Subversion of Cell Signaling by Pathogens –
Evading the Immune response
Ryan Rego
Antibiotic resistance: World on cusp of 'post-antibiotic era'
The world is on the cusp of a "post-antibiotic era", scientists have warned after
finding bacteria resistant to drugs used when all other treatments have failed.
There has not been a new class of antibiotics discovered since the 1980s.
• Most ‘primitive of immune systems??
Primitive Immune Systems
Innate Immunity
COMPONENTS
ACTIVITY
RESPONSE AND
POTENCY
SPECIFICITY
COURSE
MEMORY
Adaptive Immunity
An example of infection by a pathogen and the start of the innate immune response
followed by activation of the adaptive response, clearing of the infection and the
presence of memory cells ready to produce antibodies for future responses to infection
by the same pathogen.
PAMP – Pathogen Associated Molecular Pattern
Bacterial carbohydrates (LPS, mannose)
Flagellin
lipoteichoic acid
peptidoglycan
double stranded RNA
unmethylated CpG
DAMP – Damage-Associated Molecular Pattern
Purine metabolites (ATP, adenosine, uric acid)
DNA and RNA
PRR – Pathogen Recognition Receptor
Innate Immune Response based on PAMP or DAMP recognition
Valles et al., 2014
Pattern recognition by TLRs, NLRs, CLRs and RLRs
Toll-like receptors (TLRs) are type I transmembrane proteins of the interleukin-1 receptor
family that possess an amino-terminal leucine-rich repeat (LRR) domain for ligand binding, a
single transmembrane domain and a carboxy-terminal intracellular signalling domain. TLRs
are widely expressed by many cell types, although most cells express only a specific subset
of these receptors.
NOD-like receptors (NLRs) are cytosolic receptors that contain N-terminal caspaserecruitment domains (CARDs), a central nucleotide oligomerization domain (NOD) and a Cterminal LRR domain. NLRs recognize a wide variety of microbial PAMPs and endogenous
damage-associated molecular patterns (DAMPs), and several notable examples of this family
are NOD1, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and absent in melanoma 2
(AIM2).
C-type lectin receptors (CLRs) comprise a large family of soluble and transmembrane
proteins that possess one or more C-type lectin domain, which was initially characterized as
a calcium-dependent carbohydrate-binding domain in mannose-binding lectin (MBL). CLRs
recognize a wide range of carbohydrate structures on pathogens, although many CLRs also
recognize self molecules and are therefore suggested to participate in both innate immune
responses and cell and tissue homeostasis. Notable examples of this family include the
soluble CLR MBL and the transmembrane proteins dectin 1 (also known as CLEC7A) and DCspecific ICAM3-grabbing non-integrin (DC-SIGN).
Immune cells involved in the immune response
Cellular location of TLRs and the identity of their ligands/agonists
Mifsud et al., 2014
TLR’s interact with MyD88 and NF-kappaB to produce various adaptive response molecules
Mechanisms of defense against viruses
Mechanisms of innate immunity
- inhibition of infection and induction of antiviral state
type I interferons (IFN-α and β)
- killing of infected cells (NK cells)
Antiviral action of type I interferons
Uninfected
cells
Infected
cells
Expression of
enzymes that inhibit
viral replication
Protection from
infection
Expression of
class I MHC
molecules
Killing of infected
cells by CTLs
Destruction of infected cells by NK cells
Destruction of infected cells by NK cells
Destruction of infected cells by NK cells
Mechanisms of defense against viruses
Mechanisms of adaptive immunity
Humoral immunity
B cells and antibodies
- neutralization (IgG and IgA), ADCC (IgG) and opsonization (IgG)
Cell-mediated immunity
Neutralization of viruses
Protective mechanisms of antibodies
Mechanisms of defense against viruses
Mechanisms of adaptive immunity
Humoral immunity
B cells and antibodies
- neutralization (IgG and IgA), ADCC (IgG) and opsonization (IgG)
Cell-mediated immunity
CD8+ and CD4+ T cells
- killing of infected cells (CD8+ T cells)
- activation of CD8+ T cells and and B cells (CD4+ helper T cells)
Mechanism of killing
by CTLs
Mechanism of killing
by CTLs
Mechanism of killing
by CTLs
Mechanism of killing
by CTLs
Mechanism of killing
by CTLs
Mechanisms of defense against viruses
Mechanisms of immune evasion
- inhibition of antigen processing and presentation (many viruses)
- inhibition of immune response (many viruses)
- infection of immune cells (HIV...)
