Apoptosis and pyroptosis are two common programmed cell death types induced by various
microbial infections. Apoptosis is non-inflammatory programmed cell death and can
be triggered through intrinsic or extrinsic pathways and with or without the contribution
of mitochondria. Pyroptosis is an inflammatory cell death and is typically triggered
by caspase-1 after its activation by various inflammasomes. Non-canonical caspase-11-mediated
pyroptosis has been identified. A NLRP3 (cryopyrin)-dependent but casepase-1-independent
proinflammatory necrosis called pyronecrosis (Willingham et al., 2007), and a caspase-2-dependent
but caspase-1-independent proinflammatory cell death (Chen et al., 2011) have also
been reported. Microbial pathogens are able to modulate host apoptosis, pyroptosis,
and inflammasomes through different triggers and pathways. The promotion and inhibition
of host cell death vary and depend on the microbe types, virulence, and phenotypes.
In this Special Research Topics issue, recent advances in microbial modulation of
host programmed cell death, with a special focus on apoptosis and pyroptosis, were
captured in a total of 11 research and review articles. The special issue includes
three Original Research Articles, five Review Articles, and three Mini Review Articles.
Two articles were published for each of the three pathogens: Brucella spp. (Bronner
et al., 2013; Pei et al., 2014), Legionella pneumophila (Abu Khweek et al., 2013;
Casson and Shin, 2013), and Mycobacterium tuberculosis (Aguilo et al., 2013; Parandhaman
and Narayanan, 2014). Modulation of host immune defenses by Aeromonas and Yersinia
species is introduced in Rosenzweig and Chopra (2013). While (Cunha and Zamboni, 2013)
summarizes the subversion of inflammasome activation and pyroptosis by eight pathogenic
bacteria, (Malireddi and Kanneganti, 2013) introduces the role of type I interferons
in inflammasome activation and cell death induced by microbial infections. The apoptosis-associated
uncoupling of bone formation and resorption in osteomyelitis is reviewed in Marriott
(2013). The intestinal epithelial cell apoptosis in the setting of altered microbiota
with enteral nutrient deprivation is reviewed in Demehri et al. (2013).
Brucella causes brucellosis, one of the most common zoonotic diseases in the world
in humans and a variety of animal species. The Brucella-macrophage interaction is
critical to Brucella virulence. Virulent smooth Brucella strains inhibit macrophage
cell death. This is an important strategy employed by several intracellular pathogens
to maintain the survival of the eukaryotic cell that represents its niche. Many attenuated
rough Brucella strains induce macrophage cell death. The Original Research Article
(Pei et al., 2014) demonstrates that after smooth Brucella invade and replicate inside
host macrophages, some smooth bacteria can automatically dissociate into rough mutants
that can then cause the macrophage cytotoxicity. The cytotoxicity of infected macrophages
is critical for Brucella egress and dissemination. The macrophage necrotic cell death
also induces inflammatory responses and recruits more macrophages to the infection
site.
The rough attenuated B. abortus vaccine strain RB51 was found to induce caspase-2-mediated
but caspase-1-independent apoptotic and necrotic cell death (Chen and He, 2009). Original
Research Article (Bronner et al., 2013) from this special issue further illustrates
this mechanism. In RB51-infected macrophages, caspase-2 regulates many genes and several
cell death pathways: (i) proapoptotic caspases-3 and -8 activation; (ii) mitochondrial
cytochrome c release and TNFα production; (iii) caspase-1 and IL-1β production driven
by caspase-2-mediated mitochondrial dysfunction. Unlike S. typhimurium-induced caspase-1-mediated
pyroptosis, RB51-induced pore formation does not contribute to RB51-induced proinflammatory
cell death. Therefore, caspase-2 appears to act as a “master regulator” that regulates
various genes and pathways and induces a hybrid cell death with features of both apoptosis
and pyroptosis. The caspase-2-mediated cell death was also conserved in macrophages
treated with cellular stress inducers including etoposide, naphthalene, or anti-Fas
(Bronner et al., 2013).
Interesting study by Abu Khweek compared the innate immune response of planktonic
and biofilm-derived L. pneumophila. L. pneumophila, the causative agent of Legionnaire's
disease, replicates inside macrophages to establish infection. In the Original Research
Article (Abu Khweek et al., 2013), the authors demonstrated that compared to planktonic
L. pneumophila, biofilm-derived L. pneumophila (i) replicate more in murine macrophages,
(ii) lacks flagellin expression, (iii) do not activate caspase-1 or -7, (iv) trigger
less cell death, and (v) are mostly enclosed in vacuoles that do not fuse with lysosomes.
Therefore, biofilm-derived L. pneumophila which closely reproduces the natural mode
of the bacterial infection in human is able to evade the innate immune response in
murine macrophages.
The canonical pyroptosis is triggered by the inflammasome, a multi-protein complex
assembled in the cytosol to activate caspase-1. A non-canonical inflammasome activates
caspase-11 and also leads to pro-inflammatory cell death (Kayagaki et al., 2011).
