• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    紅內期瘧疾疫苗的研究進展

    2011-08-15 00:44:39陳琳黃復生
    成都醫(yī)學院學報 2011年2期
    關鍵詞:陳琳第三軍醫(yī)大學教研室

    陳琳,黃復生

    (第三軍醫(yī)大學基礎部病原生物學教研室,重慶 400038)

    Background

    Malaria remains one of the global devastating infectious disease,and results in 300-500 million clinical cases and nearly one million deaths annually worldwide[1,2].There are five species of Plasmodium parasites transmitted to humans:P.falciparum,P.vivax,P.ovale,P.malariae and P.knowlesi.P.falciparum is associated with the great majority of morbidity and mortality in human parasite,whereas P.vivax causes considerable symptomatic disease.Malaria is a mosquito-borne disease,and the parasite's sporozoites(SPZ)invade blood vessels and are transported to the liver after bitten by infected Anopheles mosquitoes.Here they infect hepatocytes,replicate and form a liver stage(LS)that grows asymptomatically.The blood-stage of the lifecycle commences when merozoites are released from the individual hepatocyte and infect erythrocytes.Red blood cell invasion is thought to involve multi-step process that several proteins at the parasite and erythrocyte surface receptor-ligand interaction[3].Once inside the red blood cell,parasites are partially hidden from immune recognition because erythrocytes lack a nucleus and major histocompatibility complex molecules.The parasites express proteins on the surface of infected erythrocyte and exposed to the immune system.

    Human repeated exposure to malaria parasites can naturally acquire immune and predominantly target the blood-stage parasites[4,5].Humoral-and cell-mediated immune responses play crucial roles in protective immunity against malaria parasites.But the immune effector mechanisms and the correlates of protection are poorly understood.It is suggested by passive immunoglobulin-transfer studies that antibodies are crucial components in blood-stage protective immunity,which may play a role in preventing merozoites invasion,antibody-dependent cell-mediated cytotoxity and greater clearance of infected red blood cell[6].With the development of resistance of malaria parasites to drugs and resistance of mosquitoes to insecticides,a cheap,broadly protective malaria vaccine is urgently required.A high level of antigenic diversity,redundancy of parasite invasion pathways and mechanisms of immune evasion pose significant challenges for vaccine development.The purpose of this review is to focus on the development of blood-stage vaccines,the advantages and challenges of this approach,potential target antigens expressed in the blood-stage and future directions.

    1 Potential targets

    The greatest challenge for developing effective blood-stage vaccine is the antigen diversity and identification of potential targets[7,8].At present,Merozoite surface proteins,as initial attachment antigens,and whole blood-stage parasites are the most promising candidates in blood-stage vaccine.

    1.1 Merozoite surface protein 1(MSP1)

    MSP1 is GPI(glycosylphosphatidylinositol)anchored to the merozoite surface and a 200 kDa polymorphic protein which undergoes proteolytic processing into four fragments p83,p30,p38,and p42.MSP1-42 undergoes secondary processing into two fragments p19 and p33.MSP1,which is important for the invasion process of erythrocytes by merozoite,is considered a prime candidate antigen for a blood stage vaccine.Several lines of evidence indicated thatthe C-terminal region of MSP1(MSP1-19 and-42)demonstrated the high antigenicity,and the naturally acquired antibodies to the C-terminus can inhibit the erythrocyte invasion and MSP processing[9,10].Therefore,both MSP1-42 and MSP1-19 fragments are thought to be the most advanced candidates for MSP1 vaccine development.But anti-MSP1-42 sera demonstrated strain-specific protection for P.falciparum-Aotus challenge model,and a PhaseⅡb trial of MSP1-42 in Kenyan found no protective effect[11].Antigen diversity was thought to a be major reason of failure of the vaccine.The study of genetic diversity in coding regions of PvMSP1-42 showed that 19kDa fragment at amino acid level was highly conserved in Sri Lankan isolates,whereas 33kDa fragment demonstrated extensive genetic diversity[12].But the opposite pattern was observed in P.falciparum[13].These observations indicate that the immunological interference between epitopes of PvMSP1-19 and PvMSP1-33 may affect the protection of PvMSP1-42 vaccine and a vaccine based on PvMSP1-19 alone could be effective against P.vivax infections in Sri Lankan.However,the analysis of antibody responses to PfMSP1-19 variant forms suggested the presence of cross-reactive antibody responses and non-variant specific antibodies to PfMSP1-19 in I-ranian individual infected by P.falciparum.One variant of this antigen,especially Q/KNG/L,may be sufficient for developing a PfMSP1-19-based vaccine[14].A study by Woehlbier showed that antibody elicited by entire MSP molecule can efficiently inhibit parasite multiplication and RBC invasion.Moreover,anti-MSP-1D antibodies would provide cross-protection for FCB-1 strain,a representative of K1 prototype.This study may provide the possibility of developing a vaccine based on the fullsize MSP1[15].

