Transcript Molecular Biology of the Cell

Alberts • Johnson • Lewis • Raff • Roberts • Walter
Molecular Biology of the Cell
Fifth Edition
Chapter 24
Pathogens, Infection,
and Innate Immunity
Copyright © Garland Science 2008
Pathogens and Infection
• Infectious diseases currently cause about one-third of all
human deaths in the world, more than all forms of cancer
combined.
• Tuberculosis and malaria, AIDS (acquired immune
deficiency syndrome)
• Most gastric ulcers: Helicobacter pylori
• Pathogens: the agents that cause infectious diseases
• Skin, stomach acid, RNase
• Innate immune responses (즉각, 과거X) vs adaptive
immune responses
Parasitism at many levels
벼룩
pathogenic bacteriumYersinia pestis
Phages
Figure 24-1 Molecular Biology of the Cell (© Garland Science 2008)
Pathogens Have Evolved Specific Mechanisms for
Interacting with Their Hosts
• Normal flora: commensal microbes
– for proper development of the gastrointestinal
tract in infants
– competing with disease-causing microorganisms
• Primary pathogens: cause overt disease in
unique host species or in a wide variety of
hosts
– Acute epidemic infections
– Persistent infections.
A successful pathogen
• (1) colonize the host;
• (2) find a nutritionally compatible niche in the host’s
body;
• (3) avoid, subvert, or circumvent the host’s innate and
adaptive immune responses;
• (4) replicate, using host resources;
• (5) exit and spread to a new host.
• Skillful and practical cell biologists
The Signs and Symptoms of Infection May Be
Caused by the Pathogen or by the Host’s Responses
Why would they evolve to cause
disease, that is, to damage their hosts?
Many of the symptoms and signs that we associate with
infectious disease are actually direct manifestations of the
host’s immune responses in action.
Figure 24-2 Molecular Biology of the Cell (© Garland Science 2008)
The Signs and Symptoms of Infection May Be Caused by
the Pathogen or by the Host’s Responses
Interaction between microbes and immune responses
in microbial pathogenesis
Staphylococcus epidermidis
Paramyxovirus that causes mumps
the bacterium Chlamydia trachomatis
a latent M. tuberculosis infection
the herpes simplex virus
Figure 24-2 Molecular Biology of the Cell (© Garland Science 2008)
Pathogens Are Phylogenetically Diverse
Pathogens in many forms: bacteria, virus, single-celled fungi and protozoa, parasitic
worms, prion protein
poliovirus
bacterium
Vibrio cholerae
protozoan parasite
Toxoplasma gondii
Ascaris nematodes (2살?)
Viruses vary tremendously in their size, shape, and content (DNA versus RNA, enveloped)
Figure 24-3 Molecular Biology of the Cell (© Garland Science 2008)
Bacterial Pathogens Carry Specialized
Virulence Genes
Bacterial shapes
Figure 24-4a Molecular Biology of the Cell (© Garland Science 2008)
Bacterial cell-surface structures
Streptococcus
Staphylococcus
violet dye
Figure 24-4b,c Molecular Biology of the Cell (© Garland Science 2008)
E. Coli
Salmonella
Bacterial Pathogens Carry Specialized
Virulence Genes
Bacterial shapes and cell-surface structures
Figure 24-4d Molecular Biology of the Cell (© Garland Science 2008)
Pathogens
• Obligate pathogens.
• Facultative pathogens.
• Opportunistic pathogens.
• Specialists
– Shigella flexneri (bloody
diarrhea) : humans and other
primates
• Generalists:
– the opportunistic pathogen
Pseudomonas aeruginosa
:동식물
Virulence genes and virulence factors
Genetic differences between pathogenic and
nonpathogenic bacteria
If based on molecular techniques,
they would be classified in the same genus, if not in
the same species.
