Understanding Aerobes, Anaerobes, and Human Disease Viruses

1. 109-A10 http://www.usmle-forums.com/usmle-step-1-bits-pieces/1702-aerobes-anaerobes.html (Anaerobes)These are microorganisms that can live without oxygen.Facultative anaerobescan live without oxygen but they use it if it available. Most of the bacteria we know falls in the facultative anaerobes category (e.g E. Coli).Obligate anaerobesare harmed by the presence of oxygen and these usually utilize fermentation to produce their necessary ATP.Examples of obligate anaerobes:ActinomycesBacteroidesClostridiumGood way to remember these isABCYet, there's another sub category of anaerobes and these are calledaerotolerant anaerobes. These bugs unlike the obligate ones, are not harmed in the presence of oxygen.Examples of aerotolerant anaerobes:Propionibacterium and Lactobacillus (both are normal human flora) (Aerobes) Obligate aerobesrequire oxygen to in order to oxidize nutrients and they usually have catalase and superoxide mutase. They cannot survive without oxygen.Examples of obligate aerobes:NocardiaPseudomonoa (rememberaerogenosa)MycobacteriumBacillusA good mnemonic to remember these isNaggingPetsMustBreathMicroaerophilicsare those organisms that may use oxygen but only when it's in low concentrations and the two most commonly tested bugs in this category is Campylobacter and Helicobacter (both of which are GI bugs).

2. 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

3. 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

4. Family Bunyaviridae 5 genera Genus Human disease Orthobunyavirus La Crosse encephalitis, California encephalitis Phlebovirus Rift Valley fever (RVF) Nairovirus Crimean-Congo hemorrhagic fever (CCHF) Hantavirus Hemorrhagic fever with renal syndrome (HFRS) Hantavirus pulmonary syndrome (HPS) Tospovirus Plant virus, no known human disease Encephalitis Hemorrhagic Fever Pneumonia

5. BUNYAVIRIDAE; Bunyamwera in Uganda Virion: ENV, 120nm; 3 Helical capsids; three 1X RNAs 5 Genera. 2 genera have ambisense RNAs; Phelbovirus & Tospovirus California Sin Nombre CCHF Rift Valley S+M RNAs = ambi Tospovirus 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 THIRPS Infects tomato, peanuts, watermelon, zucchini, impatiens Dr. O’Callaghan Journal Club 4/20/12

6. 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 Alenquer Chaniru Chagres Naples Punta Toro Rift Valley Fever Sicilian Toscana SFTS Virus is new GROUP of PHLBOVIRUS Genus. 9th Phlebovirus to cause disease in humans thrips These leaves show symptoms of tomato spotted leaf virus. / Kathie Rowell/The Times May 12, 2011 From Dr. O’Callaghan Virology Journal Club April 29, 2011

7. 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

8. Some deficiencies can lead to lymphoproliferative diseases (Table 4.2) • Familial hemophagocytic lymphohistiocytosis (FHL or FHLH) is caused by an inherited deficiency of perforin • Hemophagocytosis: ingestion of red blood cells by macrophages • Pfp-/- mice infected with some types of viruses result in a disease similar to FHL because the immune system is uncontrolled  demonstrates that perforin plays an important role in regulating the immune response • Hemophagocytic lymphohistiocytosis (HLH) =Hemophagocytic syndrome (HPS) =Macrophage activation syndrome

9. 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?

11. 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

12. Hemophagocytic lymphohistiocytosis (HLH) Hemophagocytic syndrome (HPS)

13. Genetic hemophagocytic lymphohistiocytosis =primary hemophagocytic syndrome Familial hemophagocytic lymphohistiocytosis (FHL or FHLH) (Table 4.2) FHL1: unidentified gene on chromosome 9 FHL2: perforin (PRF1) mutation FHL3: Munc13-4 (UNC13D) mutation FHL4: syntaxin 11 (STX11) mutation FHL5: syntaxin binding protein (STXBP) 2 (Munc 18-2) mutation All four proteins are involved in the granule-mediated cytotoxic pathway of lymphocytes Immune deficiency syndromes (Table 4.1) Chediak-Higashi syndrome 1: LYST (=CHS1) mutation Griscelli syndrome 2: RAB27A mutation LYST and RAB27A: role in vesicle trafficking in CTL X-linked lymphoproliferative syndrome: SH2D1A mutation NK cell inhibition leads to severe EB virus infection and sustained proliferation of CTL (Table 4.3a)

17. Chediak-Higashi syndrome • A defect in LYST (=CHS1), which is involved in intracelluar vesicle formation and trafficking • Reported by Moises Chediak (1954) and Ototaka Higashi (1956) • A failure of lysosomes and phagosomes to fuse properly • Phagocytes have enlarged granules and impaired intracellular killing ability • Partial albinism, abnormal platelet function, severe immunodeficiency http://www.jpeds.or.jp/saisin/saisin_100604.html Ototaka Higashi, 東音高 http://www.nurs.or.jp/~academy/igaku/t1/t1241.htm

