Johns Hopkins MD whose daughter won an Autism lawsuit against vaccine mfgs.

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Dec 10, 2010, 7:16:21 AM12/10/10
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Subject: Johns Hopkins MD whose daughter won an Autism lawsuit against
vaccine mfgs.

Date: Dec 10, 2010 7:02 AM


This would be interesting to people
who wonder about the mitochondrial
disorder claim - the only claim that
ever worked in vaccine compensation.

The argument is the same in LYMErix-
disease immunosuppression: People
who are immune suppressed/disordered
from fungal antigen exposures (see
Pam3Cys data, all
should not get attenuated whole
viral vaccines (dead viruses is better).

Similarly, LYMErix-Disease is the same
as the Great Imitators, or activated
Epstein-Barr (see Dattwyler and Nicolson

Here are the IDSA's own Imitators:

Fungal antigens in the blood (attached
to and inside of red blood cells) causing
Chronic Fatigue:
and Nicolson, again:

So, Pass that along. That's how vaccine
damaged kids parents can sue. And this
is also the proof that LYMErix was not
a vaccine, accounting for the hysteria
offered by the Tribune company on behalf
of the Israeli Lyme Crooks, who prefer to
now have other people do their dirty work.

Global warming, molds, Chronic Fatigue
Syndrome, etc...; it's all real.

It's unstoppable:

Go ^^^, "See All Related"

Fungal antigens (immunosuppression) plus
viruses are synergistic. Best friends:

I was glad to find that (below) because
such resoluteness in a "review" paper on
the topic is really compelling.

Now you know.



Nature Reviews Microbiology 8, 693-705 (October 2010) | doi:10.1038/

Interactions between bacterial pathogens and mitochondrial cell death

Thomas Rudel1, Oliver Kepp2 & Vera Kozjak-Pavlovic1 About the authors
Top of page

The modulation of host cell death pathways by bacteria has been
recognized as a major pathogenicity mechanism. Among other strategies,
bacterial pathogens can hijack the cell death machinery of host cells
by influencing the signalling pathways that converge on the
mitochondria. In particular, many bacterial proteins have evolved to
interact in a highly specific manner with host mitochondria, thereby
modulating the decision between cell life and death. In this Review,
we explore the intimate interactions between bacterial pathogens and
mitochondrial cell death pathways.

Bacterial pathogens have developed many strategies to successfully
infect their hosts, including mechanisms to adhere to, invade and
persist in host cells and tissues, as well as methods to overcome the
host's immune defences. The ability of bacteria to influence host cell
survival has emerged as a crucial determinant of pathogenicity in many
different settings. Thus, some bacteria actively induce cell death in
their hosts, for example to remove immune effector cells1 or to
overcome epithelial barriers2. Alternatively, intracellular pathogens
often inhibit host cell death to preserve their replicative niches3,
4, 5. In addition to an extensive arsenal of adhesins and invasins,
pathogenic bacteria have evolved numerous effectors and toxins to
specifically interact with host cell death signalling pathways and the
cell death executioner machinery6.

Mitochondria, which play a pivotal part in many of the biochemical
cascades that lead to cell death, are commonly thought to derive from
an ancient endosymbiotic event between ancestors of modern bacteria7.
Thus, the exploration of the mechanisms by which bacterial pathogens
modulate mitochondrial cell death pathways has an intriguing
evolutionary aspect. There is no doubt that the basic features of
early endosymbionts played a fundamental part in the evolution of the
programmed cell death machinery; for instance, death effectors might
have evolved from toxins produced by intracellular pathogens to lyse
the host cell under conditions of stress (for example, during nutrient
shortage). Control mechanisms specific for eukaryotic cells evolved in
parallel with the development of simple cell death machineries based
on effectors of bacterial origin. Some degree of similarity still
exists between bacterial and mitochondrial proteins regarding their
function and targeting signals8. It is tempting to speculate that
modern pathogenic bacteria can interfere with the mitochondrial cell
death pathway at least in part owing to this ancient relationship
between bacteria and the mitochondrial endosymbiont. The fact that
some bacterial proteins are imported into mitochondria and that the
production of reactive oxygen species (ROS), an obvious consequence of
life in an aerobic atmosphere, is increased in response to infection
supports this hypothesis.

In this Review we explore the relationship between bacterial pathogens
and mitochondrial host cell death signalling pathways. First, we give
an overview of the basic features of the different modes of cell
death. The bacterial proteins that are currently known to act directly
at the mitochondria to induce or inhibit cell death are then discussed
(Table 1). Finally, we present selected examples of the mechanisms by
which bacterial pathogens affect cell death through subverting
mitochondrial function.
Table 1 | Bacterial pathogens and their mode of interference with
mitochondrial signalling
Table 1 - Bacterial pathogens and their mode of interference with
mitochondrial signalling

* Full table
* Figures and tables index
* Download high-resolution Power Point slide (180 KB)

Modes of programmed cell death

The classical distinction between apoptosis and necrosis as programmed
versus accidental forms of cell death, respectively, has recently been
challenged by multiple lines of evidence suggesting that necrosis can
also be programmed and can be distinguished from apoptosis9, 10.
Moreover, several instances of cell death characterized by a massive
accumulation of autophagic vacuoles have been described, for which the
term autophagic cell death has, improperly, been coined11, 12. For the
purposes of this Review we collectively refer to necrotic and
autophagic cell death as non-apoptotic cell death.

Apoptosis. Apoptosis is by far the best-characterized mode of
programmed cell death. It plays a pivotal part in many physiological
settings, including the embryonic and post-embryonic development of
multicellular organisms, tissue homeostasis and the removal of damaged
and/or infected cells. Apoptotic cells display typical morphological
features such as nuclear fragmentation (karyorrhexis), chromatin
condensation (pyknosis) and cell shrinkage, and eventually break down
into apoptotic bodies13. Because the cytoplasmic membrane of cells
undergoing apoptosis remains intact throughout the entire process,
apoptosis is executed without any substantial loss of intracellular
content and hence usually elicits a limited inflammatory response.
Instead, several 'find me' signals, such as ATP, and 'eat me' signals,
such as phosphatidylserine, calreticulin and heat shock proteins, are
displayed on the surface and/or released by the dying cells (reviewed
in Ref. 14). This initiates the efficient removal of apoptotic bodies
by neighbouring cells or phagocytes15.