    1.2 Merozoite surface protein 2

    Merozoite surface protein 2(MSP-2)is a highly polymorphic 45-53 kDa protein,which like MSP-1,is also GPI anchored to the merozoite surface.High IgG3 antibody titers to MSP2 suggested that the molecule might be involved in protective immunity against P.falciparum[16,17].The N-and C-terminal domains of two allelic families,3D7 and FC27,are highly conserved with a variable region composed of central repeat region.MSP-2 was an important component in Combination B,including full-length 3D7 MSP2,block 2,3 of MSP1 and ring-infected erythrocyte surface antigen(RESA)formulated with the Montanide ISA720[18].A phase I/IIb field trial involving 120 children living in an area of Papua New Guinea reported that parasite densities were significantly decreased(62%)in the vaccine recipients[19].Furthermore,the activity of MSP-2 subunit included in the vaccine couldn't pro-tect against MSP-2 allelic family(FC27),suggesting that the major component of protective effect in Combination B was MSP-2[20].T he success of Combination B makes it possible that MSP-2 may be the most promising candidate antigen.Inclusion of both allelic variant in MSP-based vaccine could give the higher protective efficacy.Flueck found that two MSP-2 long synthetic peptides(LSP),comprising the semi-conserved family-specific domain plus the C-terminal domain of the two allelic families,could yield high titer antibody responses,and the response was associated with protective effect[21].However,MSP-2 is an intrinsically unstructured protein,which contains a single intramolecular disulphide bond and lacks hydrophobic residues.The lack of the structure knowledge of MSP-2 is the major hurdle to presume that an MSP-2 fragment will be as effective as the fulllength protein to induce a high antibody response.

    1.3 Merozoite surface protein 3

    Merozoite surface protein 3(MSP-3)is associated with merozoite surface through the non-covalent linkages and has been suggested to be involved in erythrocyte binding,although its function is unknown[22].Structurally,the C-terminal domain containing leucine zipper sequence is entirely conserved,whereas N-terminal region comprised of three blocks of heptad repeats is relatively polymorphic,which define two allele classes termed 3D7 and K1[23].The naturally acquired MSP-specific IgG3 antibody has strong antiparasitic effect in P.falciparum infected children.The cytophilic antibodies inhibited intra-erythrocytic parasite growth in a monocyte-dependent manner[24].In ADCI assays,amino acid residues 194 to 257 in C-terminal domain have been shown to exert a strong inhibition activity against P.falciparum parasite growth.MSP-3,as a long synthetic peptide,underwent a Phase Ib clinical trial among Tanzanian children and Burkina Faso adult males.The result showed that the MSP3-LSP vaccine with two adjuvants,Montanide ISA and aluminium hydroxide,was safe and immunogenic even at low dose in a malaria-na?ve population.Further studies are to define the true protective effects through Phase II clinical trial[25,26].However,recent studies demonstrated that the N-terminal domain of PfMSP3 is significantly more immunogenic than the C-terminal region.Antibody responses to N-terminal domain were largely allele specific and no been found allele specific within each allele class.These data raise the possibility for development of any PfMSP3 N-terminal domain-based vaccine[27,28].

    1.4 Apical membrane antigen-1

    AMA1 is thought to play an essential role in erythrocyte invasion.However,it is highly polymorphic and allelic-specific antibodies are not cross-protective[29].AMA1-C1 contains sequences from the FVO and 3D7 allelic form,adjuvanted with alhydrogel,and has progressed though Phase I/II trial in Mali.But the antibody levels were not maintained.Adding CPG 7909 to the AMA1/Alhydrogel formulation can improve immunogenicity[30].A vaccine containing the FVO form with three different adjuvants,including Alhydrogel,Montanide ISA 720 and ASO2A,Phase I clinical trail is ongoing and the highest antibody response were induced by ASO2A formulations[31].

    1.5 P.falciparum erythrocyte membrane protein-1

    P.falciparum erythrocyte membrane protein-1(PfEMP1)family is expressed on the surface of infected erythrocytes.PfEMP1 is encoded by 60 or more var genes.And different var genes encode PfEMP1 variants with different antigenic properties[32].The extreme variability of this antigen is a challenge for the development of a highly effective vaccine.The success of a subunit vaccine depended on its ability to elicit cross-reactive responses to different variants.A specific variant of PfEMP1,VAR2CSA,is thought to mediate parasite sequestration in the placenta and less antigenically diverse than other PfEMP1 variants.T he antibody raised against VAR2CSA is cross-reactive with different placental-binding isolates,showing that the development of an effective vaccine based on the conversed epitopes of VAR2CSA is possible[33].

    2 Whole blood-stage parasites approach

    Owing to the success of radiation-attenuated sporozoite studies,the whole-parasite vaccine has regained attention.There is evidence that na?ve adult human volunteers infected with a low dose of live P.falciparum parastes can develop cell-mediated immune response and ultra-low doses of irradiated or CpG adjuvanted killed parasites can induce cellular immunity against both heterologous and homologous parasites in animal models[34,35].The whole-parasite vaccine is likely to involve a vast array antigens,thus reducing the impact of antigenic polymorphisms.More recently,study has suggested that crude extract from Pf whole-parasite could elicit parasite antigen-specific immune response via Toll-like receptor(T LR)9,by adjuvanted with the malaria heme-detoxification byproduct,hemozoin(HZ).A synthetic HZ could be used as an adjuvant to improve immunogenicity of whole-parasite vaccines[36].However,the safety and large-scale production of whole-parasite vaccine is an important challenge for the widespread use.