Independently of the inflammasome, caspase-11 promotes the fusion of the L. pneumophila-containing
vacuole with the lysosome (Akhter et al., 2012). The diverse roles of caspase-11 and
routes of activation are described in the mini-review (Casson and Shin, 2013) L. pneumophila
triggers canonical caspase-1-dependent inflammasome activation through one of two
pathways: (i) Type 4 secretion system (T4SS)-regulated flagellin, NAIP5, and NLRC4;
(ii) host ASC and NLRP3, and a L. pneumophila-derived unknown signal. Molecular details
on caspase-11 activation in L. pneumophila-infected macrophages remain unclear. Interestingly,
the inflammasome pathway appears to cross talk with and autophagy, another immune
response (Casson and Shin, 2013).
Mycobacterium tuberculosis, another professional intracellular pathogen in this issue,
also manipulates cell death. Conflicting results have been reported to support inhibition
or induction of apoptosis as a virulence mechanism employed by mycobacteria. This
elegant review article (Aguilo et al., 2013), summarizes the evidences showing that
ESX-1-induced apoptosis during mycobacterial infection contributes to bacterial virulence.
The ESX-1 secretion system regulates the exportation of ESAT-6, a major virulence
factor whose secretion is essential for M. tuberculosis-induced apoptosis. ESAT-6
appears to trigger the mitochondrial apoptotic pathway through ER-stress activation.
ESX-1 dependent apoptosis supports cell-to-cell colonization and bacterial spread.
Highly apoptogenic M. tuberculosis nuoG mutant showed higher cell-to-cell spread and
increased antigen cross-presentation favoring the host. It is evident that apoptosis
may benefit the host or mycobacterial pathogen according to different experimental
conditions (Aguilo et al., 2013).
The well rounded report (Parandhaman and Narayanan, 2014) summarizes more than 10
different cell death modalities involving M. tuberculosis. The paper also reviews
how PknE, one of 11 mycobacterial serine/threonine protein kinases, inhibits apoptosis
and benefits the bacterial survival.
This issue also comprises a paper (Rosenzweig and Chopra, 2013) that describes toxins
secreted by pathogenic Yersiniae and most Aeromonas species that modulate infected
host cell death. The T3SS effector Yersinia outer membrane protein J (YopJ) is an
acetyltransferase that disrupts MAPK and NF-κB signaling pathways to favor apoptosis
and pyroptosis induction. Similarly, Aeromonas hydrophila AexU protein induces apoptosis
by targeting NF-κB signaling. Additionally Aeromonas includes T2- and T6SS effectors
that further modulate host immune responses to promote bacterial virulence (Rosenzweig
and Chopra, 2013).
The nice paper by Zamboni's group (Cunha and Zamboni, 2013) first reviews different
types of inflammasomes that activate caspase-1 (via NLRC4, AIM2, or NLRP3) or caspase-11
and then lead to pyroptosis. These host inflammasomes and pyroptosis pathways can
be targeted by microbial factors released via T3SS/T4SS or other mechanisms in different
pathogens. This paper reviews the mechanisms employed by eight bacterial species to
evade inflammasome activation and pyroptosis induction. These bacteria include Chlamydia
trachomatis, Coxiella burnetii, Francisella tularensis, Legionella pneumophila, Pseudomonas
aeruginosa, Shigella flexneri, Vibrio parahaemolyticus, and Yersinia spp. (Cunha and
Zamboni, 2013).
On the host side, the review by Kanneganti's group (Malireddi and Kanneganti, 2013)
in this issue introduces the role of type I interferons in inflammasome activation
and cell death during infections of five intracellular, four extracellular bacteria,
viruses, and fungi.
How cell death can lead to human disease conditions is well described by the review
paper (Marriott, 2013) that focuses on osteomyelitis, a severe infection of bone caused
by S. aureus and Salmonella spp. Osteomyelitis is often associated with bone resorption
and progressive inflammatory destruction. In the paper Marriott describes the mechanisms
underlying the destruction of bone tissue, with a focus on the apoptosis-associated
uncoupling of bone formation and resorption in osteomyelitis. Different microbial
virulence factors, host response genes and pathways, and their interactions during
the formation of osteomyelitis are introduced.
It has been well established that pathogens modulate apoptosis and pyroptosis, but
what about microbiota? The paper (Demehri et al., 2013) in this issue introduces a
shift in our understanding of intestinal microbiota such as Gram-negative Proteobacteria
after enteral nutrient deprivation. The altered microbiota setting leads to increased
intestinal proinflammatory cytokines, decreased epithelial cell proliferation, and
increased epithelial cell apoptosis. These eventually cause the loss of epithelial
barrier function.
The cover image of this E-book summarizes the key findings reported in the original
research, review, or mini-review articles included in this e-book.
As briefly introduced above, this special Research Topic issue covers a broad range
of cases and reviews demonstrating the modulation of host cell death pathways by different
bacterial pathogens and resident microbiota. While huge progress has been made in
the past decades, many challenging questions still remain.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.