondii isolates JS, CAT, CN and RH were inoculated intraperitoneally with the dose of1×102in the four designed groups, respectively. The negative control (-Ve) group was mockly inoculated with PBS alone. Blood and spleen samples were obtained on the day of inoculation (day0) and at days3,6and8post-infection to screen the immune responses. Toxoplasma circulating antigens (TCA) and T. gondii specific antibodies (IgA, IgG, IgE, IgM and subsets of IgG) in the serum were detected by enzyme-linked immunosorbent assay (ELISA) method. Subsets of T-lymphocytes (CD4+and CD8+), NK cells and major histocompatibility complex (MHC) molecules (MHC-I and MHC-II) from spleen cells were analyzed by flow cytometric method. The kinetics of cytokines (IFN-y, IL-12, IL-4, IL-10and IL-17) were evaluated by ELISA method. Serum iron, serum nitric oxide (NO) and inducible nitric oxide synthase (iNOS) activity changes were detected by colorimetric technique. IgM specific antibody to T. gondii was first to be found at day6and this level was kept untill the end of the experiment, meanwhile IgA was first detected at day8. However, no specific IgG, subsets of IgG and IgE antibodies were found during the experiment. Flow cytometric analysis indicated that increases of CD4+, CD8+T lymphocytes and NK cells in the four infected groups at days6,3and3, respectively. Thereafter, all these three factors were dropped at day8. For CD4+T lymphocytes, only CN group was showed a significant increase compared to the negative control group, while RH, CN and CAT groups were significantly higher for NK cells.However, all these four infected groups were significantly higher than the negative control group for CD8+T lymphocytes at this timepoint. MHC class I increased in the four infected groups at day6and decreased at day8while MHC class II was down-regulated from day3to8in the four infected groups but no significant differences were shown among the four infected groups. Increases in expression of IFN-y and IL-12were detected in the four infected groups at day6and decreased at day8. However, the levels of IFN-y in the four infected groups were still higher than the negative control group but only RH, CN and CAT groups showed higher levels of IL-12. Notable increases of IL-10and IL-4in the infected groups were found at day3, but dropped at day6. At this time, the levels of IL-10were still higher than the negative control group but IL-4was not. Levels of IL-17were increased markedly at day6 and kept the high levels to the day8of the experiment. A significant increase in the concentration of NO, serum iron and the activity of iNOS were observed in the infected groups at day3, and reached the peaks at day6. After that, concentrations of serum iron in the four targeted groups and the concentration of NO in CAT group were significantly higher than the negative control group at day8. However, no significant differences regarding the activity of iNOS were found in these four infected groups. These findings might partially be explain the immunopathological changes through which T. gondii infect mice. Differences of the detected markers among the four isolates suggested that the bionomic characteristics of varied origin isolates might be present variance when infected the certain host.
4. Comparisons of immunopathological changes of four isolates of Toxoplasma gondii from different animals intragastrically infected in mice
A total of250,(18-22g) mice were allocated randomly into5groups which named JS, CAT, CN, RH and a negative control group (-Ve) with50mice in each group. Tachyzoites of four different T. gondii isolates JS, CAT, CN and RH were inoculated intragastrically with the dose of1×104in the four designed groups, respectively. The negative control (-Ve) group was mockly inoculated with PBS alone. Blood and spleen samples were obtained on the day of inoculation (day0) and at days3,6,8and10post-infection to screen the immune responses. Toxoplasma circulating antigens (TCA) and T. gondii specific antibodies (IgA, IgG, IgE, IgM and subsets of IgG) in the serum were detected by ELISA method. Subsets of T-lymphocytes (CD4+and CD8+), NK cells and major histocompatibility complex (MHC) molecules (MHC-Ⅰ and MHC-Ⅱ) from spleen cells were analyzed by flow cytometric method. The kinetics of cytokines (IFN-y, IL-12, IL-4, IL-10and IL-17) were evaluated by ELISA method. Serum iron, serum nitric oxide (NO) and inducible nitric oxide synthase (iNOS) activity changes were detected by colorimetric technique. All the animals in the four infected groups were positive in TCA at day6and the high levels were kept untill the end of the experiment. IgG specific antibody to T. gondii was first to be detected at day10and the subsets IgG2a and IgG2b were both found while IgGl and IgG3were not. IgA and IgM antibodies were first to be found at day6and kept the high levels till day10without any significant differences among the