- establishment of latency (HSV, HIV...)
- inhibition of apoptosis (Herpes and Pox viruses...)
Mechanisms of defense
against parasites
Mechanisms of innate immunity
Protozoa and helminths – mostly resistant
- complement and phagocytosis (protozoa)
- eosinophils and macrophages (helminths)
Mechanisms of defense
against parasites
Mechanisms of adaptive immunity
Protozoa
B-cells, CD4+ TH1 and CD8+ T cells
- antibodies (B-cells) – Entamoeba sp., Plasmodium sp.
-IFN-γ production and macrophage stimulation (CD4+TH1 cells) - Leishmania sp.
- cytotoxicity (CD8+ T cells) – Plasmodium sp.
Helminths
B-cells and CD4+ TH2 cells
- stimulation of B-cells to produce IgE (IL-4)
- stimulation of eosinophils (IL-5 and IgE)
- degranulation of mast cells (IgE)
Strategies for Evasion
• Overwhelm the host
• Disarm host defenses
Offense versus Defense
Evasion
• Disarm innate immunity
• Regulate MHC molecules
- responsible for antigen presentation
• Interfere with CTL and Natural Killer cells
• Alter antigen presentation
• Go and hide (NOT FOR TODAY)
Signaling pathways downstream of PRRs in mammals, insects, nematodes and plants.
Mechanism of the innate Immune response in plants being colonized by different pathogens
Dang et al., 2013 Science
Pathogen infection in plant cells induce mobile immune signals important for the innate
immune response
Infection-induced host-translational blockage inhibits immune responses and
epithelial renewal – Pseudomonas entomophilia infection in plants
Chakrabarti et al., 2012
Decoy strategies elaborated by pathogens and pests to interfere with plant
hormone biosynthesis/signaling pathways.
Denance et al., 2013
Suppression of Plant PRR-Mediated Surveillance System by Pathogen Effectors
Dou and Zhou, 2012
Examples of how pathogens evade the immune response
Disruption of the pathways for activation of nitric oxide production by mycobacteria
CR3 mediated uptake of bacterial cells that help them avoid intracellular killing
Bacterial effector molecules go everywhere to help overcome the immune response
PAMPS & DAMPs are ok, what is cSADD???
The cellular surveillance-activated detoxification and defenses
(cSADD) theory postulates the presence of host surveillance
mechanisms that monitor the integrity of common cellular
processes and components targeted by pathogen effectors.
Being organelles essential for multiple cellular processes, including
innate immune responses, mitochondria represent an attractive
target for pathogens
Mitochondrial anti viral signalling protein (MAVS)
Disarming of MAVS by Vibrio cholerae
The three innate recognition systems
p53 and its role in the immune response to various cellular inputs
Deactivation of p53 by various bacterial pathogens
SUMO and SUMOYLATION
Small Ubiquitin-like Modifier (or SUMO) proteins are a family of small proteins that
are covalently attached to and detached from other proteins in cells to modify their
function. SUMOylation is a post-translational modification involved in various
cellular processes, such as nuclear-cytosolic transport, transcriptional regulation,
apoptosis, protein stability, response to stress, and progression through the cell
cycle.[1]
SUMO proteins are similar to ubiquitin, and SUMOylation is directed by an
enzymatic cascade analogous to that involved in ubiquitination. In contrast to
ubiquitin, SUMO is not used to tag proteins for degradation.
Mature SUMO is produced when the last four amino acids of the C-terminus have
been cleaved off to allow formation of an isopeptide bond between the C-terminal
glycine residue of SUMO and an acceptor lysine on the target protein.
SUMOylation/deSUMOylation dynamics:
Influence of pathogens on the host SUMOylation pathway
Lyme Disease pathogen
Borrelia burgdorferi s.l.
Activation of complement by three different pathways in response to borrelial infection
Impairment of immune function by tick saliva
Various factors that help Borrelia evade complement activation
Tick Innate Immune system
Various tick proteins that are shown
to be involved in pathogen
acquisition, transmission or
persistence within the tick
Immunity against
helminths
(TH2 response)
Immunity against helminths
(function of eosinophils)
Inhibitory molecules that play a role in the evasion of the immune response by helminths
Inhibitory molecules that play a role in the evasion of the immune response by protozoa
Thanks