Two distinct, but partially overlapping, pathways are known to lead to
apoptosis: the extrinsic, receptor-mediated pathway and the intrinsic,
mitochondrial pathway (Fig. 1). Both of these biochemical cascades
eventually result in the activation of cysteine-dependent aspartate-
specific proteases known as caspases, which cleave numerous protein
substrates (for a state of the art list of caspase substrates see the
caspase substrate database homepage).
Figure 1 | Apoptotic cell death pathways.
Figure 1 : Apoptotic cell death pathways. Unfortunately we are unable
to provide accessible alternative text for this. If you require
assistance to access this image, or to obtain a text description,
please contact n...@nature.comApoptosis is activated either by the
oligomerization of plasma membrane receptors belonging to the death
receptor superfamily (extrinsic pathway) or by the activation of
intrinsic stress sensors (intrinsic pathway). In the extrinsic
pathway, the ligand-mediated activation of death receptors results in
the recruitment of FAS-associated death domain (FADD) and pro-caspase
8 to an intracellular death-inducing signalling complex (DISC). In
this complex, pro-caspase-8 is converted to active caspase 8 by
autoprocessing and can then proteolytically activate effector caspases
(caspase 3, caspase 6 and caspase 7). The intrinsic pathway is
regulated by mitochondria. B cell lymphoma 2 (BCL-2) homology 3 (BH3)-
only proteins are activated by various intracellular stress signals,
which allows them to overcome the inhibitory effect of anti-apoptotic
BCL-2 proteins and to stimulate the recruitment of BAX to mitochondria
and the pore-forming activity of BCL-2 homologous antagonist/killer
(BAK). This results in BAX and BAK oligomerization in the outer
mitochondrial membrane, which in turn allows the release of
intermembrane space proteins such as second mitochondrion-derived
activator of caspase (SMAC; also known as DIABLO) and cytochrome c
into the cytosol. By binding to the adaptor apoptotic protease-
activating factor 1 (APAF1), cytochrome c stimulates the dATP-
dependent assembly of the apoptosome, a supramolecular platform for
the autoproteolytic activation of caspase 9 and hence the activation
of effector caspases. Caspases are negatively regulated by inhibitor
of apoptosis proteins (IAPs), which are themselves inhibited by SMAC.
In some cell types, the extrinsic and intrinsic pathways of apoptosis
converge at the level of the BH3-only protein BH3-interacting domain
death agonist (BID), which can be proteolytically activated by caspase

* Full size figure and legend (55 KB)
* Figures and tables index
* Download high-resolution Power Point slide (94 KB)

Caspases mediate most, but not all, of the apoptotic programme. For
example, cleavage of ICAD (inhibitor of caspase-activated DNase (CAD);
also known as DFF45) by caspases results in the activation and
translocation of CAD to the nucleus, where it mediates genomic DNA
degradation. The DNA repair enzyme poly-ADP ribose polymerase 1
(PARP1), by contrast, is inactivated by caspase 3. Several caspase-
independent mechanisms have been shown to cooperate with caspases in
the execution of apoptosis; for example, DNA-damaging agents and
peroxide induce a form of apoptosis that depends on the PARP1-induced
release of apoptosis-inducing factor (AIF) from mitochondria, followed
by nuclear translocation of AIF and DNA degradation16. Caspase-
independent cell death pathways can also be controlled by proteases,
including cathepsin B and cathepsin D, calpains, granzymes and other
serine proteases (reviewed in Ref. 17). Nevertheless, the cleavage of
specific caspase substrates is responsible for at least a part of the
typical morphological manifestations of apoptotic cell death. Caspases
are tightly regulated by inhibitor of apoptosis proteins (IAPs). One
of these proteins, X-linked IAP (XIAP), can directly block the
proteolytic activity of caspases following binding18.

The extrinsic apoptosis pathway is responsive to extracellular cell
death signals (for example, cross-linking of death receptors). By
contrast, intrinsic mitochondrion-mediated apoptosis is elicited by a
range of stress conditions (such as DNA damage, infection and the
presence of oxygen radicals) that arise in the intracellular
microenvironment. Intriguingly, specific triggers of apoptosis, such
as the release of perforin or granzyme by cytotoxic T cells, can
activate either the extrinsic or the intrinsic pathway depending on
the specific features of the target cells, notably the target cell

Mitochondria play a fundamental part in the regulation of apoptotic
cell death20. These organelles are not only the central integrators
for the intrinsic pathway but in some cell types they are also
crucially involved in the extrinsic pathway21. The pivotal step in
mitochondrion-regulated apoptosis is the permeabilization of the outer
mitochondrial membrane (OMM) accompanied by the loss of mitochondrial
membrane potential (ΔΨm), which is widely used as an indicator of
apoptosis. OMM permeabilization is followed by the release of caspase-
activating proteins such as cytochrome c and second mitochondrion-
derived activator of caspase (SMAC; also known as DIABLO) into the
cytosol. Together with the cytosolic adaptor apoptotic protease-
activating factor 1 (APAF1), cytochrome c drives the assembly of a
supramolecular complex known as the apoptosome, which serves as a
scaffold for the activation of the caspase cascade (Fig. 1). SMAC
counteracts the caspase-inhibitory activity of XIAP, thereby
indirectly allowing the full-blown activation of the caspase
cascade22, 23.

The permeabilization of the OMM is tightly controlled by members of
the B cell lymphoma 2 (BCL-2) protein family. This family is
characterized by the presence of at least one of four conserved BCL-2
homology (BH) domains (BH1–BH4). BH3-only proteins — a pro-apoptotic
subset of the family comprising BCL-2 antagonist of cell death (BAD),
BCL-2-interacting mediator of cell death (BIM), BCL-2-modifying factor
(BMF), NOXA (also known as PMAIP1), Puma (also known as BBC3), BCL-2-
interacting killer (BIK), harakiri (HRK), BLK and BH3-interacting
domain death agonist (BID) — function as sensors of cell stress. These
proteins are activated in response to specific apoptotic stimuli such
as cytokine deprivation, loss of contact between the cells and their
extracellular matrix or their neighbouring cells (anoikis), activated
oncogenes, DNA damage, chemotherapy and γ-irradiation (reviewed in
Refs 24,25,26). Activated BH3-only proteins can initiate mitochondrion
permeabilization by directly triggering the pore-forming activity of
the pro-apoptotic proteins BAX and/or BCL-2 homologous antagonist/
killer (BAK) in the OMM27. This process is tightly regulated by anti-
apoptotic BCL-2 family proteins such as BCL-2, induced myeloid
leukaemia cell differentiation protein 1 (MCL1) and BCL-XL, which,
among other functions, can sequester BAX, BAK and BH3-only proteins
into inactive molecular complexes.