Figure 24-5 Molecular Biology of the Cell (© Garland Science 2008)
Bacterial Pathogens Carry Specialized
Virulence Genes
Genetic organization of Vibrio cholerae
intestinal colonization
Figure 24-6a,b Molecular Biology of the Cell (© Garland Science 2008)
cholera toxins CtxA and CtxB
Bacterial Pathogens Carry Specialized
Virulence Genes
Comparative-genomics-based model for the evolution of
pathogenic V. cholerae strains
outer-membrane
lipopolysaccharide
Figure 24-6c Molecular Biology of the Cell (© Garland Science 2008)
cAMP phosphodiesterase
5’AMP
CtxB: transport CrtA (enzyme)
Figure 15-36 Molecular Biology of the Cell (© Garland Science 2008)
Cholera toxin: ADP
ribosylation of alpha subunit
(Gs)
Constitutive activation
(GTP-G protein) cAMP
Cl-, water efflux
Pertussis toxin: ADP
ribosylation of alpha subunit
(Gi)GDP-G protein
Bacterial Pathogens Carry Specialized
Virulence Genes
Anthrax toxin entry into host cells
heptameric
Edema A: adenylyl cyclase
Lethal A: protease
(MAP kinase kinases)
lethal toxin
edema toxin
Each A, B subunit
B
Figure 24-7a Molecular Biology of the Cell (© Garland Science 2008)
Gram-negative pathogens
Type III secretion systems that can deliver virulence factors into the
cytosol of a host cell
Type III: similar to flagelum
Type IV: conjugative apparatus
Figure 24-8a Molecular Biology of the Cell (© Garland Science 2008)
Fungal Parasites Have Complex Life Cycles with
Multiple Forms
Dimorphism in the pathogenic fungus Histoplasma capsulatum
Mold-to-yeast
Low temp
Figure 24-9 Molecular Biology of the Cell (© Garland Science 2008)
High temp
Saccharomyces cerevisiae
Schizosaccharomyces pombe
Protozoan Parasites Have Complex Life Cycles
with Multiple Forms
The complex life cycle of malaria parasites: Plasmodium falciparum
Figure 24-10a Molecular Biology of the Cell (© Garland Science 2008)
Blood smears from people with malaria, showing three
different forms of the parasite that appear in red blood cells:
(B) ring stage;
(C) schizont;
Figure 24-10b-d Molecular Biology of the Cell (© Garland Science 2008)
(D) gametocyte.
Time-dependent transcriptional program in malaria parasites developing
in red blood cells
Natural selection
Because malaria is so widespread and devastating, it
has acted as a strong selective pressure on human
populations in areas of the world that harbor the
Anopheles mosquito. Sickle-cell anemia, for
example, is a recessive genetic disorder caused by a
point mutation in the gene that encodes the
hemoglobin b chain, and it is common in areas of
Africa (caused by Plasmodium falciparum). The
malarial parasites grow poorly in red blood cells
from either homozygous sickle-cell patients or
healthy heterozygous carriers, and, as a result,
malaria is seldom found among carriers of this
mutation. For this reason, malaria has served to
maintain the otherwise deleterious sickle-cell
mutation at high frequency in these regions of Africa.
Figure 24-11 Molecular Biology of the Cell (© Garland Science 2008)
All Aspects of Viral Propagation Depend on
Host Cell Machinery
A simple viral life cycle
Viruses replicate in various ways.
(1) disassembly of the infectious virus
particle,
(2) replication of the viral genome,
(3) synthesis of the viral proteins by the
host cell translation machinery,
(4) reassembly of these components into
progeny virus particles.
Figure 24-12 Molecular Biology of the Cell (© Garland Science 2008)
All Aspects of Viral Propagation Depend on
Host Cell Machinery
Examples of viral morphology
450 nm, 270 k-nt
Figure 24-13 Molecular Biology of the Cell (© Garland Science 2008)
20 nm
5 k-nt
All Aspects of Viral Propagation Depend on
Host Cell Machinery
Schematic drawings of several types of viral genomes
Figure 24-14 Molecular Biology of the Cell (© Garland Science 2008)
All Aspects of Viral Propagation Depend on
Host Cell Machinery
Acquisition of a viral envelope
Figure 24-15 Molecular Biology of the Cell (© Garland Science 2008)
Despite this variety, all viral genomes encode
1) Proteins for replicating the genome,
2) Proteins for packaging the genome and delivering it to more
host cells
3) Proteins that modify the structure or function of the host
cell to enhance the replication of the virions
4) Modulate the host’s normal immune defense mechanisms.
