Transcript MEKANISME PERUSAKAN TOKSIN BAKTERI

MEKANISME PERUSAKAN
TOKSIN BAKTERI
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Agustina Setiawati
PENDAHULUAN
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Toksin : substansi terlarut yang dapat mengubah metabolisme
normal sel host sehingga kondisi fisiologisnya jg berubah
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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. Eksotoksin
2. Endotoksin
3. Eksoenzim
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EKSOTOKSIN
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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
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EKSOTOKSIN ….
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Ekstoksin masuk sel host dgn cara:
1) Receptor mediated endocytosis
2) Bergabung dengan lisosom
3) 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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EKSOTOKSIN ….
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Mekanisme toksisitas oleh EKSOTOKSIN ada 3:
1. Menghambat sintesis protein : toksin dipteri
2. Hiperaktivitas ekskresi: toksin kolera
3. Penghambatan aktivitas neurotransmitter: toksin tetanus
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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
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Corynebacterium diptheriae
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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
 Sign
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and Symptoms
Local infection
Severe inflammatory reaction
 Severe swelling in back of neck
 Sore throat, nausea, vomiting
 Formation of pseudomembrane
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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…
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Mengaktivitas
elongation factor-2)
(EF-2) yg diperlukan
untuk sintesis protein
VIBRIO CHOLERAE
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Vibrio cholerae
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Produces A + 5B exotoxin
Gram negative vibrio
Unusual disease
Cholerae does not invade tissue
 Cholerae does not damage tissue
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Lives in estuaries on copepods
Humans are incidentally infected
when ingesting contaminated food
or water
SYMPTOMS OF VIBRIO CHOLERAE
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Symptoms
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Secretory or watery diarrhea
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No blood in diarrhea
Large watery bowel movements
Loss of electrolytes
 Muscle cramps
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Low blood pressure
Rapid heart rate & feeble pulse
Vomiting
White blood cell count usually normal
Treatment
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Usually self limiting symptoms as long as IV fluids are administered with
oral rehydration solutions
CLINICAL MANIFESTATIONS
www.who.int/entity/water_sanitation_health/dwq/en/admicrob6.pdf
TREATING CHOLERA
Sack, David, et al. 2004. Seminar: Cholera. The Lancet. 363: 223-233.
MEKANISME AKSI TOKSIN KOLERA
BACILLUS ANTHRACIS
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Bacillus anthracis
 Produces 2A + B exotoxin
 Gram positive spore forming bacteria
 Found in soil
 Anthrax disease – direct exposure to spores
Inhalation – pulmonary
 Ingestion – gastrointestinal
 Invasion into surface wound – cutaneous
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No cases involve person to person spread
SYGN AND MPTOMS OF BACILLUS ANTHRACIS
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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
SYMPTOMS OF BACILLUS ANTHRACIS
 Pulmonary
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Life cycle
Macrophages engulf spores
 Travel to nodes
 Spores germinate en route
 Cells are released spreading toxins and vegetative cells into the
blood stream
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Symptoms – caused by toxins
Fever and chills
 Shortness of breath, & cough
 Massive pleural effusions
 Sepsis, shock & death
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MEKANISME AKSI TOKSIN ANTRAK
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Two primary toxins & capsule gene
 All three genes are located on plasmids
 Edema Factor A – toxin
Adenylyl cyclase enzyme – increase in cAMP
 Causes edema and pro-inflammatory response
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Lethal Factor A – toxin
Metalloprotease
 Cleaves MAP kinase required from cell division and signaling
 Causes an overall suppression of immune system
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TRANSDUKSI SINYAL SELULER ADENILAT
SIKLASE-CAMP
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MEKANISME AKSI TOKSIN
ANTRAK
EF
LF
EDEMA
Increased expression
of pro-inflammatory
mediators
B
cAMP
EF
Endosome
B
MAPK
IMMUNE SUPPRESSION
WBCs do not divide in
the presence of
pathogens; overall
decrease in phagocytosis
Acidic
Environment
CLOSTRIDIUM TETANUS
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Clostridium tetanus
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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
MEKANISME AKSI TOKSIN TETANUS
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Menghambat pelepasan ‘inhibitory neurotransmitter ‘ yaitu
GABA – aminobutyric acid γ
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ENDOTOKSIN
 Endotoksin
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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 +
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Toksik pada konsentrasi yg tinggi
 Dapat dilepaskan oleh bakteri saat lisis, spt: E.coli,
Salmonella, Shigella, Pseudomonas, Haemophilus
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Menurunkan sistem imun host
Mempunyai efek farmakologis yg berbeda pada konsentrasi
rendah atau tinggi
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MECHANISM OF ACTION OF ENDOTOXINS
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Endotoxins bind to
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Receptors on
Macrophages
 Neutrophils
 Lymphocytes
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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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 Endotoksin
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Host cell receptors (TLR) bind to
endotoxin
TLR (Toll-like Receptor)
Inflammation
Opsonization
MAC
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  inflamasi
2. Aktivasi komplemen  pelepasan histamin yg
menyebabkan vasodilatasi
3. Koagulasi
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TES PIROGEN
Rabbit Pyrogen Test
 Limulus Amoebocyte Lisate Test
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BACTERIAL EXOENZYMES
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Enzim yg dieksresikan bakteri pada matriks ekstraseluler sel,
mempunyai berbagai aktivitas:
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Merusak membran
Merusak membran sell host
 Lisis sel eritrosit
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Merusak matriks ekstraseluler (fibronectin, kolagen & MMP)
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Mengubah aktivitas obat co: Penisilanase (hidrolisis penisilin)
EKSOENZIM
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α toxin
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Pore forming toxin
Common in Staphylococcus
aureus
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Destroy red blood cells
Streptolysins – group of
hemolysins excreted by
Streptococcus
Streptokinase
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Attacks fibrin clots
From Streptococcus pyogenes
Hyaluronidase
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Hemolysins
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Breaks down hyaluronic acids
in connective tissue
Similar function for
Collagenase
 Elastases
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DNase
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DNA is viscous
Thins pus (DNA & debris)
released from WBC
CLOSTRIDIUM PERFRINGENS
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Clostridium perfringens
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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
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Lecithinase lipase c – major toxin
Lyses mammalian cells indiscriminately
 Substrate is phophatidylcholine
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Collagenase & hyaluronidase
 DNAase
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