    3 Challenges and future directions

    There are many evidences supporting the development of a vaccine based on blood-stage parasite antigens.However,the recent two Phase II clinical trials show no protective efficacy in African children.One possible hurdle for development of the blood-stage vaccine is the difference in parasitespecific,immune and pathogenic responses to malaria parasites between mice and humans.Recently,efforts are also going toward"humanize"the mouse model that a valid approach to evaluate blood-stage vaccine,but further studies are needed to evaluate their relevance.However,the greatest challenge for blood-stage vaccine development is perhaps highly antigenic polymorphism.Multiple antigens or allelic forms are possible required in a single vaccine to overcome the challenge.More knowledge on identification of potential antigens as blood-stage vaccine candidate isneeded.Highthroughput serological screening of whole plasmodium proteomes might guide vaccine and diagnostic antigen discovery[37].

    4 Conclusion

    In this review,we have highlighted the development and challenge of leading blood-stage candidate vaccine.Many target antigens expressed on the surface of merozoites have been demonstrated that antibodies to these proteins can confer protection against homologous parasite challenge.However,so far,no recombinant protein has been proved sufficiently efficacious in human test.Effective blood-stage vaccines will almost certainly need to choose several different antigens or several allelic types to overcome antigenic diversity.Therefore,there is a strong need for identification of a multitude of new antigens from genomic and proteomic insights.Recently,efforts are also underway to reexamine whole blood-stage parasite vaccines.We remain optimistic about the development of bloodstage vaccines against malaria and a highly effective vaccine is possible.

    [1]Snow RW,Guerra CA,Noor AM,et al.The g lobal distribution of clinical episodes of Plasmodium falciparum malaria[J].Nature,2005,434(7030):214-217.

    [2]Guerra CA,Gikandi PW,T atem AJ,et al.The limits and intensity of Plasmodium falciparum transmission:implications for malaria control and elimination worldwide[J].PLoS Med,2008,5(2):38.

    [3]Gilson PR,Crabb BS.Morphology and kinetics of the three distinct phases of red blood cell invasion by Plasmodium falciparum merozoites[J].International Journal for Parasitology,2009,39(1):91-96.

    [4]Marsh K,Snow RW.Host-parasite interaction and morbidity in malaria endemic areas[J].Philosophical Transactions of the Royal Society of London Series B Biological Sciences,1997,352(1359):1385-1394.

    [5]Doolan DL,Dobano C,Baird JK.Acquired immunity to malaria[J].Clin Microbiol Rev,2009,22(1):13-36.

    [6]Langhorne J,Ndungu FM,Sponaas AM,et al.Immunity to malaria:more questions than answers[J].Nat Immunol,2008,9(7):725-732.

    [7]Volkman SK,Hartl DL,Wirth DF,et al.Ex cess polymorphisms in genes for membrane proteins in Plasmodium falciparum[J].Science,2002,298(5591):216-218.

    [8]Polley SD,Conway DJ.Strong diversifying selection on domains of the Plasmodium falciparum apical membrane antigen 1 gene[J].Genetics,2001,158(4):1505-1512.

    [9]John CC,O'Donnell RA,Sumba PO,et al.Evidence that invasion-inhibitory antibodies specific for the 19-kDa fragment of merozoite surface protein-1(MSP-1 19)can play a protective role against blood-stage Plasmodium falciparum infection in individuals in a malaria endemic area of Africa[J].J Immunol,2004,173(1):666-72.

    [10]O'Donnell RA,de Koning-Ward TF,Burt RA,et al.A ntibodies against merozoite surface protein(M SP)-19 are a major component of the invasion-inhibitory response in individuals immune to malaria[J].J.Ex p.Med,2001,193(12):1403-1412.

    [11]Ogutu BR,Apollo OJ,Mckinney D,et al.Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya[J].P LoS One,2009,4(3):4708.

    [12]Dias S,Longacre S,Escalante AA,et al.Genetic diversity and recombination at the C-terminal fragment of the merozoite surface protein-1 of Plasmodium vivax(PvMSP-1)in Sri Lanka[J].Infect Genet Evol,2011,11(1):145-156.

    [13]Pacheco MA,Poe AC,Collins WE,et al.A comparative study of the genetic diversity of the 42 kDa fragment of the merozoite surface protein-1 in Plasmodium falciparum and P.vivax[J].Infect.Genet.Evol,2007,7(2):180-187.

    [14]Zakeri S,Mehrizi AA,Zoghi S,et al.Non-variant specific antibody responses to the C-terminal region of merozoite surface protein-1 of Plasmodium falciparum(PfMSP-1(19))in Iranians ex posed to unstable malaria transmission[J].Malar J,2010,9(9):257-263.

    [15]Woehlbier U,Epp C,Kauth CW,et al.Analysis of Antibodies Directed against Merozoite Surface Protein 1 of the Human M alaria Parasite Plasmodium falciparum[J].Infec Immun,2006,74(2):1313-1322.

    [16]M etzger WG,Okenu DM,Cavanagh DR,et al.Serum IgG3 to the Plasmodium falciparum merozoite surface protein 2 is strongly associated with a reduced prospective risk of malaria[J].Parasite Immunol,2003,25(6):307-312.

    [17]Stanisic DI,Richards JS,McCallum FJ,et al.IgG subclassspecific responses against Plasmodium falciparum merozoite antigens are associated with control of parasitemia and protection from symptomatic illness[J].Infect Immun,2009,77(3):1165-1174.

    [18]Genton B,Al-Yaman F,Betuela I,et al.Safety and immunogenicity ofa three-componentblood-stage malaria vaccine(MSP1,MSP2,RESA)against Plasmodium falciparum in Papua New Guinean children[J].Vaccine,2003,22(1):30-41.