A map of the HIV genome
Retrovirus life cycle
RNA splicing
capsid
Reverse transcriptase
integrase
Figure 24-16 Molecular Biology of the Cell (© Garland Science 2008)
Envelope
Eradication of a viral disease through vaccination
치료는 어려우나 백신은 효과적임
Smallpox : 사라짐
Polio  아마 곧
Figure 24-17 Molecular Biology of the Cell (© Garland Science 2008)
Prions Are Infectious Proteins
Neural degeneration in a prion infection
from yeasts to sea slugs(해삼) to humans
bovine spongiform encephalopathy
(BSE, or mad cow disease, 광우병
),
The host makes the infectious prion protein, and the prion’s
amino acid sequence is identical to that of a normal host
protein. Moreover, the prion and normal forms of the protein
are indistinguishable in their post-translational modifications.
The only difference between them appears to be in their folded
three-dimensional structure.
Figure 24-18 Molecular Biology of the Cell (© Garland Science 2008)
Figure 6-95a,b Molecular Biology of the Cell (© Garland Science 2008)
Infectious Disease Agents Are Linked To Cancer,
Heart Disease, and Other Chronic Illnesses
Chlamydia pneumoniae within a foam cell macrophage in an
atherosclerotic plaque
cardiovascular disease, frequently
brought on by atherosclerosis
EB, elementary body (bacterium);
FG, fat globule; N, macrophage
nucleus.
Figure 24-19 Molecular Biology of the Cell (© Garland Science 2008)
Summary
• Infectious diseases are caused by pathogens, which include bacteria, fungi,
protozoa, worms, viruses, and even infectious proteins called prions.
• All pathogens must have mechanisms for entering their host and for evading
immediate destruction by the host.
• Most bacteria are not pathogenic.
• Those that are contain specific virulence genes that mediate interactions with
the host, eliciting responses from the host cells that promote the replication and
spread of the pathogen.
• Pathogenic fungi, protozoa, and other eucaryotic parasites typically pass
through several different forms during the course of infection.
• Prions, the smallest and simplest infectious agents, contain no nucleic acid;
instead, they are aberrantly folded proteins that replicate by catalyzing the
misfolding of normal host proteins with the same amino acid sequence as the
prion.
CELL BIOLOGY OF INFECTION.
• Pathogens Cross Protective Barriers to Colonize
the Host
– Wounds, vectors
• Pathogens That Colonize Epithelia Must Avoid
Clearance by the Host
– specific adhesins
– H.pylori survives in the stomach is by producing the enzyme
urease, which converts urea to ammonia and carbon dioxide;
in this way, the bacterium surrounds itself with a layer of
ammonia, which neutralizes the acid in its immediate
vicinity. The bacteria also express at least five types of
adhesins
Pathogens Cross Protective Barriers to Colonize
the Host
Plague bacteria within a flea
Figure 24-20 Molecular Biology of the Cell (© Garland Science 2008)
Pathogens That Colonize Epithelia Must Avoid
Clearance by the Host
Uropathogenic E. coli in the infected bladder of a mouse
Figure 24-21 Molecular Biology of the Cell (© Garland Science 2008)
Pathogens That Colonize Epithelia Must Avoid
Clearance by the Host
Interaction of enteropathogenic E. coli (EPEC) with host cells in the gut
Figure 24-22a Molecular Biology of the Cell (© Garland Science 2008)
Pathogens That Colonize Epithelia Must Avoid
Clearance by the Host
Interaction of enteropathogenic E. coli (EPEC) with host cells in the gut
Figure 24-22b Molecular Biology of the Cell (© Garland Science 2008)
Pathogens That Colonize Epithelia Must Avoid
Clearance by the Host
Interaction of enteropathogenic E. coli (EPEC) with host cells in the gut
the DNA of the EPEC and host cell
are labeled in blue, Tir protein is
labeled in green, and host cell actin
filaments are labeled in red
Figure 24-22c Molecular Biology of the Cell (© Garland Science 2008)
Intracellular Pathogens Have Mechanisms
for Both Entering and Leaving Host Cells
• Many pathogens, including V. cholerae and
B. pertussis, infect their host without
entering host cells; they are referred to as
extracellular pathogens.