Non-apoptotic cell death. In addition to apoptosis, several
alternative cell death and stress-response mechanisms exist that can
seal the fate of the cell depending on the initiating stimulus (Fig.
2). Autophagy is a highly regulated physiological process that is
involved in the turnover of long-lived proteins and damaged or
supernumerary organelles. During autophagy, portions of the cytoplasm
and organelles, including mitochondria, are progressively enveloped by
characteristic double- or multi-membrane vesicles known as
autophagosomes, which are then delivered to lysosomes for bulk
degradation. This process is tightly regulated by proteins of the ATG
family. Old or damaged mitochondria are degraded through mitophagy, a
specialized type of autophagy that selectively targets mitochondria
for lysosomal degradation. The molecular machineries underlying
mitophagy are partially distinct from other forms of autophagy
(reviewed in Ref. 28).
Figure 2 | Non-apoptotic cell death pathways.
Figure 2 : Non-apoptotic cell death pathways. Unfortunately we are
unable to provide accessible alternative text for this. If you require
assistance to access this image, or to obtain a text description,
please contact n...@nature.coma | Non-apoptotic cell death pathways
include several forms of necrosis. In some cell types, necroptosis, a
type of regulated necrosis, is initiated by tumour necrosis factor
(TNF) and depends on the presence and catalytic proficiency of the
serine–threonine kinase receptor-interacting protein 1 (RIP1). RIP1
activation has been shown to elicit biochemical cascades involving its
cognate kinase RIP3. These cascades eventually target several
mitochondrial proteins, including enzymes involved in bioenergetic
metabolism such as glycogen phosphorylase (PYGL), glutamate
dehydrogenase 1 (GLUD1) and glutamate–ammonia ligase (GLUL). Poly-ADP
ribose polymerase 1 (PARP1) can mediate cell death in several ways;
for example, DNA damage can promote the rapid PARP1-mediated depletion
of cytosolic NAD+, which in glycolytic cells leads to necrosis by an
energy collapse. PARP1 can also stimulate the translocation from the
nucleus to mitochondria of apoptosis-inducing factor (AIF), a caspase-
independent cell death executioner that normally resides in the
mitochondrial intermembrane space. During necrosis, mitochondrial
integrity can be perturbed by the opening of a multiprotein structure
known as the permeability transition pore complex (PTPC), which forms
at the junction between the outer and the inner mitochondrial
membrane. b | Autophagy starts with the formation of the phagophore,
which typically consists of a double-membrane structure. Fusion of the
membranes results in the sequestration of organelles and long-lived
proteins in a double-membrane vesicle, called the autophagosome.
Autophagosomes further mature by fusion with lysosomes to form
autophagolysosomes, which finally degrade the contents. ROS, reactive
oxygen species.

* Full size figure and legend (62 KB)
* Figures and tables index
* Download high-resolution Power Point slide (100 KB)

In addition to being involved in the maintenance of cellular
homeostasis, autophagy also represents a mechanism of metabolic
adaptation to stress, in particular nutrient starvation, providing
cells with substrates to meet their energy demands through self-
cannibalism. In response to prolonged starvation and various other
stress conditions, cells can accumulate massive numbers of
autophagosomes and are then eliminated by phagocytes29. Such
morphological manifestations of cell death have often been
misinterpreted to indicate that autophagy contributes to the demise of
the cell. Although this is indeed the case in selected
pathophysiological scenarios such as HIV-1 infection30, 31, autophagy
mostly represents a cytoprotective mechanism that is significantly
upregulated by dying cells. Indeed, autophagy inhibition frequently
accelerates, rather than prevents, cell death. Thus, in most cases,
cell death actually occurs in spite of autophagy, not as a consequence
of it32. In response to an infection, autophagy plays an active part
in the innate immune response against invading pathogens that have
escaped from phagosomal sequestration28. Autophagy has been implicated
in the response to diverse human pathogens such as streptococci,
Helicobacter pylori and Legionella pneumophila, whereas some bacteria
such as Salmonella spp. have developed active mechanisms to avoid
autophagosomal degradation. Therefore, during infection autophagy
might be seen as a cellular attempt to clear bacteria or, if this
fails, an intermediate step towards the final fate of the cell.

In striking contrast to apoptosis, necrotic cell death is
characterized by the early permeabilization of the plasma membrane and
the consistent leaking of intracellular contents into the
microenvironment (Fig. 2). The old idea of necrosis as a completely
uncontrolled process induced by an irreparable toxic insult (for
example, treatment with detergents, high concentrations of peroxide or
freeze–thaw cycles) has recently been challenged. Even when caspases
are inhibited or apoptotic signalling is otherwise prevented,
apoptotic stimuli can still induce necrotic cell death33, 34, 35, 36,
37, 38, 39, 40, strongly pointing to the existence of signalling
routes that are specific to necrotic cell death41.

During necrotic cell death, mitochondrial integrity can be perturbed
by the opening of a multiprotein structure known as the permeability
transition pore complex (PTPC), which forms at the junction between
the OMM and the inner mitochondrial membrane (IMM). Specific cell
death triggers induce the permeabilization of the IMM, a phenomenon
known as the mitochondrial permeability transition. This is followed
in some cases by osmotic swelling of the mitochondrial matrix and,
eventually, OMM disruption42.

As with apoptosis, numerous forms of necrosis that are genetically
determined and highly controlled have been described43, 44, 45. For
example, the type of necrosis that depends on the presence and
catalytic activity of the serine–threonine kinase receptor-interacting
protein 1 (RIP1), which is stimulated by ligands such as tumour
necrosis factor, has been termed necroptosis46, 47.

