obligatenaerobes近畿大学医学部.ppt

109-A13•重症熱性血小板減少症候群•SFTS: severe fever with thrombocytopenia syndrome•SFTSウイルス：Bunyaviridae科Phlebovirus属•マダニ媒介•四類感染症•March to July 2009, Emerging infectious disease identified as the severe fever with thrombocytopenia syndrome (SFTS) in rural central China. Cause was unknown. •Major clinical symptoms included fever, thrombocytopenia, gastrointestinal symptoms, and leukocytopenia; high initial case fatality rate of 30%•Multi-organ failure developed RAPIDLY—elevated serum alanine aminotransferase, aspartate aminotransferase, creatine kinase, lactate dehyrogenase; proteinuria, hematuria.From Dr. O’Callaghan Virology Journal Club April 29, 2011Genus Genus Human diseaseHuman diseaseOrthobunyavirus Orthobunyavirus La Crosse encephalitis, California encephalitisLa Crosse encephalitis, California encephalitisPhlebovirusPhlebovirusRift Valley fever (RVF)Rift Valley fever (RVF)NairovirusNairovirusCrimean-Congo hemorrhagic fever (CCHF)Crimean-Congo hemorrhagic fever (CCHF)HantavirusHantavirusHemorrhagic fever with renal syndrome (HFRS)Hemorrhagic fever with renal syndrome (HFRS)Hantavirus pulmonary syndrome (HPS)Hantavirus pulmonary syndrome (HPS)TospovirusTospovirusPlant virus, no known human diseasePlant virus, no known human disease5 genera5 generaFamily BunyaviridaeEncephalitisHemorrhagic FeverPneumoniaBUNYAVIRIDAE; Bunyamwera in Uganda Virion: ENV, 120nm; 3 Helical capsids; three 1X RNAs5 Genera.  2 genera have ambisense RNAs;   Phelbovirus & TospovirusTospovirus genus = tomato spotted wilt virus             M & S RNAs are ambisense. NSm 34K protein = movement.  Forms tubules that penetrate thru plasmadesmata so capsids can enter neighboring cell.    NSs 52K protein binds 2X RNA that can generate siRNAs .                                                   Transmitted by THIRPSInfects tomato, peanuts, watermelon, zucchini, impatiensS+M RNAs = ambiCalifornia Sin NombreCCHFRift ValleyDr. O’Callaghan Journal Club 4/20/12Hantavirus (HFRS contact with rodents) Nairovirus (CCHF-tick) Orthobunyavirus (LAC mosquito) Phlebovirus (Rift Valley Fever; mosquito) Tospovirus (Tomato spotted wilt ; thrips)PHLEBOVIRUS: 68 serotypes. Two Groups: 1. Phlebotomus Fever Group 55 (sandflies) 2. Uukuniemi Group 13 (ticks) Eight members linked to disease humans AlenquerChaniru Chagres Naples Punta ToroRift Valley Fever Sicilian ToscanaSFTS Virus is new GROUP of PHLBOVIRUS Genus.9th Phlebovirus to cause disease in humansFrom Dr. O’Callaghan Virology Journal Club April 29, 2011thripsThese leaves show symptoms of tomato spotted leaf virus. / Kathie Rowell/The TimesMay 12, 2011109-A38•血球貪食症候群　Hemophagocytic syndrome　（HPS)•血球貪食性リンパ組織球症　Hemophagocytic lymphohistiocytosis (HLH)•EBV関連血球貪食症候群　EBV-associated hemophacotytic syndrome–EBVに感染したT細胞が増殖し、大量のサイトカインを分泌、これによって活性化したマクロファージがサイトカインの分泌や血球を貪食して起こす–標準微生物学　第12版　ｐ423　• •Familial hemophagocytic lymphohistiocytosis (FHL or FHLH) is caused by an Familial hemophagocytic lymphohistiocytosis (FHL or FHLH) is caused by an inherited deficiency of perforininherited deficiency of perforin• •Hemophagocytosis: ingestion of red blood cells by macrophagesHemophagocytosis: ingestion of red blood cells by macrophages• • • •Pfp-/- mice infected with some types of viruses result in a disease similar to FHL Pfp-/- mice infected with some types of viruses result in a disease similar to FHL because the immune system is uncontrolled because the immune system is uncontrolled  demonstrates that perforin plays an demonstrates that perforin plays an important role in regulating the immune responseimportant role in regulating the immune response• •Hemophagocytic lymphohistiocytosis (HLH) Hemophagocytic