• Others, however, including all viruses and
many bacteria and protozoa, are
intracellular pathogens.
Virus Particles Bind to Molecules Displayed on the
Host Cell Surface
Receptor and co-receptors for HIV
Figure 24-23 Molecular Biology of the Cell (© Garland Science 2008)
Virions Enter Host Cells by Membrane Fusion,
Pore Formation, or Membrane Disruption
Four virus uncoating strategies
Figure 24-24 Molecular Biology of the Cell (© Garland Science 2008)
Bacteria Enter Host Cells by Phagocytosis
Uptake of Legionella pneumophila by a human phagocyte
Figure 24-25 Molecular Biology of the Cell (© Garland Science 2008)
Bacteria Enter Host Cells by Phagocytosis
Mechanisms used by bacteria to induce phagocytosis by nonphagocytic
host cells
require the polymerization
of actin
The bacteria in green
actin filaments in red
Figure 24-26 Molecular Biology of the Cell (© Garland Science 2008)
Intracellular Eucaryotic Parasites Actively Invade
Host Cells
Mechanisms used by bacteria to induce phagocytosis by nonphagocytic
host cells
Figure 24-27a Molecular Biology of the Cell (© Garland Science 2008)
Intracellular Eucaryotic Parasites Actively Invade
Host Cells
Invasion of host cells by Trypanosoma cruzi
Figure 24-28 Molecular Biology of the Cell (© Garland Science 2008)
Intracellular Eucaryotic Parasites Actively Invade
Host Cells
Invasion of host cells by microsporidia
a spore of the microsporidian
Encephalitozoon cuniculi
Figure 24-29a Molecular Biology of the Cell (© Garland Science 2008)
Many Pathogens Alter Membrane Traffic in the
Host Cell
Choices that an intracellular pathogen faces
all viruses
Figure 24-30 Molecular Biology of the Cell (© Garland Science 2008)
Many Pathogens Alter Membrane Traffic in the
Host Cell
Selective destruction of the phagosomal membrane by
Listeria monocytogenes
Figure 24-31 Molecular Biology of the Cell (© Garland Science 2008)
Viruses and Bacteria Use the Host Cell
Cytoskeleton for Intracellular Movement
The actin-based movement of Listeria monocytogenes within and
between host cells
M24.3
Figure 24-37 Molecular Biology of the Cell (© Garland Science 2008)
Antigenic Variation in Pathogens Occurs by
Multiple Mechanisms
Antigenic variation in trypanosomes
Figure 24-41a Molecular Biology of the Cell (© Garland Science 2008)
Antigenic Variation in Pathogens Occurs by
Multiple Mechanisms
Antigenic variation in trypanosomes
Figure 24-41b Molecular Biology of the Cell (© Garland Science 2008)
Drug-Resistant Pathogens Are a Growing Problem
Antibiotic targets
Figure 24-44 Molecular Biology of the Cell (© Garland Science 2008)
Drug-Resistant Pathogens Are a Growing Problem
Three general mechanisms of antibiotic resistance
Figure 24-45 Molecular Biology of the Cell (© Garland Science 2008)
Summary
•Pathogens often colonize the host by adhering to or invading the
epithelial surfaces.
• Intracellular pathogens invade host cells and replicate inside them.
•Viruses rely largely on receptor-mediated endocytosis, whereas
bacteria exploit cell adhesion and phagocytic pathways.
•Once inside, intracellular pathogens seek out a cell compartment that
is favorable for their replication, frequently altering host membrane
traffic and exploiting the host cell cytoskeleton for intracellular
movement.
•Besides altering the behavior of individual host cells, pathogens
frequently alter the behavior of the host organism in ways that favor
spread to a new host.
