Bovine tuberculosis

Adaptive Immunity 163

More recently, it has been demonstrated
that although there was a significant reduction
in the expression of antigen-specific IFN-γ in
cattle co-infected with F. hepatica and M. bovis,
the co-infected animals had a lower burden of
M. bovis compared to cattle infected only with
M. bovis (Garza-Cuartero et al., 2016). This
appeared to be associated with a downregula-
tion of pro-inflammatory cytokines and the acti-
vation of alternatively-activated macrophages.
This may suggest that helminth infection limits
the pro-inflammatory environment, favouring a
slower development of mycobacteria, with
reduced bacterial loads, but which presents a
higher barrier for immune-based diagnostic
assays.

11.6 Adaptive Immune Responses

in Other Mammalian Models of

Mycobacterial Disease

In addition to mice, other small mammals, such
as cotton rats, rats and rabbits, as well as larger
mammals such as guinea pigs, goats, pigs and
badgers, are used as models to assess vaccine effi-
cacy for mycobacteria and to examine aspects
of the adaptive immune response with a view
to identification of correlates of immune
protection. While these models have value and,
broadly, immune responses appear to be
mediated by similar mechanisms, each has
limitations. These include access to species-
specific reagents in addition to differences in host
cell immune populations and different tissue
responses. For example, in the mini-pig model,
studies are not only impacted on by the presence
of a CD4/CD8-double positive T-cell population
in peripheral blood, but also by the fact that it is
not possible to reproduce an exudative lesion,
and thus typical TB pathology, even after locally
inoculating up to 1 × 103 bacilli (Gil et al., 2010).
In guinea pigs, the main characteristic of infec-
tion is an extreme reaction against the bacilli,

which has a very important parallelism with the

exudative lesions of humans although curiously,

this exudative response is very much dominated

by eosinophils. However, after BCG vaccination,

an early B-cell influx (Ordway et al., 2008),

accompanied by CD4 and CD8 T-cell activation,

was observed. In this model secondary lesions

occur as a consequence of blood dissemination

and a notable feature is the major destruction of

pulmonary lymph nodes. Investigations in the

CD8/CD8 response, and their kinetics in response

to infection have been performed (reviewed in

(Orme and Ordway, 2016).

Overall, in order to accurately measure the

induction and maintenance of natural or

vaccine- induced immunity in cattle against

M. bovis infection it would appear that these

models are inaccurate and that in vivo studies in

the natural host are preferable. Importantly, cat-

tle can act as a good model for human disease

(despite differences in the virulence of M. tuber-

culosis and M. bovis in cattle) (Waters et al.,

2011).

11.7 Summary

Detailed knowledge of the adaptive immune

response to mycobacterial infection is required

to inform the development of improved vaccines

and diagnostic tests. Key to this is the capability

to understand which parameters can potentially

be used as correlates of immune protection but

also those which reflect infection and disease

progression. Accurate assessment requires the

use of appropriate animal models of disease and

immunological reagents and can be informed

further by mathematical models. The knowledge

reflected in this chapter and across the related

chapters in this book suggest that we are in a

strong position to harness and integrate a wide

range of information to aid future disease con-

trol not only for bovine TB but across species to

human disease.

References

Abebe, F. (2012) Is interferon-gamma the right marker for bacille Calmette-Guérin-induced immune pro-
tection? the missing link in our understanding of tuberculosis immunology. Clinical and Experimental
Immunology 169(3), 213–219.