In addition to regulating apoptosis, mitochondria integrate signals
that control non-apoptotic cell death. RIP1 activation has been shown
to elicit biochemical cascades involving its cognate kinase RIP3.
These cascades eventually target several mitochondrial proteins,
including enzymes involved in bioenergetic metabolism48, 49, 50 and
components of the PTPC such as cyclophilin D and ADP/ATP translocase
(ANT)51 (Box 1). Recently, a genome-wide RNA interference-based screen
identified a complex network of more than 400 genes involved in the
regulation of necroptosis46, indicating the intricate nature of the
signalling circuits controlling this non-apoptotic cell death pathway.
Box 1 | The different forms of programmed cell death

* Full box

Mitochondria as targets for bacterial proteins

Bacterial proteins that interfere with mitochondrial functions must
fulfil at least two criteria: they must reach the mitochondria during
infection and they must bind to, or be taken up by, mitochondria52.
Many pathogenic bacteria possess secretion systems, such as the type
III secretion system (T3SS) or T4SS, for the direct injection of
proteins into host cells53, 54. Sometimes bacteria secrete proteins by
the classical autotransporter route (T5SS), and these proteins are
then taken up by neighbouring cells. If present, mitochondrion-
targeting sequences, either in the form of cleavable amino-terminal
presequences or internal targeting signals, direct these proteins to
mitochondria. Once at the mitochondria they are transported by the
mitochondrial protein import machinery, which includes the translocase
of the OMM (TOM) complex together with the sorting and assembly
machinery (SAM) complex, and two IMM translocase (TIM) complexes55.
Bacterial proteins can also interact with the outer surface of
mitochondria without being transported across the OMM. Using these
mechanisms, bacterial pathogens can directly modulate mitochondrion-
controlled cell death decisions in host cells (Fig. 3).
Figure 3 | Bacterial factors targeting mitochondria.
Figure 3 : Bacterial factors targeting mitochondria. Unfortunately we
are unable to provide accessible alternative text for this. If you
require assistance to access this image, or to obtain a text
description, please contact n...@nature.comBacterial proteins targeting
mitochondria can either inhibit or induce apoptosis. Anaplasma
translocation substrate 1 (Ats1) from Anaplasma phagocytophilum enters
the cell using the type IV secretion system (T4SS), translocates into
mitochondria in a presequence-dependent manner and inhibits outer
mitochondrial membrane (OMM) permeabilization. The EspF and Map
effectors are secreted into host cells by the enteropathogenic
Escherichia coli (EPEC) T3SS and possess a targeting sequence that
directs them to mitochondria, where they cause mitochondrial damage
and loss of membrane potential. The p34 subunit of VacA from
Helicobacter pylori is transported into mitochondria and shows a
strong uncoupling activity, leading to mitochondrial membrane
permeabilization (MMP), similar to the porin outer membrane protein 38
(Omp38) from Acinetobacter baumanii. PorB from Neisseria gonorrhoeae
is targeted to mitochondria by the translocase of the outer
mitochondrial membrane (TOM) complex, and integrates into the inner
mitochondrial membrane, which causes loss of mitochondrial membrane
potential and mitochondrial fragmentation. SipB from Salmonella
enterica is transported into the cell using a T3SS and leads to the
formation of autophagosome-like multivesicular bodies with
characteristics of both the endoplasmic reticulum and mitochondria.

* Full size figure and legend (54 KB)
* Figures and tables index
* Download high-resolution Power Point slide (93 KB)

Mitochondrion-targeted bacterial proteins inducing apoptosis.
Enteropathogenic Escherichia coli (EPEC), the causative agent of
severe infantile diarrhoea, attaches to intestinal epithelial cells,
which induces the effacement of brush border microvilli and the
formation of so-called attaching and effacing lesions. Attached EPEC
inject a 'cocktail' of proteins into host epithelial cells through
their T3SS. These effector proteins include EspF and mitochondrion-
associated protein (Map), which are known to target host mitochondria
through a mitochondrion-targeting sequence54, 56, 57. The importance
of these proteins has been shown in numerous studies: wild-type EPEC
strains, but not EspF mutants, induced a decrease in ΔΨm, the release
of cytochrome c and the subsequent activation of caspases and
apoptotic cell death56, 58, 59. The mitochondrion-damaging activity
could be restored in the mutant by expressing wild-type EspF, but not
EspF in which the mitochondrion-targeting sequence had been removed,
suggesting a direct role for mitochondrial EspF in the dissipation of
ΔΨm (Ref. 58). Loss of ΔΨm in vitro60 and in vivo61 is also the
consequence of the activity of Map. In addition, both Map and EspF are
known to contribute to EPEC pathogenesis59, 61, probably by inducing
tight junction disruption and microvilli effacement (reviewed in Ref.

Several bacterial proteins without typical N-terminal signal sequences
have been shown to target mitochondria. Although no common sequence
motif has been identified to explain their mitochondrial association,
most contain extended β-helix, β-sheet or β-barrel structures and can
form pores in membranes. The 88 kDa protein vacuolating cytotoxin A
(VacA)63, an important virulence factor of H. pylori, is one such pore-
forming protein that induces the formation of vacuoles in the
cytoplasm of treated cells64. VacA is secreted by a typical T5SS
involving a carboxy-terminal autotransporter segment for export across
the bacterial outer membrane. The mature secreted VacA toxin can
undergo limited proteolysis to yield a heterodimeric protein
consisting of the p34 and p58 subunits65, 66, 67. Binding of the toxin
to host cells is mediated by the p58 subunit68, and the p34 subunit
confers cytotoxicity69. Once inside the cytoplasm, p34 can target
mitochondria, causing a loss of ΔΨm and release of cytochrome c70.
Although the mitochondrial localization of p34 as a prerequisite for
the cytotoxic effect of VacA is still a matter of debate71, recent
data have shed light on the possible mechanism of p34-mediated
mitochondrial damage. A unique signal sequence at the N-terminus of
p34 directs the uptake of p34 by the TOM complex and its transfer to
the IMM. At the IMM, p34 assembles and adopts a β-barrel-like
structure to form an anion channel, explaining the high ΔΨm uncoupling
activity (that is, the ability to affect ΔΨm) that is associated with
the cytotoxic effects of p34 (Ref. 72).