• Pathogens evolve rapidly, so that new infectious diseases frequently
emerge, and old pathogens acquire new ways to evade our attempts at
treatment, prevention, and eradication.
jump
Many Pathogens Alter Membrane Traffic in the
Host Cell
Modifications of host cell membrane trafficking by bacterial pathogens
Figure 24-32 Molecular Biology of the Cell (© Garland Science 2008)
Many Pathogens Alter Membrane Traffic in the
Host Cell
Association of host cell endoplasmic reticulum (ER) membrane with
intracellular bacterial pathogens
Figure 24-33 Molecular Biology of the Cell (© Garland Science 2008)
Many Pathogens Alter Membrane Traffic in the
Host Cell
Proximity of Golgi stacks to endosomes containing Salmonella enterica
Figure 24-34a Molecular Biology of the Cell (© Garland Science 2008)
Many Pathogens Alter Membrane Traffic in the
Host Cell
Proximity of Golgi stacks to endosomes containing Salmonella enterica
Figure 24-34b Molecular Biology of the Cell (© Garland Science 2008)
Many Pathogens Alter Membrane Traffic in the
Host Cell
Complicated strategies for viral envelope acquisition
Figure 24-35a Molecular Biology of the Cell (© Garland Science 2008)
Many Pathogens Alter Membrane Traffic in the
Host Cell
Complicated strategies for viral envelope acquisition
Figure 24-35b Molecular Biology of the Cell (© Garland Science 2008)
Many Pathogens Alter Membrane Traffic in the
Host Cell
Intracellular membrane alterations induced by a poliovirus protein
Figure 24-36 Molecular Biology of the Cell (© Garland Science 2008)
Viruses and Bacteria Use the Host Cell
Cytoskeleton for Intracellular Movement
Molecular mechanisms for actin nucleation by various pathogens
Figure 24-38 Molecular Biology of the Cell (© Garland Science 2008)
Viruses and Bacteria Use the Host Cell
Cytoskeleton for Intracellular Movement
Fluorescence micrographs of herpes virus moving in an axon
Figure 24-39 Molecular Biology of the Cell (© Garland Science 2008)
Viruses and Bacteria Use the Host Cell
Cytoskeleton for Intracellular Movement
The association ofWolbachia with microtubules
Figure 24-40 Molecular Biology of the Cell (© Garland Science 2008)
Error-Prone Replication Dominates Viral
Evolution
Diversification of HIV-1, HIV-2, and related strains of SIV
Figure 24-42 Molecular Biology of the Cell (© Garland Science 2008)
Error-Prone Replication Dominates Viral
Evolution
Model for the evolution of pandemic strains of influenza virus by
recombination
Figure 24-43 Molecular Biology of the Cell (© Garland Science 2008)
Jump 끝
BARRIERS TO INFECTION AND THE INNATE
IMMUNE SYSTEM
Adaptive immune responses are slow to develop on first exposure to a new
pathogen, as specific clones of B and T cells that can respond to it have to become
activated and proliferate; it can therefore take a week or so before the responses are
effective.
By contrast, a single bacterium with a doubling time of 1 hour can produce almost
20 million progeny, a full-blown infection, in a single day. Therefore, during the first
critical hours and days of exposure to a new pathogen, we rely on our innate
immune system to protect us from infection.
The innate immune system activates adaptive immune responses.
The Adaptive Immune System
Innate and adaptive immune responses
Figure 25-1 Molecular Biology of the Cell (© Garland Science 2008)
The Adaptive Immune System
The two main classes of adaptive immune responses
Figure 25-2 Molecular Biology of the Cell (© Garland Science 2008)
Innate immune defenses
• Physical and chemical barriers
–
–
–
–
The thick layer of dead keratinized cells that forms the surface of our skin,
The tight junctions between epithelial cell
The acidic pH of the stomach
The components of the mucus layers that inhibit colonization or even kill
pathogenic bacteria.
– The normal flora also have a role in protecting body surfaces against
invaders by competing for the same ecological niche and thereby limiting
colonization.
• Cell-intrinsic responses
– Pathogen-induced phagocytosis
– Degradation of double-stranded RNA
• A specialized set of proteins (e.g. defensins) and phagocytic cells that
recognize conserved features of pathogens and become quickly
activated to help destroy invaders.
– Professional phagocytic cells such as neutrophils and macrophages,
natural killer cells, and the complement system.
Defensins
• Generally short (12–50 amino acids) and positively charged, and have
hydrophobic or amphipathic domains.