lymphohistiocytosis (HLH) • •=Hemophagocytic syndrome (HPS)=Hemophagocytic syndrome (HPS)• •=Macrophage activation syndrome=Macrophage activation syndromeSome deficiencies can lead to lymphoproliferative diseases (Table 4.2)•In FHL, mutations prevent NK cells and cytotoxic T cells from releasing their cytoplasmic granules, which leads to uncontrolled proliferation of lymphocytes and macrophages•These cells phagocytose blood cells and release huge amounts of proinflammatory cytokines•Cytokine burst explains the inflammation, fever and systemic illness•T cell and macrophage infiltration in liver, spleen, lymph nodes, bone marrow, and central nervous system•T cells and macrophages respond strongly to microbes to compensate for the CTL and NK cell defects?•Anemia•Thrombocytopenia•Hemophagocytosis in bone marrow, spleen, lymph node•Increased cytokine release: interferon-γ, TNF, IL-6, IL-10, macrophage colony-stimulating factor (M-CSF)•Treatment: control the cytokine burst by chemotherapy and immunotherapy with etoposide, corticosteroids and cyclosporine, followed by bone marrow transplantationHemophagocytic lymphohistiocytosis (HLH)Hemophagocytic syndrome (HPS)• •Familial hemophagocytic lymphohistiocytosis (FHL or FHLH) (Table 4.2)Familial hemophagocytic lymphohistiocytosis (FHL or FHLH) (Table 4.2)• •FHL1: unidentified gene on chromosome 9FHL1: unidentified gene on chromosome 9• •FHL2: perforin (PRF1) mutationFHL2: perforin (PRF1) mutation• •FHL3: Munc13-4 (UNC13D) mutationFHL3: Munc13-4 (UNC13D) mutation• •FHL4: syntaxin 11 (STX11) mutationFHL4: syntaxin 11 (STX11) mutation• •FHL5: syntaxin binding protein (STXBP) 2 (Munc 18-2) mutationFHL5: syntaxin binding protein (STXBP) 2 (Munc 18-2) mutation• •All four proteins are involved in the granule-mediated All four proteins are involved in the granule-mediated cytotoxic pathway of cytotoxic pathway of lymphocyteslymphocytes• •Immune deficiency syndromes (Table 4.1)Immune deficiency syndromes (Table 4.1)• •Chediak-Higashi syndrome 1: LYST (=CHS1) mutationChediak-Higashi syndrome 1: LYST (=CHS1) mutation• •Griscelli syndrome 2: RAB27A mutationGriscelli syndrome 2: RAB27A mutation• •LYST and RAB27A: role in vesicle trafficking in CTLLYST and RAB27A: role in vesicle trafficking in CTL• • • •X-linked lymphoproliferative syndrome: SH2D1A mutationX-linked lymphoproliferative syndrome: SH2D1A mutation• •NK cell inhibition leads to severe EB virus infection NK cell inhibition leads to severe EB virus infection and sustained proliferation of CTL (Table 4.3a)and sustained proliferation of CTL (Table 4.3a)• •Genetic hemophagocytic lymphohistiocytosis=primary hemophagocytic syndrome• •A defect in LYST (=CHS1), which is involved in intracelluar vesicle formation and A defect in LYST (=CHS1), which is involved in intracelluar vesicle formation and traffickingtrafficking• •Reported by Moises Chediak (1954) and Ototaka Higashi (1956)Reported by Moises Chediak (1954) and Ototaka Higashi (1956)• •A failure of lysosomes and phagosomes to fuse properlyA failure of lysosomes and phagosomes to fuse properly• •Phagocytes have enlarged granules and impaired intracellular killing abilityPhagocytes have enlarged granules and impaired intracellular killing ability• •Partial albinism, abnormal platelet function, severe immunodeficiencyPartial albinism, abnormal platelet function, severe immunodeficiencyChediak-Higashi syndromeOtotaka Higashi, 東音高東音高http://www.nurs.or.jp/~academy/igaku/t1/t1241.htmhttp://www.jpeds.or.jp/saisin/saisin_100604.html109-A60　含み声•muffled voice,　 　hot potato voice•くぐもったような、手で口を押さえてしゃべったときのような声くぐもったような、手で口を押さえてしゃべったときのような声•のどの奥からうるんだようなような声がれが出ることのどの奥からうるんだようなような声がれが出ること　 　