    [19]Genton B,Betuela I,Felger I,et al.A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea[J].J Infect Dis,2002,185(6):820-827.

    [20]Fluck C,Schopflin S,Smith T,et al.Effect of the malaria vaccine Combination B on merozoite surface antigen 2 diversity[J].Infect Genet Evol,2007,7(1):44-51.

    [21]Flueck C,Frank G,Smith T,et al.Evaluation of two long synthetic merozoite surface protein 2 peptides as malaria vaccine candidates[J].Vaccine,2009,27(20):2653-2661.

    [22]Rodriguez LE,Curtidor H,Ocampo M,et al.Identifying Plasmodium falciparum merozoite surface antigen 3(MSP3)protein peptides that bind specifically to erythrocy tes and inhibit merozoite invasion[J].Protein Sci,2005,14(7):1778-1786.

    [23]Huber W,Felger I,Matile H,et al.Limited sequence polymo rphism in the Plasmodium falciparum merozoite surface protein 3[J].Mol Biochem Parasitol,1997,87(2):231-234.

    [24]Roussilhon C,Oeuvray C,Mǜller-Graf C,et al.Long-term clinical protection from falciparum malaria is strongly associated with IgG3 antibodies to merozoite surface protein 3[J].PLos M ed,2007,4(11):320.

    [25]Sirima SB,Nebie I,Ouedraogo A,et al.Safety and immunogenicity of the Plasmodium falciparum merozoite surface protein-3 long synthetic peptide(MSP3-LSP)malaria vaccine in healthy,semi-immune adult males in Burkina Faso,West Africa[J].Vaccine,2007,25(14):2723-2732.

    [26]Lusingu JP,et al.Satisfactory safety and immunogenicity of MSP3 malaria vaccine candidate in Tanzanian children aged 12-24 months[J].Malar J,2009,8(6):163-171.

    [27]Polley SD,Tetteh KK,Lloyd JM,et al.Plasmodium falciparum merozoite surface protein 3 is a target of allele-specific immunity and alleles are maintained by natural selection[J].J Infect Dis,2007,195(2):279-287.

    [28]Jordan SJ,Oliveira AL,Hernandez JN,et al.Malaria Immunoepidemiology in Low Transmission:Correlation of Infecting Genotype and Immune Response to Domains of Plasmodium falciparum M erozoite Surface Protein 3[J].Infect Immun,2011,79(5):2070-2078.

    [29]Cortes A,Mellombo M,Mueller I,et al.Geographical structure of diversity and differences between symptomatic and asymptomatic infections for Plasmodium falciparum vaccine candidate AM A1[J].Infect Immun,2003,71(3):1416-1426.

    [30]Sagara I,Ellis RD,Dicko A,et al.A randomized and controlled Phase 1 study of the safety and immunogenicity of the AMA1-C1/Alhydrogel+CPG 7909 vaccine for Plasmodium falciparum malaria in semi-immune Malian adults[J].Vaccine,2009,27(52):7292-7298.

    [31]Roestenberg M,Remarque E,de Jonge E,et al.Safety and immunogenicity of a recombinant Plasmodium falciparum AM A1 malaria vaccine adjuvanted with Alhydrogel,Montanide ISA 720 or AS02[J].PLoS One,2008,3(12):3960.

    [32]Scherf A,Lopez-Rubio JJ,Riviere L.Antigenic variation in Plasmodium falciparum[J].Annu Rev Microbiol,2008,62:445-470.

    [33]Elliott SR,Duffy MF,Byrne TJ,et al.Cross-reactive surface epitopes on chondroitin sulfate A-adherent Plasmodium falciparum-infected ery throcytes are associated with transcription of var2csa[J].Infect Immun,2005,73(5):2848-2856.

    [34]Pinzon-Charry,A.and Good,M.F.Malaria vaccines:the case for a wholeorganism approach[J].Expert Opin.Biol,2008,8(4):441-448.

    [35]Pombo DJ,Lawrence G,Hirunpetcharat C,et al.Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum[J].Lancet,2002,360(9333):610-617.

    [36]Coban C,Igari Y,Yagi M,et al.Immunogenicity of wholeparasite vaccines against Plasmodium falciparum involves malarial hemozoin and host T LR9[J].Cell Host Microbe,2010,7(1):50-61.

    [37]Davies DH,Liang X,Hernandez JE,et al.Profiling the humoral immune response to infection by using proteome microarray s:high-throughput vaccine and diagnostic antigen discovery[J].Proc Natl Acad Sci U S A,2005,102(3):547-552.