• A diverse family with a broad spectrum of antimicrobial activities,
– ability to kill or inactivate Gramnegative and Gram-positive bacteria, fungi
(including yeasts), parasites (including protozoa and nematodes), and even
enveloped viruses such as HIV.
• Defensins are also the most abundant proteins in neutrophils, which
use them to kill phagocytosed pathogens.
• Uncertain how defensins kill pathogens.
– One possibility is that they use their hydrophobic or amphipathic domains to insert
into the surface membrane of their victims, thereby disrupting the integrity of the
membrane.
Epithelial Surfaces and Defensins Help Prevent
Infection
Epithelial defenses against microbial invasion
소장 villi
defensins and other
antimicrobial peptides 생산
Figure 24-46a Molecular Biology of the Cell (© Garland Science 2008)
The innate immune system
• Relies on the recognition of particular types of molecules that
are common to many pathogens but are absent in the host.
These pathogen-associated molecules (called pathogenassociated or microbe-associated immunostimulants) trigger
two types of innate immune responses
– inflammatory responses (discussed below)
– phagocytosis by professional phagocytes (neutrophils and
macrophages), and by dendritic cells, which activate T cells of the
adaptive immune system
Microbe-associated immunostimulants
Microorganism/Pathogen-Associated Molecular Patterns
(MAMP/PAMPs)
• formylated methionine
• the peptidoglycan cell wall and flagella of bacteria,
lipopolysaccharide (LPS) on Gram-negative bacteria and
teichoic acids on Gram-positive bacteria.
• molecules in the cell walls of fungi, including mannan,
glucan, and chitin.
• glycosylphosphatidylinositol in Plasmodium.
• Short sequences in bacterial or viral DNA
– a “CpG motif,” which consists of the unmethylated dinucleotide
CpG flanked by two 5’ purine residues and two 3’ pyrimidines.
Human Cells Recognize Conserved Features of
Pathogens
Structure of lipopolysaccharide
Figure 24-47 Molecular Biology of the Cell (© Garland Science 2008)
Complement Activation Targets Pathogens for
Phagocytosis or Lysis
The principal stages in complement activation by the classical, lectin,
and alternative pathways
amplify and “complement” the action
of antibodies, but some complement
components are also pattern
recognition receptors that microbeassociated immunostimulants activate
directly.
Figure 24-48 Molecular Biology of the Cell (© Garland Science 2008)
Complement Activation Targets Pathogens for
Phagocytosis or Lysis
Assembly of the late complement components to form a membrane
attack complex
Extrcellular fluid
Target Cell
membrane attack complexes
Figure 24-49 Molecular Biology of the Cell (© Garland Science 2008)
Complement Activation Targets Pathogens for
Phagocytosis or Lysis
Electron micrographs of negatively stained complement lesions in the
plasma membrane of a red blood cell
Figure 24-50 Molecular Biology of the Cell (© Garland Science 2008)
Toll-like Proteins and NOD Proteins Are an Ancient
Family of Pattern Recognition Receptors
The activation of a macrophage by lipopolysaccharide(LPS)
사람 10여개
TLP/NOD: Leu-rich repeat motif
interferon
regulatory
factors
Figure 24-51 Molecular Biology of the Cell (© Garland Science 2008)
Phagocytic Cells Seek, Engulf, and Destroy Pathogens
Phagocytosis
•
•
•
•
Macrophages:
– 전체 조직에 산재 professional phagocytes
– long-lived cells
– the first cells to encounter invading microbes
Neutrophils :
– the second major type of professional phagocytic
cells
– short-lived cells
TLRs, receptors for antibodies produced by the adaptive
immune system, and receptors for the C3b component of
complement.
Bacterial defense:
– Capsule: blocks access of complement components
to the bacterial surface and also makes it physically
difficult for the phagocytic cell to bind
– to deliver a toxin into the macrophage via a type III
secretory system (actin cytoskeleton blcoking)
Figure 24-53 Molecular Biology of the Cell (© Garland Science 2008)
Phagocytic Cells Seek, Engulf, and Destroy Pathogens
Eosinophils attacking a schistosome larva
These specialized lysosomal derivatives: lysozyme, acid hydrolases,
defensins, NADPH oxidase complexes (ROS: superoxide (O2–), hypochlorite
(HOCl, the active ingredient in
bleach), hydrogen peroxide, and hydroxyl radicals: respiratory burst),
raising the pH (activation of a group of potent neutral proteases).