four infected groups. Flow cytometric analysis indicated that increases of CD4+and CD8+T lymphocytes in the four infected groups at day6and they reached the peaks at day8. At day10, the levels of CD4+in the four infected groups were decreased without any significant differences compared to the negative control group. However, the levels of CD8+in CN, CAT and JS groups were still higher than the control negative. At day3, only JS and CAT groups were showed a markedly increase in NK cells while all the four infected groups were significantly higher than the negative control group from day8to10. Similar with NK cells, MHC class I molecules of CAT group were increased notablely at day3while all the four infected groups got the higher levels at day8. At day10, all the targeted groups except JS were still higher than the control negative. However, MHC class II molecules were down-regulated from day3to10without any significant differences among the four infected groups. Increases in expression of IFN-y were detected in the different infected groups at days6and8, respectively, and dropped to the level of negative control group at day10. For IL-12, levels of RH and CAT groups were started to increase at day3. However, at day6all the infected groups showed a significant increase. Except of CAT group, at day10, the levels of IL-12were dropped and showed no significance compared with the negative control group. For IL-4, only RH and CAT groups showed the significant increase at day6. IL-17of CN, JS and CAT groups was increased at day8and level declined at day10except JS group. A noteably increase in the concentrations of NO, serum iron and the activity of iNOS were observed in the infected groups at day3and kept the levels to day8. While no significant differences were found at day10when compared to the negative control group. These findings might partially explain the immunopathological changes through which T. gondii infect mice. When compared with the results of intraperitoneally infected mice, positive response of IgG antibody, higher titres and early expressed of IgA and delayed TCA might be present variance when using different routes to establish an infection with T. gondii.
5. Comparisons of the immunopathological changes with four different isolates of Toxoplasma gondii in chickens
In this study,4isolates (JS, CAT, CN and RH) were used to compare the immunopathological changes in chickens and to investigate whether the origins of T. gondii could play some roles in the pathogenicities of T. gondii and the susceptibilities of different animals. A total of300,10-day-old chickens were allocated randomly into five groups which named JS, CAT, CN, RH and a negative control group (-Ve) with sixty birds in each group. Tachyzoites of JS, CAT, CN and RH were inoculated intraperitoneally with the dose of1×107in the four designed groups, respectively. The negative control (-Ve) group was mockly inoculated with PBS alone. Blood and spleen samples were obtained on the day of inoculation (day O) and at days4,11,25,39and53post-infection to screen the immunopathological changes. Toxoplasma gondii circulating antigens (TCA) and T. gondii specific antibodies (IgA, IgG and IgM) in the serum were detected by ELISA method. Subsets of T-lymphocytes (CD4+and CD8+) and major histocompatibility complex (MHC) molecules (MHC-Ⅰ and MHC-Ⅱ) from spleen cells were analyzed by flow cytometric method. The kinetics of cytokines (IFN-y, IL-12, IL-4, IL-10and IL-17), serum iron, serum nitric oxide (NO) and inducible nitric oxide synthase (iNOS) activity changes were evaluated by ELISA method. Differential cell counts including neutrophils, lymphocytes and monocytes in the peripheral blood were carried out with an automated electronic cell Coulter counter. Higher levels of specifc IgA, IgG and IgM antibodies were detected in the targated groups. Increased CD4+and CD8+T cells, highly expressed MHC I molecules and up-regulated MHC Ⅱ molecules were noticed during the early stages of infection. However, MHC Ⅱ molecules was down-regulated after the the early stages. High concentrations of IFN-y, IL-12, IL-10and IL-17were also observed. Higher concentrations of NO, iron and high activity of iNOS were also noticed in the infected groups. These findings might partially explain the resistance to T. gondii infection in chickens. Compared to the other3isolates, JS group showed significant high levels of CD4+and CD8+T cells, high levels of IFN-y, IL-12, IL-10, high concentrations of NO and high activity of iNOS. These might be related to the sources of the isolates origins. When compared with the results of mice, positive response of IgG antibody, up-regulated MHC II molecules at the early stage of infection and early expressed of IFN-y and IL-12might be the reasons for the sensitive differences of chicken and mouse when infected with T. gondii.
引文
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