    猜你喜歡
    陳琳第三軍醫(yī)大學教研室
    海軍軍醫(yī)大學生理學教研室
    The Effects of θ on Stability in the θ-Milstein Method for Stochastic Differential Equations
    陳琳作品《一口清茶,板栗飄香》
    大眾文藝(2022年16期)2022-09-07 03:07:44
    海軍軍醫(yī)大學神經生物學教研室
    海軍軍醫(yī)大學免疫學教研室
    沒有絕對的天分,也沒有絕對的天才——指揮家陳琳專訪
    紅十字 從這里起飛 第三軍醫(yī)大學2017年運動會剪影
    解放軍健康(2017年3期)2017-11-23 02:19:52
    喜鵲 “驚魂”
    光明所系 幸福相托
    ——走進第三軍醫(yī)大學大坪醫(yī)院眼科??漆t(yī)院
    趣聞
    分憂(2014年9期)2014-09-22 04:55:36
    丰满人妻一区二区三区视频av | 好看av亚洲va欧美ⅴa在| 国产黄a三级三级三级人| 美女大奶头视频| 亚洲国产精品999在线| 婷婷精品国产亚洲av在线| 2021天堂中文幕一二区在线观| 91久久精品电影网| 亚洲国产高清在线一区二区三| 全区人妻精品视频| 每晚都被弄得嗷嗷叫到高潮| 中文字幕av成人在线电影| 精品电影一区二区在线| 日韩欧美精品v在线| 热99在线观看视频| 在线观看午夜福利视频| 欧洲精品卡2卡3卡4卡5卡区| 一级黄色大片毛片| 亚洲人成网站在线播放欧美日韩| 在线天堂最新版资源| 精品国产三级普通话版| 母亲3免费完整高清在线观看| 欧美一级毛片孕妇| 国内精品一区二区在线观看| 国产伦精品一区二区三区视频9 | 在线播放无遮挡| 三级国产精品欧美在线观看| 国产三级黄色录像| 两人在一起打扑克的视频| 麻豆一二三区av精品| 一进一出抽搐gif免费好疼| 亚洲精品色激情综合| 欧美成人一区二区免费高清观看| 国产又黄又爽又无遮挡在线| 黄色日韩在线| 色吧在线观看| 性色avwww在线观看| 法律面前人人平等表现在哪些方面| 两性午夜刺激爽爽歪歪视频在线观看| 中文字幕人成人乱码亚洲影| 男女视频在线观看网站免费| 国产 一区 欧美 日韩| 一级黄色大片毛片| 亚洲熟妇中文字幕五十中出| 国产精品美女特级片免费视频播放器| 精品一区二区三区av网在线观看| 精品久久久久久久人妻蜜臀av| 99热精品在线国产| 在线免费观看不下载黄p国产 | 熟妇人妻久久中文字幕3abv| 日本熟妇午夜| 欧美乱码精品一区二区三区| 国产精品一区二区三区四区免费观看 | 老鸭窝网址在线观看| 青草久久国产| 成年免费大片在线观看| 久久草成人影院| 国产精品永久免费网站| 国产成人啪精品午夜网站| 国内久久婷婷六月综合欲色啪| 欧美高清成人免费视频www| 国产乱人视频| 欧美日韩乱码在线| 欧美国产日韩亚洲一区| 欧美日韩黄片免| 国产私拍福利视频在线观看| 欧美日韩福利视频一区二区| 91九色精品人成在线观看| 神马国产精品三级电影在线观看| 欧美日韩乱码在线| 天堂影院成人在线观看| 亚洲一区二区三区不卡视频| 哪里可以看免费的av片| 久久精品综合一区二区三区| 丰满乱子伦码专区| 国内毛片毛片毛片毛片毛片| 我要搜黄色片| 国产精品久久久久久人妻精品电影| 久久久色成人| 又爽又黄无遮挡网站| 国产精品永久免费网站| 免费一级毛片在线播放高清视频| 免费av观看视频| 国产精品一区二区三区四区免费观看 | 天堂av国产一区二区熟女人妻| 国内精品一区二区在线观看| 亚洲美女视频黄频| 十八禁人妻一区二区| 最近最新中文字幕大全电影3| 国产99白浆流出| 一二三四社区在线视频社区8| 久99久视频精品免费| 法律面前人人平等表现在哪些方面| 日韩欧美在线二视频| 午夜福利在线在线| 亚洲精品亚洲一区二区| 亚洲av成人不卡在线观看播放网| 国内揄拍国产精品人妻在线| 18禁国产床啪视频网站| 亚洲狠狠婷婷综合久久图片| 美女cb高潮喷水在线观看| 91麻豆av在线| 欧美不卡视频在线免费观看| 长腿黑丝高跟| 午夜激情福利司机影院| 黄色成人免费大全| 宅男免费午夜| 久久久久性生活片| 国产免费男女视频| 国内揄拍国产精品人妻在线| 在线观看日韩欧美| 成人高潮视频无遮挡免费网站| 国内揄拍国产精品人妻在线| 日韩有码中文字幕| 亚洲国产精品合色在线| www.999成人在线观看| 一级作爱视频免费观看| 99国产精品一区二区三区| 亚洲片人在线观看| 一级作爱视频免费观看| 色老头精品视频在线观看| 搡女人真爽免费视频火全软件 | 免费观看精品视频网站| 18禁黄网站禁片免费观看直播| 亚洲国产精品成人综合色| 