Whereas macrophages generally survive this killing frenzy and
live to kill again, neutrophils usually do not.
Salmonella, induce an inflammatory response in the gut at the initial site of
infection, thereby recruiting macrophages that they then invade. In this way,
the bacteria hitch a ride to other tissues in the body.
If a pathogen is too large to be successfully phagocytosed (if it is a large
parasite such as a nematode, for example), a group of macrophages,
neutrophils, or eosinophils will gather around the invader and kill it by
secreting various toxic molecules
.
Figure 24-54 Molecular Biology of the Cell (© Garland Science 2008)
Phagocytic Cells Seek, Engulf, and Destroy
Pathogens
Neutrophils eject their chromatin to trap bacteria in a sticky web
fibrous strands
(arrow).
Because its sole function is to sacrifice
itself to kill invading pathogens, a
neutrophil has no hesitation in using
every tool available, including its own
DNA, to accomplish this task.
Figure 24-55 Molecular Biology of the Cell (© Garland Science 2008)
Activated Macrophages Contribute to the
Inflammatory Response at Sites of Infection
Inflammation of the airways in severe asthma
Inflammatory response:pain,
redness, heat, and swelling at the
site of infection
cytokines produced by macrophages are
chemoattractants (called chemokines).
Some of these attract neutrophils, which
are the first cells recruited in large
numbers to the site of a new infection.
Other cytokines trigger fever, a rise in
body temperature.
Figure 24-56 Molecular Biology of the Cell (© Garland Science 2008)
Virus-Infected Cells Take Drastic Measures to
Prevent Viral Replication
• dsRNA:
– RNAi mechanism: viral RNAi suppressor
– Cytokinines: interferon-alpha, beta: viral blocking
•
•
•
•
Jak-STAT signaling pathway
Ribonuclase activation
eIF2 inactivation
Apoptosis: viral inhibition of cell apoptosis
• CpG dinucleotide: TLR9
• APOBEC: deaminate cytosines to uridine
– Viral ubiquitination and proteasome-mediated protein
degradation of APOBEC
• Natural killer (NK) cell activation
Natural Killer Cells Induce Virus-Infected Cells to
Kill Themselves
A natural killer (NK) cell attacking a cancer cell
NK cells destroy virus-infected cells by
inducing the infected cells to kill
themselves by undergoing apoptosis
NK cells selectively kill host cells
expressing low levels of MHC
proteins
Cytotoxic T-cell  MHC (virus repress MHC expression)
NK cells (virus MHC-like protein expression)
Figure 24-57 Molecular Biology of the Cell (© Garland Science 2008)
The Innate and Adaptive Immune Systems Work Together
How the innate immune system can help activate the
adaptive immune system
: Dendritic Cells Provide the Link
co-stimulatory
proteins
TLRs
NOD
MHC proteins
Figure 25-5 Molecular Biology of the Cell (© Garland Science 2008)
The innate immunity in plants
Basal defense
- PAMP-triggered immunity
pathogen associated molecular pattern
Gene-for-Gene resistance
- Effector-triggered immunity
PTI : PAMP-triggered immunity
Gene-for-Gene resistance
Basal defense
e.g. flagellin
PRR
Plant Cell
Pattern recognition receptors (PRRs) on the membrane
Mitogen-activated protein kinase (MAP Kinase)
signaling cascades
Activation of transcription factors
The inducible expression of defense-related genes
Immune response
ETS : Effector-triggered susceptibility
Basal defense
PRR
Plant Cell
Immune response
ETI : Effector-triggered immunity
Basal defense
Gene-for-Gene resistance
PRR
Plant Cell
Immune response
HR
M/PAMPs
Definition
Microbe/Pathogen-Associated Molecular Patterns
Structural element from within pathogen-derived molecules
Species
In bacteria
Gram-negative bacteria – lipopolysaccharide (LPS),
flagellin, elongation factor Tu (EF-Tu)
Gram-positive bacteria –peptidoglycans
In fungi
Fungal cell walls-glucans, chitins, and proteins
Nürnberger et al., Immunological Reviews (2004) ,198: 249–266
Vega and Kalkum, 2011 Int J Microbiol. 2012;2012:920459
The guard model: surveillance of the host immune
regulator RIN4 by the R proteins RPM1 and RPS2
NOD proteins
Nature Reviews of Immunology Spoel and Dong 2012
Summary
•
•
•
•
Physical barriers preventing infection, cell-intrinsic responses to infection, and innate
immune responses (IIR) provide early lines of defense against invading pathogens. All
multicellular organisms possess these defenses. In vertebrates, IIR can also recruit
adaptive immune responses.
