Molecular pathogenesis

of infection

Andriansjah, Anis Karuniawati, T. Mirawati Sudiro

Departemen Mikrobiologi FKUI
 Kochs Postulates (1890) by Robert Koch
!
The microbe must be present in every case of
the disease

The microbe must be isolated from the diseased

host and grown in pure culture

The disease must be reproduced when a pure

culture is introduced into a non-diseased
susceptible host

The microbe must be recoverable from an

experimentally infected host
! Exception to Kochs Postulates
The microbes could not always be grown in the
laboratory

Cofactors or genetic and immunologic factors in

the host may play a vital part

Ethical considerations prevent applying Kochs

postulates to diseases and pathogens that occur
in human only

The disease do not appear until many years

after a specific infection
 Guidelines for establishing the causes of infectious diseases
Koch`s postulat Moleculer Koch`s
postulat
1. The microbe must be 1. The phenotype or
present in every case of property under
the disease investigation should be
significantly associated
with pathogenic strains of
a species and not with
nonpathogenic strains
2. The microbe must be 2. Specific inactivation of
isolated from the diseased the gene or genes
host and grown in pure associated with the
culture suspected virulence trait
should lead to a
measurable decrease in
pathogenicity or
virulence
Molecular guidelines for
establishing microbial
disease causation
1. The nucleic acid sequence of a
putative pathogen should be
present in most cases of an
infectious disease:
Note:
The presence of nucleic acid
!
sequence can be detected by
molecular method such as PCR that
is specific for the sequence of a
pathogen
2. The nucleic acid sequence of a
putative pathogen should be
absent from most healthy controls.
If the sequence is detected in healthy
control, it should be present with a
lower prevalence as compared with
patient with disease, and in lower
copy number
!
 Colonization !
To colonize a site populated by normal flora,
the new arrival must compete successfully
with:
established organisms for space and
nutrients (siderophores)
overcome their toxic product
counter the bodys defenses aimed at
protecting the surfaces (IgA proteases)
 Adhesion / Attachment !
The process by which microorganisms
attach themselves to cells

Adhesion factors:
Specialized structures
Adhesion disk (protozoa), suckers, hooks
(helminthes)
Ligands: Surface lipoprotein and
glycoprotein (bacteria, viruses)
Adhesin (bacteria): found on fimbrae,
flagella, glycocalyses
Attachment protein (viruses)
 !
factors support the adherence mechanism

Pili and fimbriae mediate attachment

Pili constanly lost and reform allow some bacteria

avoid host defenses

Adhesins protein, eg. nonfibrillar adhesins of

Streptococcus pyogenes mediates attachment to
fibronectin, a protein found on many host cell surface

Signal transduction signal which affect to activate or

repress the expression of some gene
Binding of adhesins to receptor on host cell may activate or
repress virulence genes of bacterial cells
 !
Lost the ability to make ligands:
Genetic change or mutation
Exposure to certain physical or chemical agent
harmless or avirulent

Some bacterial pathogens do not attach to host

cells directly, but instead interact with each other
to form a sticky web of bacteria and
polysaccharides called a biofilm, which adheres
to a surface within a host (example: dental
plaque)
 Receptor molecule on Host Cells !
typically glycoprotein containing sugar molecule
such as mannose and galactose

Not present for the benefit of the infectious

agents; they have specific functions in the life of
the cells

Present only in certain cells, which are then

uniquely susceptible to infection (specificity of
pathogens for particular hosts):
N.gonorrhoeae has adhesin on its fimbrae that
adhere to cells lining the urethra and vagina of human
 Pathogenicity
The ability a of microorganism to cause disease
!
Virulence
Degree of pathogenicity

Virulence factors
A variety of traits that interact with a host and enable
the pathogen to enter a host, adhere to host cells,
gain access to nutrients, and escape detection or
removal by the immune system
 Virulence Factors of Bacteria !
Extracellular Enzymes (Hyaluronidase and
collagenase, Coagulase, Kinase)
Toxin (Exotoxin, endotoxin)
Antiphagocytic factor (capsule, antiphagocytic chemical)
Invasion factor
Siderophore
Lipopolysacharides
 Eksotoksin
Dieksresi oleh sel hidup
Endotoksin
Bagian integral dinding sel
bakteri negatif Gram. Dilepaskan
!
pada saat bakteri mati dan
sebagian selama pertumbuhan
Diproduksi oleh bakteri postif Bakteri negatif Gram saja
dan negatif Gram
Polipeptida Lipopolisakarida (LPS)
Relatif tak stabil pada Stabil
pemanasan> 600C
Sangat antigenik Imunogenik lemah
Dapat diubah menjadi toksoid Tidak dapat
Sangat toksik Sedang
Biasanya terikat pada reseptor Tidak
spesifik
Tidak menimbulkan demam Demam
Sering dikontrol oleh gen Disintesis langsung oleh gen
ekstrakromosomal (plasmid) kromosomal
 Superantigens

