Innate Immune Response in Bovine Tuberculosis 143
could result in the transport of bacteria to the
lymph nodes and therefore, bacterial dissemina-
tion (Denis and Buddle, 2008).
10.3.3 Natural killer cellsNK cells are large granular lymphocytes with
diverse functions that include cytotoxicity and
cytokine production, and that interact with DCs
and other myeloid cells to remove damaged and
infected cells (Bastos et al., 2008; Boysen and
Storset, 2009). NK cells respond to target cells
through the activation and inhibition of recep-
tors. In addition, NK directly recognize PAMPs,
TLRs and PRRs.
Bovine active NK cells have high expression
levels of CD2 (Boysen and Storset, 2009; Sid-
diqui et al., 2012). Activated NK cells use gran-
ule exocytosis and release of cytotoxic proteins
(perforins and granulysins) to reduce myco-
bacteria viability, inducing target cell death
( Siddiqui et al., 2012). It has been demonstrated
that bovine NK cells can reduce M. bovis replica-
tion in bovine macrophages through direct con-
tact with the infected cell and IL-12 stimulation
(Denis et al., 2007; Bastos et al., 2008; Boysen
and Storset, 2009). The ability to control
M. bovis growth was associated with an increase
in IL-12 and nitric oxide release in M. bovis-
infected macrophages, which in turn cooperated
to amplify a Th1 response, NK cell activation
and macrophage apoptosis. An increase in gra-
nulysin, IFN-γ and perforin was associated with
the cytotoxic activity of activated bovine NK
cells against M bovis BCG-infected alveolar and
monocyte-derived macrophages (Endsley et al.,
2006). On the other hand, neonatal BCG vacci-
nation induced a significant increase in NK cells
of peripheral blood and within lymph nodes
(Siddiqui et al., 2012).
10.3.4 NeutrophilsNeutrophils are professional phagocytes that
play an essential role in the innate immune
response. Recent findings have identified that
these cells also participate in the activation and
regulation of adaptive immune responses at
different levels, including regulation of B and T
lymphocytes, and even control the homeostasis
of NK cells. Neutrophils also produce large
amounts of cytokines and neutrophil extracel-
lular traps (NETs). All these activities support a
key role for neutrophils in the protection against
intracellular pathogens, such as viruses and
mycobacteria (Mantovani et al., 2011; Mocsai,
2013).
During infection with mycobacteria, neu-
trophils are recruited within a few hours at the
site of infection, where they phagocytize the
bacilli (Lowe et al., 2012). Once they encounter
M. bovis antigens, neutrophils are able to release
cytokines and chemokines that attract inflam-
matory cells, including T lymphocytes (Shu
et al., 2014). Bovine neutrophils infected with
M. bovis show an increase in CD32, CD64 and
TLR4 expression, as well as increased TNF-α and
IL-10 secretion. Secretion products of infected
neutrophils promoted macrophage activation
through the classical pathway, producing pro-
inflammatory cytokines and chemokines (Wang
et al., 2013). Another effect on human neutro-
phils infected with M. tuberculosis was the for-
mation of NETs. These structures are part of the
innate immune response, being phagocytized by
macrophages, promoting their activation and
the production of cytokines and interleukins,
such as IL-6, TNF-α, IL-1β and IL-10, confirm-
ing the importance of neutrophils and their
close interaction with macrophages during
mycobacteria infections (Braian et al., 2013).
Neutrophils are able to phagocytize bacte-
ria by direct recognition and opsonization, pro-
moting rapid phagosome fusion with lysosomes
and killing bacteria through oxidation reactions
by producing reactive oxygen and nitrogen
species. However, it is controversial whether
neutrophils can eliminate phagocytized myco-
bacteria, especially virulent strains, because it
has been reported that neutrophils are the main
cells found in the bronchoalveolar washings and
sputum of patients with active tuberculosis,
which have an increased load of bacilli. Virulent
strains of M. tuberculosis can live in neutrophils
despite the microbicidal components of these
cells, and it has been shown that they can escape
neutrophil-induced death by necrosis (netosis)
(Corleis et al., 2012). M. bovis is capable of sur-
viving and escaping from bovine neutrophils, in
addition to inducing autophagy in an undeter-
mined way (Wang et al., 2013).