IIR rely on the body’s ability to recognize conserved features of microbial molecules.
These microbe-associated immunostimulants include many types of molecules on
microbial surfaces, as well as the double-stranded RNA of some viruses. Many of these
microbial molecules are recognized by pattern recognition receptors, including the tolllike receptors (TLRs) found in both plants and animals.
In vertebrates, microbial surface molecules also activate complement, a group of blood
proteins that are activated in sequence to target the microbe for phagocytosis by
macrophages and neutrophils. The phagocytes use a combination of degradative
enzymes, antimicrobial peptides, and reactive oxygen species to kill the invading
microorganism; in addition, they secrete signal molecules that trigger an inflammatory
response.
Cells infected with viruses produce interferons, which induce a series of cell responses,
inhibit viral replication, and activate the killing activities of natural killer cells.
Dendritic cells of the innate immune system ingest microbes at sites of infection and
carry them and their products to local lymph nodes, where they activate T cells of the
adaptive immune system to make specific responses against the microbes.
Chitin
Chitin: Poly-β-(1→4)-N-acetyl-D-glucosamine
The cellulose-like biopolymer distributed in
nature in marine invertebrates, insect
exoskeletons, fungal cell walls, and yeasts but not
in plants.
a Pathogen Associated Molecular Pattern (PAMP)
Chitin signaling in plants
Chitin
Chitinase
Fungus
 Fungal pathogens attack plants
 Exochitinase released from plants hydrolyzes chitin
polymer in fungal cell wall
Apoplast
LysM RLK1
Plant Cell
 Chitin fragments are recognized by chitin receptor
LysM RLK1 : : Lysin motif receptor like kinase 1
 MAPK cascade
MAPK cascade
Transcription factors
Defense genes
 Activation of transcription factors
 Induction of defense gene
 Enhanced disease resistance
Adapted from Wan et al., Plant Signal Behav. 2008 Oct;3(10):831-3
Kombrink et al., Microbes Infect. 2011 Dec;13(14-15):1168-76
PTI suppression by effector proteins
Ecp6
Avr4
Fungus
Fungus
Apoplast
LysM RLK1
Plant Cell
Apoplast
LysM RLK1
Plant Cell
MAPK cascade
MAPK cascade
Transcription factors
Transcription factors
Defense genes
Defense genes
Adapted from Wan et al., Plant Signal Behav. 2008 Oct;3(10):831-3
Kombrink et al., Microbes Infect. 2011 Dec;13(14-15):1168-76
The 118 transcription factors respond to chitin elicitor
qRT- PCR : quantative Reverse Transcription PCR
Chitin 8-mer
LysM RLK1
Plant Cell
MAPK cascade
Transcription factors
Defense genes
Immune response
The type of transcription factor
No.
AP2/EREBP (ERF)
27
C2H2 zinc finger
15
MYB domain transcription factor
11
WRKY domain transcription factor
14
HSF, Heat-shock transcription factor
6
NAC domain transcription factor
6
GRAS transcription factor
4
bZIP transcription factor
5
bHLH, Basic Helix-Loop-Helix
3
WHIRLY
3
NPR1-like
2
C2H2(Zn) CO-like, Constans-like zinc finger
2
CHP-rich expressed protein
2
C2C2(Zn) DOF zinc finger
1
F-box protein
1
Etc
16
total
118
Libault et al., MPMI(2007), 8:900-911
A common signaling machinery is
used differently in PTI and ETI
Current Opinion in Plant
Biology 2010, 13:459