Superantigens form a bridge

between the MHC class II of
macrophages or other APCs !
and receptor on T cells that
interact with the class II MHC:
Many APCs will have
superantigens molecules bound to
their surface
Superantigen also bind T cell
receptor indiscriminately
forms many more APC-T helper
cell pairs than would normally form
 Superantigens

Normal response to antigen : APC stimulation 1

in 10,000 T cells
Superantigen : APC stimulation 1 in 5 T cells
Result : excessively high levels of IL-2 to be
released bloodstream symptoms :
nausea, vomiting, malaise, and fever
Excess production of other cytokines,
which leads to shock
E.g. staphylococcal toxin!
 Pathogenesis of Viral Diseases !
Maintain a reservoir
Enter a host
Contact and enter susceptible cells
Replicate within the cells
Release from the host cells
Virus-host interactions engender host immune
response
Be either cleared from the body of the host,
establish a persistent infection, or kill the host
Be shed back into the environment
 Contact, entry, and primary replication
Entrance: one of the body surfaces; needle
sticks, blood transfusions, organ transplants,
insect vectors
Adsorption or attachment: process of
penetrates a host cells to gain access to the
! cells replicative machinery
Adsorption occurs because of specific protein
ligand:
Enveloped virus use spikes (viral protein that
! protrude from their membrane)
Naked virus: their ligands as part of their capsid
protein
2. Tropisma dan penyebaran virus dalam tubuh
- Mekanisme penyebaran dalam tubuh
bervariasi: aliran darah, limfatik, saraf
perifer, antar sel
- spesifik jaringan/ sel
- Faktor-faktor sel/ jaringan dan faktor-
faktor virus yang mempengaruhi tropisma
- reseptor spesifik
! - ekspresi gen virus
- enzim yg diperlukan untuk replikasi virus
Virus Immune cells Interaction

!
!
Mekanisme pertahanan tubuh :
- Spesifik dan non-spesifik
- Kekebalan seluler dan humoral
- Proses imunopatologis
misal flu-like sistemic symptoms
! (interferon), DHF
Usaha virus dalam mengatasi sistem imun !
- Menginfeksi sel-sel yang berperan pada sistem imun
(HIV)
- Menginfeksi sel neuron yg sedikit atau tidak
mengekspresi MHC class I (virus herpes)
- Menghasilkan protein imunomodulator yang
menghambat MHC (adenovirus)
- Bermutasi antigen berubah (virus influenza, HIV)
- Ekspresi protein permukaan ditekan (virus herpes)
 !
Protooncogenes: genes
that play a role in cell
division

Factors contribute to the

inhibition of oncogene
repressor and the
activation of
oncogenes (UV,
radiation, carcinogens
and viruses)
MEKANISME INDUKSI TUMOR OLEH VIRUS

Tidak langsung
1. Supresi sistem imun pejamu
(HTLV-1, HIV-1, CMV, avian reticuloendotheliosis virus,
feline leukemia virus, Mareks disease virus)
2. Stimulasi proliferasi sel, target perubahan neoplastik
lain bertambah.
a. Regenerasi sel setelah sitolisis oleh virus
(kemungkinan : HBV, HCV)
b. Mitogenesis sel imunokompeten atau sel lain
(kemungkinan : beberapa virus lekemia mencit,
HTLV-1, HIV-1)
 MEKANISME INDUKSI TUMOR OLEH VIRUS

Langsung
1. Hit & run
- DNA atau fungsi virus bekerja sesaat
- Keberadaan gene atau struktur virus tidak perlu menetap
- Contoh : BPV, beberapa virus herpes (a.l. EBV)
2. Bagian gen virus yang penting tetap berada di sel
a. Virus memiliki gen yang produknya secara langsung

! atau tidak langsung berfungsi dalam terjadinya tumor

(onkogen)
I. Onkogen telah berevolusi dari proto-onkogen sel
normal (RSV)
ii. Onkogen langsung ditransduksi dari protoonkogen
saat infeksi virus (FLV, ALV)
iii. Onkogen tidak mempunyai homolog gen sel normal
(SV40, polyomavirus, papillomavirus, adenovirus, EBV,
HTLV-1)
2.b. Mutagenesis dengan insersi
- Insersi DNA virus pada genome sel meningkatkan atau
! menekan ekspresi gen normal
(a.l. ALV, beberapa virus papilloma)
 !

Adenovirus E1A,
SV40-LT, HPV16&18 E7
-- bind to Rb-related proteins

Contoh : Inaktivasi tumor supresor oleh protein virus

 TERIMA KASIH

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