162 J. Hope and D. Werling
antibodies such as the regulation of APC func-
tion via Fc receptors, regulatory actions of
immune complexes and antibody-dependent
cytotoxicity likely contribute to the induction of
immune responses (Achkar et al., 2015). Cur-
rently little is known regarding the role for B cells
in M. bovis infection in cattle, although these
cells have been demonstrated to be present
within TB granulomas (Aranday-Cortes et al.,
2013; Salguero et al., 2016). Likewise, B-cell
aggregates are consistently detected in associa-
tion with tuberculous lesions in mice, non-
human primates and humans infected with
M. tuberculosis. These tertiary structures contain
naive, memory and plasma B cells as well
as intermixed CD4+ and CD8+ T cells, follicular
dendritic cells and M. tuberculosis-infected APCs
(Ulrichs et al., 2004). In mice, formation of B-cell
follicles within infected lung tissues is dependent
upon IL-23 and CXCL13, and CXCL13 produc-
tion is dependent upon IL-17A and IL-22 in this
response (Khader et al., 2011). The presence of
ectopic germinal centres indicates that the
M. tuberculosis complex – and the ensuing
inflammation – induces active B-cell clusters that
modulate the host response. Thus, these follicles
provide at least a partial framework for coordi-
nated immune control of mycobacterial growth
in the affected tissues (Ulrichs et al., 2004).
In cattle, early granulomas (stages I and II)
displayed scattered B cells, whereas more
advanced granulomas (stages III and IV) showed
clusters of CD79a+ cells located peripherally and
outside of the fibrous capsule (Salguero et al.,
2016). In BCG-vaccinated, M. bovis-infected
cattle, although few stage II and IV granulomas
were observed, the numbers of B cells were sig-
nificantly increased compared to non-vaccinated
M. bovis cattle. Further studies in cattle are
required to elucidate the roles for B cells and to
determine whether they could or should be tar-
gets for vaccine-driven intervention strategies.
11.5 Co-Infection Alters the Adaptive
Immune ResponseCo-infection of individuals with mycobacteria
and other pathogenic organisms affects the
nature of the adaptive immune response. The
best cited example of this is co-infection of
humans with M. tuberculosis and HIV, where the
progressive loss of CD4+ T cells as HIV infection
develops into AIDS has significant negative
consequences on the growth of M. tuberculosis.
Early co-infection studies suggested that co-
infection of cattle with bovine viral diarrhoea
virus (BVDV) and mycobacteria impacts on the
results of the interferon-gamma release assay,
due to the effect of BVDV on type I interferon
production, specifically in the case on non-
cytopathic BVDV.
Concurrent infection with parasitic worms
or with other environmental mycobacteria has
been reported to significantly alter the capacity
to respond to BCG vaccination or to control
M. tuberculosis infection in humans and in
murine studies (Stanford et al., 1981; Flaherty
et al., 2006; Babu and Nutman, 2016). Under
experimental conditions it has been demon-
strated that co-infection of cattle with M. avium
complex organisms (including M. avium subsp.
paratuberculosis) and M. bovis leads to altered
antigen specificity of the T-cell response (How-
ard et al., 2002; Thom et al., 2008), leading to a
masking of diagnostic accuracy (Barry et al.,
2011). There is a significant body of evidence
suggesting that co-infection with liver fluke
( Fasciola hepatica) has a major impact on the out-
come of infection with M. bovis and the accu-
racy of diagnostic tests for bovine TB. In the UK,
areas with high bovine TB prevalence are gener-
ally associated with high endemic prevalence of
helminthic infections (Salimi-Bejestani et al.,
2005). It has been reported that co-infection
with F. hepatica significantly altered the diagno-
sis of M. bovis by both the tuberculin skin test
and the IFN-γ blood test (Flynn et al., 2007,
2009). In a large-scale epidemiological study,
Claridge et al. (2012) estimated that co-infection
would lead to significant under-estimation of
bovine TB in the UK dairy herd. The reduced
sensitivity of the diagnostic tests was shown
to be associated with alterations in the ratio of
IL-4 and IFN-γ, and therefore hypothesized to be
due to altered Th bias or immunosuppression
induced by F. hepatica infection. A downregula-
tion of the Th1 immune response due to Fasciola
co-infection has also been shown to be associ-
ated with an increase in bacterial loads in mice
infected with Salmonella enterica serovar Dublin
or Bordetella pertussis (Aitken et al., 1978; Brady
et al., 1999).