Similar to VacA, several other toxins associate with host mitochondria
if applied in a purified form to host cells, inducing ΔΨm dissipation,
cytochrome c release and apoptosis or necrosis. These include
Staphylococcus aureus α-toxin73, 74, 75 and Panton–Valentine
leukocidin (PVL)76, Streptococcus pneumoniae pneumolysin77,
Clostridium difficile toxin A78 and toxin B79, and Clostridium
sordellii lethal toxin80. All of these toxins consist of an extended β-
sheet structure, and their homo-multimers form membrane pores.
Although it remains to be proven, it is likely that pore formation in
mitochondrial membranes is the mechanism by which these proteins
induce cell death.

Cell death by targeting mitochondria can also be induced by some
bacterial porins, which form β-barrel structures in the outer membrane
of Gram-negative bacteria. Porins from Acinetobacter baumanii81,
Neisseria gonorrhoeae and Neisseria meningitidis have been shown to
induce82 or inhibit83 apoptotic cell death by targeting mitochondria.
A. baumanii is an important opportunistic pathogen responsible for
nosocomial infections, and N. gonorrhoeae and N. meningitidis are the
causative agents of gonorrhoea and meningitis, respectively. Recent
work has produced some insights into the mechanisms underlying the
function of these porins; for example, gonococcal PorB was shown to be
imported into mitochondria through the general import route, but
instead of entering the OMM it accumulated in the IMM, resulting in
cell death84. This was unexpected, as the SAM complex normally
recognizes bacterial porins and sorts them to the OMM, at least in
yeast mitochondria85. However, results obtained with neisserial PorB84
and H. pylori VacA p34 (Ref. 72) indicate that targeting the IMM by
pore-forming proteins constitutes a more general mechanism used by pro-
apoptotic bacterial proteins with uncoupling activity.

In contrast to other porins sorted to the OMM85, neisserial PorB
possesses an increased ability to uncouple mitochondria, which is
controlled by binding ATP. Following ATP binding, PorB induces
dissipation of ΔΨm, condensation of the mitochondrial matrix and
reorganization of cristae (the internal compartments formed by the
IMM), which is characterized by the loss of typical crista structure
as observed by electron microscopy84. The crista junctions become
widened, enabling the liberation of cytochrome c from crista
inclusions84. However, crista reorganization alone does not induce
apoptosis; it also requires the PorB-independent opening of the OMM
through the BIM- and BMF-induced activation of BAK and BAX84, 86, 87.
This intricate interdependence of bacterial and host cell factors
demonstrates the tight control of cell life and death at multiple
levels and, in cases when bacteria benefit from the modulation of host
cell apoptosis, could represent the result of the evolutionary
adaptation of bacterial pathogens.

Recently, 34 Chlamydia trachomatis proteins affecting yeast cell
functions were identified88. One protein, the phospholipase D-like
protein CT084, severely restricted the growth of yeast under all
conditions tested. When overexpressed, CT084 localized to
mitochondria, suggesting that the toxicity of this protein might be
connected to its ability to subvert mitochondrial function. Whether
this protein has a similar effect on human cells remains to be

Mitochondrion-targeted bacterial proteins inhibiting apoptosis.
Bacterial proteins with typical N-terminal mitochondrion-targeting
signals can also interfere with the induction of apoptosis. One
remarkable example is Anaplasma translocation substrate 1 (Ats1) from
Anaplasma phagocytophilum, an obligatory intracellular bacterium
causing granulocytic anaplasmosis in humans. This pathogen resides in
a membrane-bound vacuole inside the host cell and secretes Ats1 across
the vacuolar membrane into the host cell cytosol through a T4SS. Once
in the cytosol, Ats1 enters mitochondria by virtue of its N-terminal-
targeting signal using the mitochondrial protein import machinery.
Imported Ats1 not only interferes with apoptotic signalling in the
mitochondria of mammalian cells but also prevents BAX-induced cell
death in yeast cells, suggesting an evolutionarily conserved anti-
apoptotic activity89.

Unlike gonococcal PorB, meningococcal PorB has been shown to have anti-
apoptotic activity. Meningococcal PorB associates with human voltage-
dependent anion channel (VDAC), a porin located in the OMM83. Although
the general role of VDAC in apoptosis signalling is unclear owing to
recent data obtained with mouse fibroblasts lacking the three known
isoforms of VDAC90, the association of meningococcal PorB with VDAC
suggests that it localizes to the OMM and not the IMM like gonococcal
PorB. This differential localization of gonococcal and meningococcal
PorB may explain the observed opposing effects on apoptosis

Proteins targeting mitochondria have only recently been recognized as
pathogenicity factors of phytopathogenic bacteria. Plants respond to
microorganism-associated molecular patterns with an innate immune
response known as the hypersensitive response, a form of programmed
cell death. The type III effector protein HopG1 is broadly conserved
in bacterial plant pathogens and functions as a suppressor of innate
immune responses. HopG1 from the bacterial plant pathogen Pseudomonas
syringae and NP_638946 from Xanthomonas campestris pv. campestris
target host cell mitochondria, impairing mitochondrial respiration and
suppressing the hypersensitive response91.

Mitochondrion-targeted bacterial proteins inducing autophagy.
Salmonella enterica, the causative agent of food poisoning and typhoid
fever, induces cell death in macrophages by several different
mechanisms, all of which are strictly dependent on the T3SSs encoded
by Salmonella pathogenicity island 1 (SPI-1) and SPI-2. A rapid form
of caspase 1-dependent cell death, now termed pyroptosis92 (Box 1),
occurs within 1 hour of S. enterica infection. Caspase 1-independent
cell death is slower, as it starts 5 hours after infection, requires
mitochondrial signalling and probably occurs through an apoptotic
pathway93. During S. enterica infection of macrophages, SipB, a
bacterial protein with membrane fusion activity, localizes to
mitochondria94. Endogenous expression of SipB resulted in efficient
killing of caspase 1-deficient macrophages, indicating that SipB is
sufficient for the caspase 1-independent death of these cells. As SipB-
triggered killing of host macrophages is highly efficient, mechanistic
investigations were also carried out in COS-2 cells, which are
naturally resistant to Salmonella-induced cell death. In these cells,
transiently overexpressed SipB induced the formation of multivesicular
fusion structures that were reminiscent of autophagic vesicles and
contained marker proteins of the endoplasmic reticulum and
mitochondria. As no cleavable presequence could be identified, SipB
probably possesses internal mitochondrion-targeting signals.
Mitochondria integrate infection death signals

