1.

EXTRACELLULAR AND
INTRACELLULAR PATHOGEN
 Introduction
• Pathogen : mikroorganism that can cause a
disease to human, plant or animal
• Pathogenycitys is the ability of microorganism to
cause a disease in host cell
• Determinants virulence of pathogen are any of
its genetic or biochemical, structure that enable
it to produce disease
• Microba pathogen : virus, bacteria, fungi and
parasit
• Pathogen can infect cell by extracellular or
intracellular mechanism or both
 Introduction
• The development of an infectious disease in an
individual involves complex interactions between
the microbe and the host
• The key events during infection include entry of
the microbe, invasion and colonization of host
tissues, evasion of host immunity, and tissue
injury or functional impairment
• In order to giving response to the infection of
pathogen, the body has immunity sistem as self
defenses against pathogen
 Patogen ??
agen biologis yang menyebabkan
penyakit pada inangnya
Patogen Intraselular
- Tumbuh dan berkembang
dalam sel host
- sistem imun  aktivitas
sitotoksik pada sel terinfeksi
atau mengaktivasi sel lain
untuk melawan patogen
Patogen Ekstraselular
- Tumbuh dan Berkembang
dia luar sel host
-Sistem imun  ditujukan
untuk menghancurkan
patogen dan netralisasi
produknya
Imunity against pathogen
BACTERIA
 Bacterial structure
• Bacteria can be arranged
based on their cell wall • Gambar structur
structure that are gram (-) bacteri
and gram (+)
• Bacteria surface also can be
coated by protective capsul
• Protein and polisakarida on
this capsul can stimulate
immun response
• Bacteria has peptidoglican
(target of lisozim)
• Gram (-) has second
membran composed by
protein and
lipopolisakarida/LPS
IntracellularBacteria
Immunity to Intracelluar Bacteria
• A characteristic of facultative intracellular
bacteria is their ability to survive and even to
replicate within phagocytes
• This bacterial can find place to hide from
antibody in circulation
• To elimination, need cellular immunity
mechanism
• Cellular immunity include innate immunity
and adaptive immnunity
Immunity to Intracelluar Bacteria
 Innate Immunity
• The innate immune response: Phagocytes and
natural killer (NK) cells
• pathogenic intracellular bacteria are resistant
to degradation within phagocytes
• Intracellular bacteria directly activate NK cells
by inducing expression of NK cell–activating
ligands on infected cells and by stimulating
dendritic cell and macrophage production of
IL-12 and IL-15 (NK cell–activating cytokines)
• Activated NK cells produce IFN-γ, which in turn
activates macrophages and increased its power
killing of the phagocytosed bacteria
 Adaptive Immunity
• The major protective immune response:
T cell–mediated immunity

cell-mediated immunity consists of two

types of reactions:
• CD4+ T cells recruit phagocytes
• CD8+ cytotoxic T lymphocytes (CTLs) kill
infected cells
 CD4+ T cells recruit phagocytes

• Intracellur bacteria internalize by macrofag and dendritic cell and

degradate into peptide and form complex with MHCII (exogenous
pathway) and released IL-12
• IL-12 stimulate differentiate CD4+ Th to Th1 effector
• T h1express CD40 ligand and secrete IFN-γ: activate macrophages to
produce several microbicidal substances, including reactive oxygen
species, nitric oxide, and lysosomal enzymes

CD8+ cytotoxic T lymphocytes (CTLs)

 Phagocytosed bacteria stimulate CD8+ T cell responses if bacterial antigens are
transported from phagosomes into the cytosol or if the bacteria escape from
phagosomes and enter the cytoplasm of infected cells
 In cytoplasm/cytosol bacteria will enter the endogeous pathway forming kompleks
MHC I-peptida
 This kompleks recognized by CD8+ Tc and killed by CTL
Immune evasion by Intracellular
bacteria
Extracellular
Bacteria
 Innate Immunity
The principal mechanisms: complement
activation, phagocytosis and the
inflammatory response
complement activation
 Peptidoglycan (gram +) and LPS (gram -) activate the alternative
pathway of complement in the absence of antibody
 Bacteria that express mannose on their surface may bind mannose
binding lectin, activate the lectin pathway
 Result of complement activation is opsonization and enhanced
phagocytosis of the bacteria also lysis by MAC (ex. Neisseria)
 Activation of phagocytes
 Use various surface receptors, including mannose receptors and
scavenger receptors, to recognize extracellular bacteria
 Use Fc receptors and complement receptors to recognize bacteria
opsonized with antibodies and complement proteins respectively.