19. 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 • 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 https://www.youtube.com/watch?v=96n_nrgBV44

20. 109-B16 • 原発性免疫不全症 • 慢性肉芽腫症　Chronic granulomatous disease (CGD)

21. Primary Immunodeficiency Expert Committee http://www.iuisonline.org/iuis/index.php/primary-immunodeficiency-expert-committee.html

22. 5. Congenital defects of phagocytes MSMD: Mendelian susceptibility to mycobacterial disease

23. Immunodeficiencies of phagocytic cells Myeloid deficiencies primarily affect the innate immune system Phagocyte immunodeficiencies can be grouped into 4 types: Deficiency in • Phagocyte production: Development – defect in gene required for myeloid progenitor cell differentiation • Phagocyte adhesion • Phagocyte activation: Phagocytosis • Killing

24. Defects in phagocytic cells are associated with persistence of bacterial infection 5.1: Defects of neutrophil differentiation 5.2: Defects of motility 6.2, 6.3: IRAK4, MyD88 deficiency 5.3: Defects of respiratory burst Table 4.1: Immunodeficiency with hypopigmentation

25. Leukocyte adhesion deficiency (LAD) (Table 5.2) • 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 endothelium Caused 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 adhesion

26. LAD type 1 • Leukocyte adhesion deficiency (LAD) results from mutation in the CD18 molecule – the b2 chain of the integrin family • The result is a loss of surface expression of key integrin molecules: Abnormal functions: endothelium adherence, neutrophil chemotaxis, phagocytosis, cytotoxicity Mac-1 p150:95

28. 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　　

29. 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

30. Dermatitis herpetiformis After gluten-free diet Skin IgA deposition

31. 109-D14 急性リウマチ熱 Acute rheumatic fever (ARF) • A multisystem disease resulting from an autoimmune reaction to infection with group A streptococci • Almost all of the manifestations in many parts of the body resolve completely • Exception is cardiac valvular damage: rheumatic heart disease (RHD) • Disease of poverty: less crowded housing and better hygiene resulted in reduced transmission of group A streptococci + antibiotics and improved medical care Harrison’s Online http://www.accessmedicine.com/content.aspx?aID=2881862

32. Molecular mimicry in rheumatic fever

33. RHD :rheumatic heart disease

34. 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

35. 12-4 Epitope (determinant) spreading In animals, autoimmune disease can be generated by immunizing autoantigen (protein X) in adjuvant First response is dominated by T cell response to one peptide derived from protein X Later, tissue damage release protein X and other self proteins (protein Y) Further activate T cell responses to proteins X and Y Example: 12-7 Experimental allergic encephalomyelitis (EAE), animal model for multiple sclerosis

36. Epitope spreading • Self-antigen is released from damaged tissue can be taken up by antigen presenting cells (APCs), processed and presented to autoreactive T cells • Further tissue destruction by activated T cells causes the release of more self-antigen from tissues • The response can then spread to involve T cells (or antibodies) specific for other self-antigens in a process known as epitope spreading

37. 109-D44 Mumps 急性耳下腺炎

38. Mumps Mumps; “Otafuku” in Japanese Otafuku, Japanese mask(“fuku” = swelling) Child with parotitis (CDC web site: http://www.cdc.gov/mumps/about/photos.html) Mumps causes salivary gland swelling, particularly the parotid gland

39. 109-D49 項部硬直 髄膜炎

40. Viral Meningitis (Enteroviruses, HIV, HSV type 2, Arboviruses) Headache Stiff neck Photophobia Little alteration in consciousness No focal signs Viral Encephalitis (HSV, Arboviruses, Rabies, Nipah virus) Altered consciousness Focal neurological signs Seizures Meningeal signs Viral Meningitis vs. Encephalitis Dr. John E. Greenlee, MD, University of Utah https://www.youtube.com/watch?v=bj2CNkjvY4o

41. 109-E50 慢性炎症性脱髄性多発根神経炎

43. 109-E52 クループ

44. Paramyxoviridae Human Diseases Family includes numerous human disease-causing members: PaRaMyxovirus: Parainfluenza, Respiratory syncytial virus, Rubeola (Measles), Mumps Subfamily 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.

45. Croup http://www.edexitvideo.com/patient/videoplayer/7xDM8vuVEPo

46. 109-E52 急性喉頭蓋炎：選択肢 2016年近畿大学６年 寺田徹さんクリクラ 正常

47. 109-F13 選択肢：手足口病

48. 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 days http://pathmicro.med.sc.edu/virol/picorna.htm

49. Coxsackievirus • The first strains were isolated from two paralyzed boys in the village of Coxsackie, New York • Meningitis and encephalitis • Myocarditis

50. 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