Most (if not all) bacterial pathogens subvert signalling cascades to
modulate cell death decisions in their host6. Because of their central
role in integrating diverse cell death signals, mitochondria are often
affected during infection. It is possible that as-yet-unidentified
bacterial factors directly targeting mitochondria play an active part
in controlling cell death signals in this organelle. Other cell death
signals can originate from the engagement of cell surface receptors,
the activation or inhibition of signalling cascades by bacterial
proteins injected into the cell during infection, or a combination of
both (Fig. 4).
Figure 4 | Cell death-modulating signalling pathways converging at the
Figure 4 : Cell death-modulating signalling pathways converging at the
mitochondria. Unfortunately we are unable to provide accessible
alternative text for this. If you require assistance to access this
image, or to obtain a text description, please contact
n...@nature.comMost pathogenic bacteria affect the cell death
signalling cascades of their host cell. Chlamydia spp. inhibit
apoptosis by inducing the degradation of B cell lymphoma 2 (BCL-2)
homology 3 (BH3)-only proteins or by causing mislocalization of pro-
apoptotic BCL-2 antagonist of cell death (BAD) and consequent
upregulation of the anti-apoptotic protein induced myeloid leukaemia
cell differentiation protein 1 (MCL1). Chlamydia spp. infection also
causes the upregulation of inhibitor of apoptosis proteins (IAPs) and
the stabilization of IAP–IAP complexes. Piliated Neisseria gonorrhoeae
can, similarly to Chlamydia spp., cause downregulation of BH3-only
proteins, thereby inhibiting apoptosis. By contrast, opacity (Opa)-
expressing N. gonorrhoeae cause cytoskeletal rearrangements and the
release of pro-apoptotic BCL-2-interacting mediator of cell death
(BIM) and BCL-2-modifying factor (BMF). Avirulent strains of
Mycobacterium tuberculosis induce apoptosis by affecting outer
mitochondrial membrane (OMM) permeabilization, which leads to the
release of cytochrome c and caspase activation. The prevention or
induction of OMM permeabilization during infection is therefore
ultimately controlled at the level of BAX and BCL-2 homologous
antagonist/killer (BAK) oligomerization. In immune cells, the
replication of Legionella pneumophila is controlled by the activation
of the receptor NLR family apoptosis inhibitory protein 5 (NAIP5),
which results in the induction of caspase 1-dependent cell death. The
same bacteria interfere with programmed necrosis with the help of
SdhA. Necrosis is also affected during infection with Shigella
flexneri, which modulates the nucleotide-binding oligomerization
domain 1 (NOD1) signalling pathway, resulting in stabilization of B
cell lymphoma 2 (BCL-2). BCL-2 in turn inhibits BNIP3, a regulator of
the mitochondrial permeability transition through modulation of the
formation of the permeability transition pore complex (PTPC).
Streptococcus pyogenes induces necrotic cell death in macrophages
using pore-forming streptolysin O and streptolysin S, which initiate
the mitochondrial permeability transition through a CypD-dependent
pathway. CypD is also necessary for necrosis induced by virulent
strains of M. tuberculosis. The control of cell death pathways and the
mode of cell death (apoptosis or necrosis) strongly affect bacterial
growth and the outcome of the infection. JNK1, Jun N-terminal kinase
1; NF-κB, nuclear factor-κB; RIP2, receptor-interacting protein 2;
ROS, reactive oxygen species; T4SS, type IV secretion system.

* Full size figure and legend (72 KB)
* Figures and tables index
* Download high-resolution Power Point slide (111 KB)

Affecting apoptosis at the mitochondrial cell death checkpoint.
Chlamydia spp. are highly prevalent obligate intracellular bacteria
that cause sexually transmitted, ocular and pulmonary diseases. These
bacteria have a biphasic lifecycle in which they alternate between the
replicative intracellular form known as reticulate bodies and
infectious, non-replicative elementary bodies. As loss of the host
cell would not only limit bacterial replication but also release non-
infectious reticulate bodies into the surrounding cytoplasm (a dead
end for the organism), Chlamydia spp. use numerous strategies to
prevent premature host cell death. For instance, pro-apoptotic BH3-
only proteins known to target mitochondrial BCL-2 inhibitors are
degraded in cells infected with Chlamydia spp.95, 96, possibly by
Chlamydia protease-like activity factor (CPAF), which is secreted into
the cytoplasm of infected cells97, 98. BH3-only proteins can also be
inactivated in Chlamydia-infected cells by mislocalization. For
example, BAD is phosphorylated and accumulates in the chlamydial
inclusion, which probably prevents it from translocating to
mitochondria and inducing apoptosis99. Interestingly, one of the
direct targets of BH3-only proteins, the mitochondrial apoptosis
inhibitor MCL1, is strongly upregulated and stabilized in Chlamydia-
infected cells100, indicating that Chlamydia spp. can prevent incoming
pro-apoptotic signals both upstream and at the level of mitochondria.

BH3-only proteins have a central role in the translation of cell
stress into pro-apoptotic action at mitochondria, so it is not
surprising that other pathogenic bacteria can also modulate the levels
and activity of these proteins. Similarly to Chlamydia spp. infection,
N. gonorrhoeae infection has been shown to prevent apoptosis in
epithelial cells by inducing the degradation of the BH3-only proteins
BIM and BAD, thereby blocking the signalling cascade upstream of OMM
permeabilization101. Anti-apoptotic signalling and BH3-only
degradation depend on the adherence of the bacteria to epithelial
cells through type IV pili, which initiates the activation of the
cytoprotective extracellular signal-regulated kinase (ERK)101.
However, gonococci can switch off type IV pilus expression and produce
opacity (Opa) proteins, a class of adhesins and invasins that interact
with heparin sulphate proteoglycans or the carcinoembryonic antigen-
related cell adhesion molecule (CEACAM) family of receptors102. Opa-
expressing bacteria activate pro-apoptotic signalling cascades by
massive reorganization of the cytoskeleton and the release of the
cytoskeleton-associated BH3-only proteins BIM and BMF86, which target
and inactivate specific anti-apoptotic BCL-2 family members. The
combined inactivation of the inhibitory BCL-2 family proteins MCL1 and
BCL-XL by the activated BH3-only proteins explains the necessity of
the coordinated action of both BIM and BMF for full-blown apoptosis
under these conditions86.