•急性喉頭蓋炎、扁桃周囲膿瘍など急性喉頭蓋炎、扁桃周囲膿瘍など109-B16•原発性免疫不全症•慢性肉芽腫症　Chronic granulomatous disease (CGD)　Primary Immunodeficiency Expert Committee Primary Immunodeficiency Expert Committee http://www.iuisonline.org/iuis/index.php/primary-immunodeficiency-expert-committee.htmlMSMD: Mendelian susceptibility to mycobacterial disease5. Congenital defects of phagocytes Immunodeficiencies of phagocytic cells• •Myeloid deficiencies primarily affect the innate immune systemMyeloid deficiencies primarily affect the innate immune system• •Phagocyte immunodeficiencies can be grouped into 4 types: Deficiency in Phagocyte immunodeficiencies can be grouped into 4 types: Deficiency in 1. 1.Phagocyte production: Development – Phagocyte production: Development – defect in gene required for defect in gene required for myeloid progenitor cell differentiationmyeloid progenitor cell differentiation2. 2.Phagocyte adhesionPhagocyte adhesion3. 3.Phagocyte activation: PhagocytosisPhagocyte activation: Phagocytosis4. 4.KillingKillingDefects in phagocytic cells are associated with persistence of bacterial infection5.3: Defects of respiratory burst6.2, 6.3: IRAK4, MyD88 deficiency5.2: Defects of motility5.1: Defects of neutrophil differentiationTable 4.1: Immunodeficiency with hypopigmentation•The most significant problem is the inability of cells to attach to the vascular endothelium and migrate to sites of inflammation•LAD type 1 (LAD-1): deficient expression of β2 integrins due to CD18 gene mutations•LAD type 2 (LAD-2): absence of sialyl Lewis X: ligand on neutrophils required for binding to E-selectin and P-selectin on endotheliumCaused by fucose transporter gene mutation: the failure to transport fucose into the Golgi complex results in failure to synthesize sialyl Lewis X•LAD type 3, deficiency of Kindlin-3, required for firm adhesionLeukocyte adhesion deficiency (LAD) (Table 5.2)Leukocyte adhesion deficiency (LAD) (Table 5.2)• •Leukocyte adhesion deficiency (LAD) results from mutation in the CD18 molecule – Leukocyte adhesion deficiency (LAD) results from mutation in the CD18 molecule – the the b b b b2 chain of the integrin family2 chain of the integrin family• •The result is a loss of surface expression of key integrin molecules:The result is a loss of surface expression of key integrin molecules:• •Abnormal functions: endothelium adherence, neutrophil chemotaxis, phagocytosis, Abnormal functions: endothelium adherence, neutrophil chemotaxis, phagocytosis, cytotoxicitycytotoxicityLAD type 1Mac-1 p150:95109-D4•解答：d. 落葉状天疱瘡•選択肢：e. 疱疹状皮膚炎 dermatitis herpetiformis–ヘルペスウイルスとは無関係–グルテン過敏腸症　　Celiac disease (Celiac sprue gluten sensitive enteropathy)•Chronic small intestinal immune-mediated enteropathy precipitated to dietary gluten•A common cause of malabsorption in Caucasians•In the US, estimated incidence: 1:113•Onset; from the first year through the eight decade•Diarrhea, steatorrhea, weight loss, consequence of nutrient depletion (anemia and metabolic bone disease)•Gliadin, a component of gluten (wheat, barley, rye)•Serum antibodies: antigliadin IgA, anti-transglutaminase IgA•HLA-DQ2 allele present in 80-95% of patients; HLA-DQ8•Associated with dermatitis herpetiformis (IgA deposition in the skin), diabetes mellitus type I, thyroiditis, IgA deficiency•Enteropathy-associated T-cell lymphomaAfter gluten-free dietDermatitis herpetiformisSkin IgA depositionØA multisystem disease resulting from an autoimmune reaction to infection with group A streptococciØAlmost all of the manifestations in many parts of the body resolve completelyØException is cardiac valvular damage: rheumatic heart disease (RHD)ØDisease of poverty: less crowded housing and better hygiene