MEKANISME PERUSAKAN TOKSIN BAKTERI
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MEKANISME PERUSAKAN TOKSIN BAKTERI
Agustina Setiawati
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PENDAHULUAN Toksin : substansi terlarut yang dapat mengubah metabolisme
normal sel host sehingga kondisi fisiologisnya jg berubah
Sel penghasil = bakteri, juga berperan dalam proses yg disebabkan oleh protozoa, cacing dan fungi
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Toksin mikroba menjadi dibedakan menjadi 2:1. Eksotoksin2. Endotoksin3. Eksoenzim
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Protein yg diproduksi oleh bakteri, baik yg diekskresikan atau terikat pada permukaan bakteri dan dilepaskan ketika bakteri lisis.
Ditransport ke dalam sel host Mengubah fisiologi dan metabolisme sel host Umumnya terdiri dari sub unit A dan B Contoh eksotoksin: toksin diphteri, kolera dan anthrax
EKSOTOKSIN
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EKSOTOKSIN ….
Ekstoksin masuk sel host dgn cara:1) Receptor mediated endocytosis2) Bergabung dengan lisosom3) Suasana asam pd lisosom memecah ikatan disulfida dan melepas sub unit A dalam sel 4) Sub unit A berperan dalam berbagai toksisitas intraseluler
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Mekanisme toksisitas oleh EKSOTOKSIN ada 3:1. Menghambat sintesis protein : toksin dipteri2. Hiperaktivitas ekskresi: toksin kolera3. Penghambatan aktivitas neurotransmitter: toksin tetanus
EKSOTOKSIN ….
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ANTIGENIK EKSOTOKSIN Eksotoksin bersifat antigenik
Aktivitas eksotoksin diturunkan oleh antibody dalam tubuh host Eksotoksin tidak stabil, pada suatu saat sifat toksisitasnya
hilang tetapi tetap bersifat antigenik Sifat inilah yg dimanfaatkan utk pembuatan TOXOID TOXOID: toksin yg dilemahkan tetapi masih mempunyai sifat
antigenik (memacu produksi antibodi). Toxoid digunakan dalam imunisasi
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CORYNEBACTERIUM DIPHTHERIAE Corynebacterium diptheriae
Produces AB exotoxin Gram positive rod w/ tapered ends Significant cause of mortality until 1950s Decline due to vaccination with toxoid (DPT) Spread by close contact via droplets from human carriers or humans
with active infection Common location upper respiratory tract
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Sign and SymptomsLocal infection
Severe inflammatory reaction Severe swelling in back of neck
Sore throat, nausea, vomiting Formation of pseudomembrane
Systemic Toxemia as toxin is absorbed
from throat and carried by blood to target organs
Heart and nervous system
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MEKANISME AKSI TOKSIN DIPTERI
A subunit…Mengaktivitas
elongation factor-2) (EF-2) yg diperlukan untuk sintesis protein
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VIBRIO CHOLERAE Vibrio cholerae
Produces A + 5B exotoxin Gram negative vibrio Unusual disease
Cholerae does not invade tissue Cholerae does not damage tissue
Lives in estuaries on copepods Humans are incidentally infected
when ingesting contaminated food or water
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SYMPTOMS OF VIBRIO CHOLERAE Symptoms
Secretory or watery diarrhea No blood in diarrhea
Large watery bowel movements Loss of electrolytes Muscle cramps
Low blood pressure Rapid heart rate & feeble pulse Vomiting White blood cell count usually normal
Treatment Usually self limiting symptoms as long as IV fluids are administered with
oral rehydration solutions
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CLINICAL MANIFESTATIONS
www.who.int/entity/water_sanitation_health/dwq/en/admicrob6.pdf
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TREATING CHOLERA
Sack, David, et al. 2004. Seminar: Cholera. The Lancet. 363: 223-233.