Consistent with a major role for BH3-only proteins as integrators of
pro-apoptotic insults, infection-induced inhibition and activation of
apoptosis ultimately either prevents or induces the permeability of
the OMM by regulating BAK and BAX. OMM permeabilization is the final
step in these cascades and leads to the release of pro-apoptotic
signalling molecules such as cytochrome c, SMAC and AIF and the
activation of caspases in the cytoplasm. Destruction of epithelial
cells by gonococcus-induced apoptosis requires the coordinated and
hierarchical activation of BAK and BAX87.

The destruction of epithelial barriers by the induction of apoptosis
is thought to be beneficial for bacteria, but BAK and BAX also control
apoptosis that is induced as an innate immune response to limit
bacterial replication. L. pneumophila, the causative agent of
Legionnaires' disease, replicates in macrophages and dendritic cells,
and this is controlled by the activation of the pattern recognition
receptor NLR family apoptosis inhibitory protein 5 (NAIP5) and caspase
1 (Ref. 103). In the absence of NAIP5 or caspase 1, dendritic cells
prevent the replication of L. pneumophila by activating BAK- and BAX-
dependent apoptotic pathways103, which suggests that there is
crosstalk between the apoptotic and non-apoptotic antibacterial
defence mechanisms. Preventing apoptosis seems to have a crucial role
in the replication of L. pneumophila in phagocytic cells, as the
bacterium secretes another effector, SidF, to protect infected cells
from undergoing apoptosis and to allow maximal bacterial
multiplication104. SidF, which is secreted by the Dot/Icm (defect in
organelle trafficking/intracellular multiplication) T4SS, contributes
to apoptosis resistance in cells infected with L. pneumophila by
specifically interacting with and neutralizing the effects of BNIP3
and BCL-rambo (also known as BCL-2L13), two pro-apoptotic members of
the BCL-2 protein family. Thus, L. pneumophila protects host cells
from apoptosis by using translocated effectors to inhibit the
functions of host pro-apoptotic proteins104.

Effects on programmed non-apoptotic cell death. Several bacterial
pathogens cause a caspase-independent regulated necrotic type of cell
death following infection of host cells. A common theme of the
different regulated forms of necrosis (Box 1) is the loss of ΔΨm
before the perforation of the cytoplasmic membrane105. The term
'regulated necrosis' implies that it is possible to interfere with
signalling cascades to prevent the perforation of the cytoplasmic
membrane and the release of cell contents. Indeed, it seems that
bacterial pathogens can interfere with infection-induced non-apoptotic
cell death at different levels; for instance, L. pneumophila injects
the Dot/Icm-translocated substrate SdhA into its macrophage host,
thereby facilitating L. pneumophila replication by controlling cell
survival106. Macrophages harbouring L. pneumophila SdhA mutants showed
increased signs of apoptotic and necrotic cell death. After only 5
minutes of infection with an L. pneumophila SdhA mutant, the
mitochondria disintegrated, leading to early activation of caspases.
However, active caspases played only a minor part, as caspase-
independent cell death pathways and the perforation of the cytoplasmic
membrane dominated long-term infection, leading to aborted replication
of the mutant106.

Other bacterial pathogens such as Shigella flexneri are also known to
control non-apoptotic cell death signalling pathways107. S. flexneri,
a causative agent of bloody diarrhoea, induces a form of cell death
known as pyroptosis (Box 1) during infection of macrophages, which
depends on caspase 1 and is accompanied by the release of the pro-
inflammatory cytokines interleukin-1 (IL-1) and IL-18 (Ref. 108).
Infection of non-myeloid cells with S. flexneri was thought to be non-
toxic, as these cells remained intact even though the bacteria were
still replicating. It turned out that cell death in non-myeloid cells
is actively prevented by a host signalling pathway requiring the Nod-
like receptor (NLR) family member nucleotide-binding oligomerization
domain 1 (NOD1), which recognizes S. flexneri and activates the
production of the pro-inflammatory cytokine IL-8 (Ref. 107).

Interestingly, Nod1−/− mouse cells infected with S. flexneri underwent
necrosis-like cell death preceded by a rapid loss of ΔΨm. The infected
cells then produced high levels of ROS, a well-known consequence of
interrupting the mitochondrial electron transport chain. The induction
of ROS eventually induces the loss of cytoplasmic membrane integrity,
and cell death occurs either directly by oxidizing lipids or
indirectly by interfering with membrane transporters. The crucial
question therefore was how S. flexneri infection controls ΔΨm. Loss of
ΔΨm in cells infected with S. flexneri depended on BNIP3 and CypD, a
known regulator of the mitochondrial permeability transition. BNIP3
was inhibited by BCL-2, which in turn seemed to be stabilized in a
NOD1-dependent manner107. In this system, the balance between the
induction of the mitochondrial permeability transition by BNIP3 and
its inhibition by BCL-2 determines whether or not cell death occurs.

The induction of the mitochondrial permeability transition is probably
the crucial decision point in many other forms of programmed necrosis
that are induced by bacterial pathogens. A recent example is the
induction of necrosis in macrophages infected with Streptococcus
pyogenes109. S. pyogenes produces the toxins streptolysin S and
streptolysin O, which form large pores in eukaryotic membranes and are
required to induce necrotic cell death. However, the obvious
assumption that the direct cause of necrosis is toxin-mediated
perforation of the cytoplasmic membrane has been questioned109.
Treatment with purified recombinant streptolysin S and streptolysin O
as well as infection with S. pyogenes induced the mitochondrial
permeability transition, and consequently necrotic cell death, using
CypD-dependent pathways109. Again, the mitochondrial permeability
transition initiated the production of ROS. Preventing ROS production
by blocking NADPH oxidase reduced the toxicity of S. pyogenes and
recombinant streptolysin and streptolysin O, which indicates a crucial
role for ROS produced by the mitochondrial electron transport chain in
this cell death pathway.