丰满人妻熟妇乱又伦精品不卡| 午夜福利在线观看免费完整高清在 | 欧美一区二区国产精品久久精品| 亚洲欧美激情综合另类| 黄色日韩在线| 国产高清视频在线观看网站| 性欧美人与动物交配| 欧美精品啪啪一区二区三区| АⅤ资源中文在线天堂| 精品日产1卡2卡| 熟女电影av网| 极品教师在线免费播放| 校园春色视频在线观看| 国产高清视频在线播放一区| 女人十人毛片免费观看3o分钟| 丰满人妻熟妇乱又伦精品不卡| 国内精品美女久久久久久| 色综合站精品国产| 亚洲avbb在线观看| 国产免费一级a男人的天堂| 九九热线精品视视频播放| 国产单亲对白刺激| 又紧又爽又黄一区二区| 国内毛片毛片毛片毛片毛片| 久久人妻av系列| 91字幕亚洲| 亚洲av美国av| 午夜老司机福利剧场| 在线看三级毛片| 在线观看舔阴道视频| 欧美日韩黄片免| 日韩免费av在线播放| 久久精品国产自在天天线| 中文字幕熟女人妻在线| 亚洲av免费高清在线观看| 国产又黄又爽又无遮挡在线| 国产精品1区2区在线观看.| 又粗又爽又猛毛片免费看| 丰满人妻一区二区三区视频av | 偷拍熟女少妇极品色| 午夜激情欧美在线| xxx96com| 成年版毛片免费区| tocl精华| 国内久久婷婷六月综合欲色啪| 757午夜福利合集在线观看| 又黄又粗又硬又大视频| 亚洲欧美日韩东京热| 国产午夜精品久久久久久一区二区三区 | 制服人妻中文乱码| 熟妇人妻久久中文字幕3abv| 久久精品人妻少妇| 黄片小视频在线播放| 偷拍熟女少妇极品色| 一进一出抽搐动态| 久久久久久久亚洲中文字幕 | 九九在线视频观看精品| 18禁黄网站禁片免费观看直播| 国产一区二区三区在线臀色熟女| 国产亚洲av嫩草精品影院| 精品久久久久久成人av| 国产亚洲精品av在线| 精品久久久久久久人妻蜜臀av| 国产免费一级a男人的天堂| 在线免费观看的www视频| 久久6这里有精品| 午夜免费激情av| 成熟少妇高潮喷水视频| 亚洲欧美日韩东京热| 麻豆久久精品国产亚洲av| 99热只有精品国产| 狂野欧美激情性xxxx| 夜夜看夜夜爽夜夜摸| 听说在线观看完整版免费高清| 内地一区二区视频在线| 午夜免费成人在线视频| 99在线视频只有这里精品首页| 国产精品亚洲美女久久久| 美女黄网站色视频| 欧美中文综合在线视频| 亚洲精品在线美女| 长腿黑丝高跟| 成人无遮挡网站| 国产成人福利小说| a在线观看视频网站| 99热6这里只有精品| 99久国产av精品| 成人欧美大片| 九九在线视频观看精品| 他把我摸到了高潮在线观看| 男女下面进入的视频免费午夜| 一个人免费在线观看的高清视频| 成人无遮挡网站| 国产精品美女特级片免费视频播放器| 淫妇啪啪啪对白视频| 精品福利观看| 亚洲人成网站在线播放欧美日韩| 熟女电影av网| 欧美一区二区精品小视频在线| АⅤ资源中文在线天堂| 搡老妇女老女人老熟妇| 国产高清videossex| 999久久久精品免费观看国产| 国产精品爽爽va在线观看网站| 性欧美人与动物交配| 国产亚洲精品一区二区www| 国产高清视频在线播放一区| 亚洲av成人不卡在线观看播放网| 久久精品国产清高在天天线| 久久久久九九精品影院| 欧美极品一区二区三区四区| 国产精品99久久99久久久不卡| 色综合亚洲欧美另类图片| 色精品久久人妻99蜜桃| 真实男女啪啪啪动态图| 我的老师免费观看完整版| 国产精品久久久久久精品电影| 国产亚洲精品久久久com| 中文字幕高清在线视频| 亚洲乱码一区二区免费版| or卡值多少钱| 中文字幕人妻丝袜一区二区| 国产中年淑女户外野战色| 熟妇人妻久久中文字幕3abv| 国产午夜精品久久久久久一区二区三区 | 黄片小视频在线播放| 欧美乱妇无乱码| 人人妻人人看人人澡| 中文字幕av成人在线电影| 琪琪午夜伦伦电影理论片6080| e午夜精品久久久久久久| 国产毛片a区久久久久| 日韩 欧美 亚洲 中文字幕| 成人性生交大片免费视频hd| 国产99白浆流出| 亚洲国产精品成人综合色| 色综合婷婷激情| 国产精品免费一区二区三区在线| 校园春色视频在线观看| 成人三级黄色视频| 亚洲成a人片在线一区二区| 1000部很黄的大片| 午夜精品在线福利| 久久精品91蜜桃| 亚洲av熟女| 色综合婷婷激情| 男女床上黄色一级片免费看| 国产 一区 欧美 日韩| 日韩 欧美 亚洲 中文字幕| 少妇人妻精品综合一区二区 | 国产野战对白在线观看| 国产成人av教育| 全区人妻精品视频| www.www免费av| 特级一级黄色大片| 超碰av人人做人人爽久久 | 草草在线视频免费看| 国产成人av教育| 国语自产精品视频在线第100页| 人人妻人人澡欧美一区二区| www日本在线高清视频| 亚洲国产精品久久男人天堂| 波野结衣二区三区在线 | 