Inflammation response
 Dendritic cells and phagocytes that are activated by the microbes
secrete cytokines, which induce leukocyte infiltration into sites of
infection (inflammation)
 The recruited leukocytes ingest and destroy the bacteria
 Adaptive Immunity
Humoral immunity is a major protective
immune response against extracellular bacteria
The effecto rmechanisms used by
antibodies :
 Neutralization by high-affinity
IgG, IgM, and IgA isotypes

 opsonization by some
subclasses of IgG

 complement activation by IgM

and subclasses of IgG (classic
pathway)
 Adaptive Immunity
The protein antigens also activate CD4+ helper T cells to produce
cytokines

 Antigen protein phagosited by DC and proses peptida to MHC-II and also

released cytokin
 Kompleks MHC II-peptida recognized by CD4 Th and differentiation to
effector Th 1 and Th 17
 Th1 : released IFN-γ (activate macrofag and antibody)
 Th 17 : recruit Neutofil and monosite (promote inflamation)

Immune evasion by extracellular
bacteria
VIRUS
Virus structure
• capsid protect component
genetic of virus
• Component genetic and
capsid called nukleocapsel
• Capsid consist of simple
subunit protein form heliks,
isometrik or kerucut
• some virus, their capsid
cated by double layer
fosfolipi from host cell
(envelop)
• Envelope can be the target
of antibody
 Immunity to Viruses
• Viruses typically infect various cell types by
using normal cell surface molecules as
receptors to enter the cells.
• viruses can cause tissue injury and disease
by any of several mechanisms.
• Viral replication interferes with normal
cellular protein synthesis and function and
leads to injury and ultimately death of the
infected cell
• Innate and adaptive immune responses to
viruses are aimed at blocking infection and
eliminating infected cells
 Innate Immunity Response
• Principal mechanisms :
Inhibition of infection by
type I interferons and NK
cell–mediated killing of
infected cells
• Innate immune response
begins with the
recognition of PAMPs
• PAMPs inducing the
expression of type I
interferons (IFN- α and
IFN- β) and the activation
of NK cells
• Type I interferons induce an
antiviral response or
resistance : Activating the
JAK-STAT pathway and the
production of new
transcripts (encodes an
enzyme leads to viral RNA
degradation)
• The binding of type I
interferon to NK cells induces
lytic activity
• This activity is enhanced by
IL-12, a cytokine that is
produced by dendritic cells
very early in the response to
viral infection
Innate Immunity Response
 Adaptive immunity response
• Adaptive immunity: Mediated by
antibodies and by CTLs
• Antibodies are effective against viruses
only during the extracellular stage
• Antibodies bind to viral envelope or capsid
antigens and neutralizing to prevent virus
attachment and entry into host cells
• To neutralization : opsonize viral particles
and promote their clearance by phagocytes
• Complement activation : promoting
phagocytosis and possibly by direct lysis of
viruses with lipid envelopes
 Adaptive immunity response
• Primary immunity for intracellular virus is CD8+ or CTL
• Imun response intracellular: kompleks MHC-I and peptida
virus which recognized by CD8+ Tc or CTL (endogen
pathway)
• For full differentiation, CD8+ needs cytokin released by
CD4+ Th and costymulatory released by infected cell
• If the infected cell is a tissue cell and not a professional
APC, such as a dendritic cell, the infected cell may be
phagocytosed by the dendritic cell, which processes the
viral antigens and presents them to naive CD8+ T cells
• The antiviral effects of CTLs are mainly due to killing of
infected cells
• Other mechanisms CTL: include activation of nucleases
within infected cells that degrade viral genomes and
secretion of cytokines such as IFN-γ, which activates
phagocytes and may have some antiviral activity
Overall Immunity response
Immune evasion by viruses
FUNGI
 Structure Fungi
• Eukariotic organism,
• No klorofil
• Complex cell wall structure
composed by glucans
(polymers of glucose),
mannans (long chains of
mannose), and chitin (a
polymer of N-
acetylglucosamine)
• Glucans is a PAMPs
recognized by innate immun
system
• Membran consist of 2 layer
containing sterol
 Innate Immunity
• The defense barriers of innate immunity control most
fungi. Commensal organisms also help control the
growth of potential pathogens
• The principal mediators of innate immunity against
fungi are neutrophils and macrophages
• PAMPs fungi will be recognized by Toll-like receptors
2, 4 and 9, as well as complement receptor 3 (CR3)
• recognition of these cell wall components leads to
the activation of complement (via both alternative
and lectin pathways) along with the induction of
phagocytosis and destruction of fungal cells
• Neutrophils liberate fungicidal substances, such as
reactive oxygen species and lysosomal enzymes, and
phagocytose fungi for intracellular killing
 Adaptive immunity
• Intracellular fungi is eliminated by the same cellular
mechanisms that are effective against intracellular
bacteria (ex. Histoplasma capsulatum and C.
neoformans);elicit Th1 response
• Extracellular fungi elicit strong Th17 responses.
• Fungal glucans binding to dectin-1(C-type lectin
receptor) will activate dendritic cells
• dendritic cell released cytokines (IL-6, IL-23) result
in the production of Th17
• Th17 cells stimulate inflammation and the recruited
neutrophils and monocytes destroy the fungi
 Immunity Evasion by Fungi
• Fungi have evolved mechanisms to
evade the innate immune response with
production of a capsule, as in the case
of C. neoformans, which blocks PRR
binding
• Fungi-induced expulsion from
macrophages that does not kill host
cells and therefore avoids inflammation
PARASITE
 Parasit
• In infectious disease terminology, parasitic
infection refers to infection with animal
parasites such as protozoa and helmints
• It is estimated that about 30% of the world’s
population suffers from parasitic infestations
• Malaria alone affects more than 100 million
people worldwide and is responsible for 1 to 2
million deaths annually
 Innate Immunity
The principal innate immune response :
Protozoa
 Phagocytosis but many are resistant to phagocytic killing and may even replicate
within macrophages
 Some protozoa express surface molecules that are recognized by TLRs and activate
phagocytes
 Example :Plasmodium species (malaria), Toxoplasma gondii (toxoplasmosis) etc, all
express glycosyl phosphatidylinositol lipids that can activate TLR2 and TLR4

