146 J. Carrisoza-Urbina et al.
suggesting a possible role of macrophage-
secreted mediators in the induction of apoptosis
(Gutiérrez-Pabello et al., 2002).
It has been postulated that host resistance
and the virulence of the strain influenced the
degree of macrophage apoptosis. Macrophages
from resistant donors underwent apoptosis as
a consequence of M. bovis infection at higher
levels than from susceptible donors. At the same
time, virulent strains showed a tendency to
induce a higher percentage of apoptosis than
BCG. Although experimental results indicate a
possible role of host resistance and bacterial vir-
ulence in macrophage apoptosis, further investi-
gation is required to validate these observations
(Esquivel-Solís et al., 2013).
Induction of bovine macrophage apoptosis
has been described using whole M. bovis cells;
however, experimental data also indicates that
M. bovis cell-free protein extract and individual
proteins can also induce macrophage apoptosis.
Furthermore, bovine macrophage apoptosis can
occur in the absence of caspase activation with
participation of the mitochondrial apoptosis
inducing factor (AIF). These results strongly
suggest that M. bovis infection drives the release
of AIF into the cytosol and its translocation to
the nucleus, where it participates in chromatin
condensation and DNA fragmentation in a
caspase-independent pathway (Vega-Manriquez
et al., 2007). Recent studies suggested that
M. bovis infection results in loss of Ca2+ from the
ER and an increase in the intracellular redox
state which results in accumulation of unfolded
or misfolded proteins in the ER resulting in ER
stress. M. bovis effectively induced apoptosis
in murine macrophages via ER stress. The
STING-TBK1-IRF3 pathway mediates cross-talk
between ER stress and apoptosis during M. bovis
infection which can control intracellular bacte-
ria effectively (Cui et al., 2016). Taken together,
these observations illustrate the importance of
macrophage apoptosis in the patho genesis of
bovine tuberculosis and the role of apoptosis as a
bovine innate immune mechanism.
10.5 InflammasomeThe innate immune system has the ability to
combat microbial infections and at the same
time handle pathological inflammation. The
inflammasome is a multiprotein complex that
plays a central role in this process, regulating
the production and action of pro-inflammatory
cytokines such as IL-1β, IL-18, IL-33, and a type
of cell death (pyroptosis) in response to patho-
gens and internal warning signs.
The inflammasome allows the release of
active IL-1β and has been considered to be part
of resistance to tuberculosis since interleukin
deficient mice infected with M. tuberculosis
exhibit acute mortality and increased pulmo-
nary bacterial load (Mayer-Barber et al., 2010).
In macrophages and dendritic cells, one path-
way to IL-1β production is due to inflammasome
activation; another route is through serine pro-
teinases such as proteinase-3, elastase and
G-cathepsin from neutrophils and macrophages
involved in pro-IL-1β cleavage (Netea et al.,
2010).
Because IL-1β is synthesized as a pro-IL-1β
biological precursor, it needs to be activated by
cleavage of caspase 1, allowing its maturation
and exit into the extracellular space. This pro-
cess is regulated by the multiprotein complexes
referred as inflammasomes, which are: (i) IPAF
(protease activator factor); (ii) NLRP1 (oligomer-
ization domain by nucleotide binding contain-
ing protein 1); and (iii) NLRP3 and AIM2 (absent
receiver in melanoma 2). It is known that
virulent strains of M. tuberculosis activate the
NLRP3 through the recognition of ESAT-6 pro-
tein (Mishra et al., 2010). Also, virulent M. bovis
activates NLRP7 in THP-1 macrophages, and
induces pyroptosis, TNF-α and CCL3 expression,
whereas the non-virulent M. bovis BCG strain is
unable to activate the inflammasome (Zhou
et al., 2016). Moreover, it also has been shown
that M. bovis can activate the AIM2 inflamma-
some, which recognizes double-stranded DNA
(Yang et al., 2013).
In a mouse model of M. tuberculosis infec-
tion it was demonstrated that the IL-1 regula-
tion was induced through INF-γ produced by T
lymphocytes, and that this process was mediated
by NO, which inhibited the NLRP3 inflamma-
some assembly through thiol nitrosylation; this
in turn inhibited persistent neutrophil recruit-
ment, preventing tissue damage (Mishra et al.,
2012).
During chronic infections like tuberculosis,
inflammasomes are a double-edged sword. On