欧美黑人欧美精品刺激| 男女之事视频高清在线观看| 两人在一起打扑克的视频| 网址你懂的国产日韩在线| 少妇丰满av| 18禁美女被吸乳视频| 级片在线观看| 亚洲美女视频黄频| 欧美中文综合在线视频| 亚洲片人在线观看| 少妇的丰满在线观看| 久久久久久九九精品二区国产| 国产成人影院久久av| 成年版毛片免费区| 99久久无色码亚洲精品果冻| 激情在线观看视频在线高清| av视频在线观看入口| 欧美高清成人免费视频www| 天堂√8在线中文| 国产aⅴ精品一区二区三区波| 午夜a级毛片| 成年女人毛片免费观看观看9| 91字幕亚洲| 1024手机看黄色片| 国产高清视频在线播放一区| 国产真实乱freesex| 一区二区三区激情视频| 精品久久久久久久末码| 在线观看66精品国产| 91在线精品国自产拍蜜月 | 亚洲精品影视一区二区三区av| 欧美绝顶高潮抽搐喷水| 天美传媒精品一区二区| 欧美乱色亚洲激情| 免费大片18禁| 两性午夜刺激爽爽歪歪视频在线观看| 国产伦人伦偷精品视频| 欧美乱码精品一区二区三区| 亚洲狠狠婷婷综合久久图片| 搡老熟女国产l中国老女人| 九九热线精品视视频播放| 国产欧美日韩精品一区二区| 久久香蕉国产精品| 小蜜桃在线观看免费完整版高清| 天堂√8在线中文| 精品久久久久久久久久免费视频| 亚洲av免费在线观看| www.熟女人妻精品国产| 亚洲片人在线观看| 在线播放国产精品三级| 国产精品,欧美在线| 国产高清videossex| 九九久久精品国产亚洲av麻豆| 精品日产1卡2卡| 搡老岳熟女国产| 久久精品国产99精品国产亚洲性色| 国产av在哪里看| aaaaa片日本免费| 日韩精品青青久久久久久| 一进一出抽搐动态| 婷婷精品国产亚洲av在线| 三级毛片av免费| 精品人妻偷拍中文字幕| 美女 人体艺术 gogo| 亚洲 国产 在线| 99精品久久久久人妻精品| 精品一区二区三区视频在线观看免费| 嫁个100分男人电影在线观看| 欧美最新免费一区二区三区 | 成人av在线播放网站| 亚洲一区二区三区色噜噜| 男人的好看免费观看在线视频| 国产视频一区二区在线看| 最后的刺客免费高清国语| 成人国产综合亚洲| 母亲3免费完整高清在线观看| 国产毛片a区久久久久| 亚洲av熟女| 婷婷亚洲欧美| 久久久久国内视频| 国产99白浆流出| 日韩亚洲欧美综合| 好男人电影高清在线观看| 国产成人av教育| 国产精品影院久久| 欧美中文日本在线观看视频| 丁香欧美五月| 熟女少妇亚洲综合色aaa.| 男人舔女人下体高潮全视频| 亚洲男人的天堂狠狠| 久久精品国产自在天天线| 熟女少妇亚洲综合色aaa.| 久久亚洲精品不卡| 国产高清videossex| 国产精品一及| 欧美一级a爱片免费观看看| avwww免费| 99热6这里只有精品| 亚洲国产高清在线一区二区三| 综合色av麻豆| 亚洲精品日韩av片在线观看 | 桃红色精品国产亚洲av| 国产午夜精品论理片| 亚洲av免费在线观看| 欧美色欧美亚洲另类二区| 国产午夜福利久久久久久| 国产伦人伦偷精品视频| 国产伦精品一区二区三区四那| 黄色女人牲交| 国产中年淑女户外野战色| 国产一区二区三区视频了| 亚洲av电影在线进入| 日本撒尿小便嘘嘘汇集6| 老汉色∧v一级毛片| 亚洲无线在线观看| 日韩欧美在线二视频| 九九久久精品国产亚洲av麻豆| 精品久久久久久久久久久久久| 欧美午夜高清在线| 久久久久久久亚洲中文字幕 | 国产成人aa在线观看| 国产乱人视频| 亚洲av成人精品一区久久| 中文字幕人妻丝袜一区二区| 少妇的逼水好多| 国产精品自产拍在线观看55亚洲| 亚洲国产精品合色在线| 国产成人影院久久av| 色哟哟哟哟哟哟| 成人av在线播放网站| 国产三级中文精品| 婷婷丁香在线五月| www.色视频.com| 国产色爽女视频免费观看| 一二三四社区在线视频社区8| 免费一级毛片在线播放高清视频| 超碰av人人做人人爽久久 | 国产精品女同一区二区软件 | 亚洲一区二区三区不卡视频| 日韩av在线大香蕉| 欧美三级亚洲精品| 亚洲人与动物交配视频| 精华霜和精华液先用哪个| 亚洲人成网站在线播| 久久精品国产亚洲av香蕉五月| 久久国产精品人妻蜜桃| 成人特级av手机在线观看| 国产熟女xx| 日日干狠狠操夜夜爽| 亚洲专区国产一区二区| 一级作爱视频免费观看| 无遮挡黄片免费观看| 日韩欧美在线二视频| 亚洲av美国av| 国产成人a区在线观看| 国产一区二区亚洲精品在线观看| 国产精品嫩草影院av在线观看 | 人妻丰满熟妇av一区二区三区| 亚洲熟妇中文字幕五十中出| 亚洲午夜理论影院| av视频在线观看入口| 九九在线视频观看精品| 久99久视频精品免费| 午夜免费成人在线视频| 蜜桃久久精品国产亚洲av| 99热只有精品国产| 亚洲午夜理论影院| 