The mitochondrial permeability transition is the initial decision
point for the rapid induction of necrosis and is therefore also
crucial for the outcome of Mycobacterium tuberculosis infection.
Attenuated strains of M. tuberculosis induce apoptosis in human
macrophages independently of the mitochondrial permeability
transition, whereas virulent strains induce the mitochondrial
permeability transition and necrosis in macrophages110. Whether
infected macrophages undergo apoptosis or necrosis has a markedly
different effect on bacterial growth. As the membranes of apoptotic
cells remain intact, the engulfed bacteria are trapped in apoptotic
bodies and are cleared by activated phagocytes110, which initiates an
adaptive immune response that is primed by antigen-specific T
cells111, 112. By contrast, the rapid necrosis that is induced by
virulent strains is associated with bacterial replication and escape
from the immune response113. Induction of the mitochondrial
permeability transition requires CypD, indicating that mycobacterial
infection induces necrosis in a regulated manner113. Recent work has
shown that lipid mediators activated by virulent and attenuated M.
tuberculosis have a crucial role in the control of the mitochondrial
permeability transition and therefore in the decision of whether an
infected cell dies by apoptotic or necrotic cell death114. Macrophages
infected with attenuated strains produced high levels of PGE2
(prostaglandin E2 receptor EP3 subtype), which promotes protection
against the mitochondrial permeability transition and necrosis by
inducing cyclic AMP and activating protein kinase A. By contrast,
virulent strains of M. tuberculosis actively inhibit PGE2 production
and thereby promote the mitochondrial permeability transition and
necrotic cell death, which enhances M. tuberculosis replication in a
lung infection model. These observations show how the outcome of an
infection can be altered depending on whether an infected cell
undergoes apoptosis or necrosis114.
Conclusions and future directions

Numerous bacterial pathogens interfere with the cell death machinery
during infection. The central role of mitochondria in the regulation
of nearly all known forms of cell death make these organelles a prime
target for bacterial apoptosis-modulating factors and for the
signalling cascades that are influenced by bacterial infection.
Multiple bacterial proteins that specifically interact with the
effectors and regulators of the cell death machinery have been
identified6. We are, however, just starting to understand how
bacterial factors interact with mitochondria. Although the import
routes into mitochondria have been delineated for only a few bacterial
proteins, these examples show that bacterial effectors often use
mitochondrial protein import machineries to enter these organelles.
Once inside the mitochondria, the factors targeted by these bacterial
proteins are still mostly unknown. Likewise, although the host cell
death signalling pathways that respond to bacterial infection have
been extensively investigated, many questions remain unanswered. How
are these pathways initiated? Which host factors are involved in these
signalling cascades and how are parallel pathways integrated? How
exactly do they affect mitochondrial effector function? Do these
signalling cascades depend on cell type? Powerful functional genomics
applications such as high-throughput RNA interference linked to
specific assays of mitochondrial dysfunction might help to delineate
entire signalling pathways and define their importance.

The key question that remains is the in vivo importance and relevance
of the different cell death modes induced or inhibited in response to
bacterial infection. Most investigations have been carried out in
transformed cells, but efforts should be undertaken to verify these
findings in primary cells or tissues. Primary cells as infection
models will help us to acquire more relevant information about the
mechanisms of infection-induced cell death signalling in general, and
the role of mitochondria in particular. But the ultimate verification
of the results will require the use of animal models. The use of
knockout mice as infection models is hampered, however, by the fact
that many cell death genes are essential for embryonic development and
their deletion results in embryonic lethality. Therefore, it is
important to generate mice with inducible knockouts of cell death
genes in tissues relevant for different infections. Using such mice,
the roles of specific genes in bacterial replication and colonization
and tissue damage could be better understood. New developments in
imaging technology are opening fresh perspectives in the investigation
of the interactions between bacteria and the various cell types and
tissues they target during infection. The field of intravital
microscopy115 might prove important for elucidating the effect of
certain infections on apoptosis, necrosis and autophagy in precisely
defined tissues. Small tissue areas or even single cells could be
isolated from infected living animals, and their transcriptomes and
proteomes could be compared with that of uninfected tissue. These new
in vivo approaches with single-cell resolution are likely to
revolutionize our understanding of the relevance and interplay of
different cell death modes during the course of bacterial infection.

* Thomas Rudel's homepage
* The caspase substrate database homepage

Top of page

We thank L. Galluzzi for helpful advice during the preparation of the
manuscript and L. Ogilvie for critically reading the manuscript.
Competing interests statement

The authors declare no competing financial interests.
Top of page


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Top of page
Author affiliations

1. Lehrstuhl für Mikrobiologie, Biozentrum der Universität
Würzburg, Am Hubland, 97074 Würzburg, Germany.
2. INSERM U848, Institut Gustav Roussy, Faculté Sud-Université
Paris 11, F-94804 Villejuif, France.

Correspondence to: Thomas Rudel1 Email: thomas...@biozentrum.uni-

Published online 6 September 2010


Dec 11, 2010, 1:14:42 AM12/11/10
On Dec 10, 7:16 am, Kathleen <> wrote:
> To:,,
>,, news-
>,, editor@greenwich-
> Cc:,,

> Subject: Johns Hopkins MD whose daughter won an Autism lawsuit against
> vaccine mfgs.
> Date: Dec 10, 2010 7:02 AM
> ===============================================
> This would be interesting to people
> who wonder about the mitochondrial
> disorder claim - the only claim that
> ever worked in vaccine compensation.
> The argument is the same in LYMErix-
> disease immunosuppression:  People
> who are immune suppressed/disordered
> from fungal antigen exposures (see
> Pam3Cys data, all

> should not get attenuated whole
> viral vaccines (dead viruses is better).
> Similarly, LYMErix-Disease is the same
> as the Great Imitators, or activated
> Epstein-Barr (see Dattwyler and Nicolson

> Here are the IDSA's own Imitators:
> Fungal antigens in the blood (attached
> to and inside of red blood cells) causing
> Chronic Fatigue:

> and Nicolson, again:
> So,  Pass that along.  That's how vaccine
> damaged kids parents can sue.  And this
> is also the proof that LYMErix was not
> a vaccine, accounting for the hysteria
> offered by the Tribune company on behalf
> of the Israeli Lyme Crooks, who prefer to
> now have other people do their dirty work.
> Global warming, molds, Chronic Fatigue
> Syndrome, etc...; it's all real.
> It's unstoppable:
> Go ^^^, "See All Related"
> Fungal antigens (immunosuppression) plus
> viruses are synergistic.  Best friends:
> I was glad to find that (below) because
> such resoluteness in a "review" paper on
> the topic is really compelling.
> Now you know.
> KMDickson
> =========================================
> Correspondence to: Thomas Rudel1 Email:

> Published online 6 September 2010
YES- lyme criminals- they will have their day - in court - in the

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