Helminthic
 Phagocytosis and secrete microbicidal substances to kill organisms that are too
large to be phagocytosed
 Some helmints also activate alternatif pathway complement system
 Adaptive Immunity
Different protozoa and helminths vary greatly in their structural and
biochemical properties, life cycles, and pathogenic mechanisms. These
conditions lead to different adaptive immune response

Protozoa
 The principal defense mechanism against protozoa that survive within
macrophages is cell-mediated immunity, particularly macrophage
activation by TH1 cell–derived cytokines (Intracelular protozoa) similar to
immunty for virus and bacteria intracellular
 TH1 CD4+ T cells, which produce IFN-γ and thereby activate macrophages
to destroy intracellular parasites
 Some protozoa which can replicate in host cell will stimulate Imun
response of CTL (endogenous pathway). Ex. Malaria parasit
 Adaptive Immunity
Helmints
 Metazoa such as helminths survive in extracellular tissues
 Immun response: mediated by the activation of TH2 cells, which results in
production of IgE antibodies and activation of eosinophils
 Helminths stimulate differentiation of naive CD4+ helper T cells to the Th2
subset of effector cells
 Th2 secrete IL-4 and IL-5
 IL-4 : stimulates the production of IgE, which binds to the Fcε receptor of
eosinophils and mast cells
 IL-5 :stimulates the development and activates eosinophils
 Parasit in GIT destroy by IgG, IgE or ADCC
Adaptive Immunity
Immunity response against
parasit
Immune evasion by parasite
 PUSTAKA
• Abul K. Abbas, Andrew H. Lichtman, Shiv Pillai-
Cellular & Molecular Immunology, 7th Edition -
Saunders Elsevier (2011)
• Janeway, C. A. Jr., P. Travers, M. Waldport, and M.
J. Immunobiology, The Immune System in Health
and Disease
• Goldsby, R.A., T. J. Kindt, B. A. Osborne, and J.
Kuby, 2010, Immunology,7th ed., W. H.
Freeman and C.,New York
• Baratawidjaja, karnen., rengganis, iris. 2010.
Immunologi dasar. Ed 10. Penerbit FK UI:Jakarta