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MEKANISME AKSI TOKSIN KOLERA
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BACILLUS ANTHRACIS Bacillus anthracis
Produces 2A + B exotoxin Gram positive spore forming bacteriaFound in soil Anthrax disease – direct exposure to spores
Inhalation – pulmonary Ingestion – gastrointestinal Invasion into surface wound – cutaneous
No cases involve person to person spread
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SYGN AND MPTOMS OF BACILLUS ANTHRACIS Cutaneous
Spores enter abrasions or cut in skin
Germination of spore causes local ulceration of the skin
Painless black eschar with edema
Antibiotics prevent invasion into blood stream
Usually heals completely without scarring
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SYMPTOMS OF BACILLUS ANTHRACIS Pulmonary
Life cycle Macrophages engulf spores Travel to nodes Spores germinate en route Cells are released spreading toxins and vegetative cells into the
blood stream Symptoms – caused by toxins
Fever and chills Shortness of breath, & cough Massive pleural effusions Sepsis, shock & death
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Two primary toxins & capsule geneAll three genes are located on plasmids Edema Factor A – toxin
Adenylyl cyclase enzyme – increase in cAMP Causes edema and pro-inflammatory response
Lethal Factor A – toxin Metalloprotease Cleaves MAP kinase required from cell division and signaling Causes an overall suppression of immune system
MEKANISME AKSI TOKSIN ANTRAK
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TRANSDUKSI SINYAL SELULER ADENILAT SIKLASE-CAMP
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B. Anthracis
EF
B
LF
BB
LFEF
LF
EF Endosome
Acidic Environment
BcAMP
MAPK
EDEMA Increased expression of pro-inflammatory
mediators
IMMUNE SUPPRESSION WBCs do not divide in
the presence of pathogens; overall
decrease in phagocytosis
MEKANISME AKSI TOKSIN ANTRAK
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CLOSTRIDIUM TETANUS Clostridium tetanus
Produces AB exotoxin Produces irreversible muscle contraction Spastic paralysis Symptoms result entirely from toxin Anaerobic gram + spore forming rod Lives in soil usually on rusty metal Enters from puncture wound or cut Organism does not spread form entry point Begins with stiff back and neck muscles Death results from respiratory failure
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Menghambat pelepasan ‘inhibitory neurotransmitter ‘ yaitu GABA – aminobutyric acid γ
MEKANISME AKSI TOKSIN TETANUS
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ENDOTOKSIN Endotoksin
Nama sering menyebabkan salah arti Toksin tidak berada dalam sel bakteri, tetapi bagian membran sel
bakteri Toksin terletak pada bagian luar membran sel bakteri
Lipopolisakarida (LPS)bakteri gram - Asam lipotekoat bakteri gram +
Toksik pada konsentrasi yg tinggiDapat dilepaskan oleh bakteri saat lisis, spt: E.coli,
Salmonella, Shigella, Pseudomonas, Haemophilus
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Menurunkan sistem imun hostMempunyai efek farmakologis yg berbeda pada konsentrasi
rendah atau tinggi
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MECHANISM OF ACTION OF ENDOTOXINS
Endotoxins bind to Receptors on
Macrophages Neutrophils Lymphocytes
Proteins of complement Complement is a group of proteins which circulate at constant levels in the
blood When activated complement is a powerful tool against invading pathogens Increased inflamation, opsonization, & MAC
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EndotoksinHost cell receptors (TLR) bind to
endotoxinTLR (Toll-like Receptor)
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Inflammation Opsonization
MAC
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PIROGEN Merupakan salah satu endotoksin, ada yg menyebutkan
ENDOTOKSIN=PIROGEN Bagian Lipid A membran bakteri gram – Potensi lebih rendah dibandingkan eksotoksin Aksi tidak spesifik Stabil terhadap pemanasan selama 30’, Tidak bersifat antigenik (tidak bisa diubah menjadi toksoid)
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MEMBRAN SEL BAKTERI
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LIPOPOLISAKARIDA Bagian paling luar membran sel Total 3- 10% berat kering sel 3-4 juta molekul tiap sel Bagian yg disebut pirogen: Lipid A Lipid A menstimulasi sistem imun
manusia
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MEKANISME AKSI PIROGEN LPS terikat pada protein plasma LPS binding protein (LBP) LBP berikatan dgn reseptorpd makrofag dan monosit sehingga
menyebabkan:1. Produksi sitokin (IL, TNF) memicu produksi prostglandin & leukotrien inflamasi2. Aktivasi komplemen pelepasan histamin yg menyebabkan vasodilatasi3. Koagulasi
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TES PIROGEN Rabbit Pyrogen Test Limulus Amoebocyte Lisate Test
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BACTERIAL EXOENZYMES
Enzim yg dieksresikan bakteri pada matriks ekstraseluler sel, mempunyai berbagai aktivitas: Merusak membran
Merusak membran sell host Lisis sel eritrosit
Merusak matriks ekstraseluler (fibronectin, kolagen & MMP)
Mengubah aktivitas obat co: Penisilanase (hidrolisis penisilin)
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EKSOENZIM α toxin
Pore forming toxin Common in Staphylococcus aureus
Hemolysins Destroy red blood cells Streptolysins – group of hemolysins excreted by Streptococcus
Streptokinase Attacks fibrin clots From Streptococcus pyogenes
Hyaluronidase Breaks down hyaluronic acids in connective tissue Similar function for
Collagenase Elastases
DNase DNA is viscous Thins pus (DNA & debris) released from WBC
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CLOSTRIDIUM PERFRINGENS
Clostridium perfringens Ananerobic gram + spore forming rod Widely distributed in nature Myonecrosis Entry of spores by traumatic injury Not highly invasive so it requires exoenzymes for a supportive growth
environment Exoenzymes
Lecithinase lipase c – major toxin Lyses mammalian cells indiscriminately Substrate is phophatidylcholine
Collagenase & hyaluronidase DNAase
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TERIMA KASIH