Bovine tuberculosis

Innate Immune Response in Bovine Tuberculosis 141

immunity in natural resistance to bovine
tuberculosis.

10.2 Pathogen-Recognition

Receptors

Cells of the innate immune system have different
types of PRRs: (i) Toll-like receptors (TLRs); (ii)
complement receptor 3 (CR3); (iii) the nucleotide-
binding oligomerization domain (NOD); (iv) reti-
noic acid-inducible gene 1-like receptor (RIG-1);
(v) mannose-binding receptor; and (vi) dendritic
cell-specific intercellular adhesion molecule-
3-grabbing non-integrin (DC-SIGN). These
receptors are mainly expressed on the cell sur-
face, the endosomal compartments or in the
macrophage and dendritic cell cytoplasm.
Although there are different receptors for
M. bovis recognition, TLRs are the most studied
receptors participating in the innate response
to tuberculosis. TLRs permit macrophage
activation and production of pro-inflammatory
mediators and oxygen- and nitrogen-reactive
intermediates that act to restrict bacterial
growth. Among the receptors that compose
the TLR family, TLR1, TLR2, TLR4, TLR8 and
TLR9 have been associated with the recognition
of Mycobacterium tuberculosis (Mortaz et al.,
2015). However, the TLR type and the activated
inflammatory response are dependent on the
host species, as well as the species and Mycobacte-
rium strain present during the infection. For
example, TLR4 activation was described in
human neutrophils infected with different myco-
bacterial species. Under these latter experimental
conditions, M. tuberculosis H37Rv induced
increased expression of CD32, CD64, CXCR3 and
TLR4, as well as TNF-α secretion and a decrease
of early apoptosis in infected cells, whereas
M. bovis bacillus Calmette–Guérin (BCG) infec-
tion only showed increased CD32 expression and
M. indicus pranii could not activate an immune
response in neutrophils (Ma et al., 2016). On the
other hand, M. indicus pranii infection in macro-
phages induced a higher activation of TLR2 com-
pared to M. bovis BCG, suggesting that atypical
mycobacteria may have increased levels of TLR2
ligands compared to M. bovis BCG (Kumar et al,
2014). In a bovine model, M. bovis and M. tuber-
culosis induced a significant increase in the

expression of TLR2 and RIG-1 type receptors in

alveolar macrophages. Comparatively, M. bovis

was able to maintain the expression of TLR2 for a

longer time period than M tuberculosis (Magee

et al., 2014). Similarly, there is evidence of

TLR activation in a MyD88-dependent and

• independent fashion in cattle and sheep bron-
  chial epithelial cells infected with M. bovis and
  M. tuberculosis (Ma et al., 2016). It is evident that
  each Mycobacterium species induces specific
  changes depending on the infected host. Further-
  more, while M. bovis is capable of causing tuber-
  culosis in different animal species including
  humans, M. tuberculosis mainly infects humans
  and it does not cause or induce a transient infec-
  tion in cattle. These data suggest key differences
  in the innate response among bacterial species,
  possibly related to the host species-specific TLRs
  and to genetic differences between the mycobac-
  terial species and strains (Widdison et al., 2008;
  Ma et al., 2016).

10.3 Cells of the Innate Immune

Response in Bovine Tuberculosis

10.3.1 Macrophages

Macrophages are specialized phagocytic cells

involved in the homeostasis, development and

repair of damaged tissue, and are considered the

first line of defense against mycobacteria. Dur-

ing a classical M. bovis infection, alveolar macro-

phages and DCs phagocytize the bacilli, initiating

the immune response in order to control

bacterial dissemination (Hussain Bhat and

Mukhopadhyay, 2015).

Different studies have demonstrated that

bovine monocyte-derived macrophages phago-

cytize virulent and avirulent M. bovis strains.

Bacteria phagocytized by resting macrophages

range from 1.25 to 2.64 per macrophage,

suggesting that phagocytosis was very similar

regardless of bacterial virulence (Gutiérrez-

Pabello and Adams, 2003). Infection of bovine

macrophages with BCG or virulent M. bovis

revealed a functional difference in controlling

growth of both strains among cattle. Virulent

M. bovis grew to higher colony-forming unit

numbers in macrophages from 24 different

donors compared to BCG. Levels of nitric oxide