resulted in reduced transmission of group A streptococci + antibiotics and improved medical care109-D14急性リウマチ熱急性リウマチ熱Acute rheumatic fever (ARF) OnlineMolecular mimicry in rheumatic feverRHD :rheumatic heart disease •Streptococcal M protein are immunologically similar to myosin, tropomyosin, keratin, actin, laminin, vimentin, and N-acetylflucosamine•Antibodies that recognize cardiac myosin in the myocardium also recognize the valve endothelium and laminin•Once disease has become chronic in the valve, other proteins in the valve such as laminin, vimentin, collagen and others may be presented to the immune system and epitope spreading would be predicted to occur12-4 Epitope (determinant) spreadingIn animals, autoimmune disease can be generated by immunizing autoantigen (protein X) in adjuvantFirst response is dominated by T cell response to one peptide derived from protein XLater, tissue damage release protein X and other self proteins (protein Y)Further activate T cell responses to proteins X and YExample: 12-7 Experimental allergic encephalomyelitis (EAE), animal model for multiple sclerosisØSelf-antigen is released from damaged tissue can be taken up by antigen presenting cells (APCs), processed and presented to autoreactive T cellsØFurther tissue destruction by activated T cells causes the release of more self-antigen from tissuesØThe response can then spread to involve T cells (or antibodies) specific for other self-antigens in a process known as epitope spreadingEpitope spreading109-D44Mumps急性耳下腺炎急性耳下腺炎Mumps Child with parotitis (CDC web site: http://www.cdc.gov/mumps/about/photos.html)Mumps causes salivary gland swelling, particularly the parotid glandMumps; “Otafuku” in JapaneseOtafuku, Japanese mask(“fuku” = swelling) 109-D49項部硬直項部硬直髄膜炎髄膜炎Viral Meningitis vs. EncephalitisViral Meningitis(Enteroviruses, HIV, HSV type 2, Arboviruses) •Headache•Stiff neck•Photophobia•Little alteration in consciousness•No focal signsViral Encephalitis (HSV, Arboviruses, Rabies, Nipah virus) •Altered consciousness•Focal neurological signs•Seizures•Meningeal signsDr. John E. Greenlee, MD, University of Utah109-E50慢性炎症性脱髄性多発根神経炎慢性炎症性脱髄性多発根神経炎109-E52クループクループParamyxoviridae Human Diseases Family includes numerous human disease-causing members:PaRaMyxovirus: Parainfluenza, Respiratory syncytial virus, Rubeola (Measles), MumpsSubfamily Paramyxovirinae•Morbillivirus (measles) – fever, cough, conjunctivitis leading to macropapular rash; can be fatal; Subacute sclerosing panencephalitis (SSPE) •Rubulavirus (mumps) – fever leading to salivary (parotid) gland swelling; can be testicular and central nervous system (CNS) involvement; occasionally fatal•Rubulavirus (human parainfluenza virus 2/4a/4b) – acute respiratory tract disease; fever leading to bronchitis and possibly pneumonia •Respirovirus (human parainfluenza virus 1/3) – acute respiratory tract disease; fever leading to bronchitis and possibly pneumonia; “croup” in infants <6 mos. Croup109-E52急性喉頭蓋炎：選択肢急性喉頭蓋炎：選択肢正常正常2016年近畿大学６年寺田徹さんクリクラ109-F13選択肢：手足口病選択肢：手足口病Hand, foot and mouth disease (HFMD)•Vesicular lesions on the hands, feet, mouth, and tongue•Occurs in children•Caused by enteroviruses, including coxsackievirus A16, 10, and enterovirus 71•Mildly febrile, and the illness subsides in a few dayshttp://pathmicro.med.sc.edu/virol/picorna.htmCoxsackievirus•The first strains were isolated from two paralyzed boys in the village of Coxsackie, New York•Meningitis and encephalitis•Myocarditis•Aphtho: from Greek aphtha, "vesicles in the mouth"; English: aphtho, "thrush” •Entero: from Greek enteron, "intestine”•Hepato: from Greek hepatos, "liver“•Kobu: from Japanese Kobu "hump or knob“•Rhino: from Greek rhis, rhinos, "nose"The two original human rhinovirus species have been moved to the genus Enterovirus; the genus Rhinovirus no longer exists. Whitton et al., Nature Reviews Microbiology 2005 v. 3 p. 765nGenus Aphthovirus nType species: Foot-and-mouth disease virus (FMDV)nInfect cloven-hoofed animals (cattle, goats, pigs, sheep)nRarely infect humansn7 serotypes, each with subtypesnLose infectivity at low pH values of less than 6.8The “type species”: the virus initially necessitated the creation of the genus and best defines or identifies the genus Picornavirus Picornavirus pathogenesispathogenesisThe target tissue infected by the virus determines the predominant disease caused by the virus. Coxsackie; coxsackievirus echo; echovirus; HAV; hepatitis A viruspolio; poliovirusrhino; rhinovirus.109-I67SSPE亜急性硬化性全脳炎亜急性硬化性全脳炎ADEM, acute disseminated encephalomyelitisMIBE; measles inclusion body encephalitisADEM, demyelination; MIBE; inclusion body and viral antigenSubacuteChronicAcuteSSPE, subacute sclerosing panencephalitis •Occurs years or decades after an initial measles infection•0.4 to 9.7 per million patients with measles•Mutations in the M protein•Clonal expansion of the mutated virus within the brain•M protein is not produced, no budding•Cell fusion by the F and H proteins is maintained, allowing the virus to spread within the brain by local cell fusion; virus evades the immune system, anti-virus antibodies other than M proteinBrain atrophy, gliosis and mononuclear cell infiltration, and rarefied and gliotic white mattergliosis [´´ + osis, condition]: proliferation of astrocytes= scar in the CNS.•A rare disease in the US, with fewer than 10 cases per year, since the introduction of measles vaccine (0.4 to 9.7 per million patients with measles)•Most patients had their measles infection prior to the age of 2 years•the onset of disease occurs between the ages of 5 to 15 years in 85% of patients•The disease usually begins with poor school performance, personality changes and then dementia (stage I). Myoclonus, seizures, and movement disorders occur in stage II. Eventually the comatose and akinetic mutism stages ensue (stage III and IV). Death usually occurs in 1 to 3 years (subacute).Myoclonus in SSPEA pediatric patient with progressively developing degenerative neurologic disease/disorder has an elevated CSF antibody titer to measles virus.  You should suspect which of the following? (A) Acute Lyme disease(B) Fifth disease(C) Possible hepatitis B infection(D) Possible subacute sclerosing panencephalitis (SSPE) (E) Susceptibility to chicken pox Answer (D)伝染性紅斑伝染性紅斑=Erythema infectiosum =fifth disease109-I68サイトメガロウイルスサイトメガロウイルスフクロウの目フクロウの目Cytomegalic cellsInclusion bodies known as “owl eye” inclusionsCytomegalovirus (CMV) encephalitis109-I69クロイツフェルト・ヤコブ病クロイツフェルト・ヤコブ病Sporadic Creutzfeldt-Jakob disease•The most common human prion disorder–1 in 1 million per year–85% of all cases of human prion disease•Age of patients: ave. 65 years•Time between disease onset and death: 2.5 – 6 monthsAge of death in sporadic CJD. Most cases in the seventh decade of life. Uncommon under the age of 40 yearsLaboratory tests of CJD•The electroencephalogram (EEG): 60% to 95% of patients have periodic synchronous discharge (PSD) occurring on the average of one per second•The stress protein, 14-3-3, elevated in 85% of sporadic CJD CSF samples•MRI: 90% of patients show increased intensity in the basal ganglia and cortical ribboningMRI of Creutzfeldt-Jakob diseasestriatal lesions (A), cerebral cortical lesions (B), a combination of both lesions (C)Dorsomedial and pulvinar thalamic hyper intensity “hockey stick sign” in variant CJD。