99久久无色码亚洲精品果冻| 三级国产精品欧美在线观看| 两人在一起打扑克的视频| 国内揄拍国产精品人妻在线| 人妻丰满熟妇av一区二区三区| 嫩草影院精品99| 久久精品国产亚洲av涩爱 | 两个人看的免费小视频| 久久久久久大精品| 欧美日韩瑟瑟在线播放| 嫁个100分男人电影在线观看| 国产爱豆传媒在线观看| 免费看日本二区| 欧美午夜高清在线| 成人精品一区二区免费| 亚洲欧美日韩卡通动漫| 国内精品美女久久久久久| 中文字幕精品亚洲无线码一区| 欧美在线黄色| 亚洲av成人精品一区久久| 床上黄色一级片| 日日摸夜夜添夜夜添小说| 中文字幕人成人乱码亚洲影| 午夜免费观看网址| 18禁在线播放成人免费| 国产69精品久久久久777片| 国产精品综合久久久久久久免费| 最后的刺客免费高清国语| 99久久九九国产精品国产免费| 搡老妇女老女人老熟妇| 搡老熟女国产l中国老女人| 一二三四社区在线视频社区8| 中文字幕人妻熟人妻熟丝袜美 | 男人的好看免费观看在线视频| 亚洲专区国产一区二区| 欧美成人a在线观看| 一个人看的www免费观看视频| 欧美zozozo另类| 伊人久久精品亚洲午夜| 精品免费久久久久久久清纯| 久久久久国产精品人妻aⅴ院| 午夜亚洲福利在线播放| 国产精品99久久久久久久久| 国产一区二区三区在线臀色熟女| 国产欧美日韩精品一区二区| 麻豆国产97在线/欧美| 99精品在免费线老司机午夜| АⅤ资源中文在线天堂| 人妻丰满熟妇av一区二区三区| 国产成年人精品一区二区| 国产又黄又爽又无遮挡在线| 精品久久久久久,| 国产精品亚洲av一区麻豆| 国产真实伦视频高清在线观看 | 男女床上黄色一级片免费看| 亚洲av成人精品一区久久| 中文字幕人妻丝袜一区二区| 午夜精品一区二区三区免费看| 国产成年人精品一区二区| 国内精品久久久久精免费| 国产精品一区二区三区四区久久| 国产高清三级在线| 波多野结衣高清作品| 午夜精品一区二区三区免费看| 亚洲av成人av| 国产高清三级在线| www.999成人在线观看| 国产探花在线观看一区二区| 国产一区二区亚洲精品在线观看| 亚洲国产欧美网| 亚洲av一区综合| 免费看光身美女| 69av精品久久久久久| 婷婷亚洲欧美| 性色avwww在线观看| 成人国产一区最新在线观看| 欧美3d第一页| 亚洲18禁久久av| 久久精品亚洲精品国产色婷小说| 禁无遮挡网站| 久久国产乱子伦精品免费另类| 午夜久久久久精精品| 99国产综合亚洲精品| 日韩中文字幕欧美一区二区| e午夜精品久久久久久久| 国产精品免费一区二区三区在线| 国产精品亚洲美女久久久| 久久九九热精品免费| 97人妻精品一区二区三区麻豆| 两个人看的免费小视频| 一夜夜www| 国产午夜福利久久久久久| 亚洲精品456在线播放app | 久久精品国产清高在天天线| 国产午夜精品论理片| 国产亚洲精品久久久com| 日韩欧美精品v在线| 天堂网av新在线| 岛国在线免费视频观看| 99久久久亚洲精品蜜臀av| 精品午夜福利视频在线观看一区| 麻豆国产97在线/欧美| 老司机在亚洲福利影院| 精品无人区乱码1区二区| 亚洲美女视频黄频| 亚洲午夜理论影院| 美女cb高潮喷水在线观看| 成人三级黄色视频| 可以在线观看毛片的网站| 日本 欧美在线| 国产av在哪里看| 亚洲人成网站高清观看| av视频在线观看入口| 在线观看av片永久免费下载| 国内久久婷婷六月综合欲色啪| 久久久久久大精品| 国产精品久久久久久久电影 | 国产精品免费一区二区三区在线| 熟妇人妻久久中文字幕3abv| 午夜精品久久久久久毛片777| 18禁黄网站禁片免费观看直播| 日日夜夜操网爽| 久久精品91无色码中文字幕| 国产av在哪里看| 亚洲欧美日韩高清在线视频| 免费搜索国产男女视频| 精品人妻1区二区| 亚洲在线自拍视频| 免费人成视频x8x8入口观看| 1000部很黄的大片| svipshipincom国产片| 国产精品精品国产色婷婷| 动漫黄色视频在线观看| 成人亚洲精品av一区二区| a级毛片a级免费在线| 久久精品91蜜桃| 欧美日韩亚洲国产一区二区在线观看| 国产一区二区亚洲精品在线观看| 欧美日韩综合久久久久久 | 一个人观看的视频www高清免费观看| 日韩免费av在线播放| 高清在线国产一区| 狠狠狠狠99中文字幕| 又粗又爽又猛毛片免费看| 国产色爽女视频免费观看| 欧美zozozo另类| 午夜福利在线在线| 黑人欧美特级aaaaaa片| 丰满乱子伦码专区| 成年女人看的毛片在线观看| 午夜福利成人在线免费观看| 露出奶头的视频| 久久国产精品影院| xxxwww97欧美| 亚洲内射少妇av| 国产视频一区二区在线看| 亚洲欧美精品综合久久99| 亚洲av电影在线进入| 人妻夜夜爽99麻豆av| av黄色大香蕉|