The United Nations predicts that the current world population of 7.2 billion is projected
to reach 9.6 billion by 2050, which can only mean one thing for global agriculture,
and that is increased pressure on production. One step to increase food supply is
the abolition of the milk quota restrictions in the EU in 2015. It is inevitable with
expansion and intensification of production that risks associated with disease will
be exacerbated. This will have critical consequences for the sustainability of farming
systems, for the safety of the food chain, and for human health. In this context,
it is appropriate that we redouble every effort to understand the immune response,
particularly to recalcitrant infectious diseases in cattle.
The publication of the bovine genome in 2009 and the advent of new high-throughput
technologies have facilitated a massive expansion in our knowledge of the immune response
in cattle. Genomic selection means we can now identify animals with superior genetics
at birth and use them as parents of the next generation, thereby rapidly increasing
the rate of genetic gain. While these methods are currently in use to breed cattle
with superior genetics for production traits, they are not yet available to improve
disease resistance. Mycobacterial and mammary gland (Mastitis) infections represent
two diseases that severely impact global cattle production, with an annual estimated
cost of $3 billion for TB globally (1) and multiples of this value for mastitis, especially
when the costs associated with subclinical infection are included (2, 3). Both these
diseases, as well as complementary analyses on the regulation of bovine immunity,
are addressed by cutting edge papers in this edition of Frontiers.
Mycobacterium tuberculosis causes TB in human beings and over one-third of the world’s
population are infected with this disease. Similarly, in cattle, related mycobacterial
species cause potentially zoonotic infections, which are endemic in many parts of
the world, despite stringent global surveillance and control programs. The advent
of Next-Generation Sequencing (NGS) technologies holds significant promise to overcome
limitations in current generation test sensitivity and specificity and as discussed
by McLoughlin et al., transcript biomarker signatures have been identified, which
discriminate between TB patients with active and latent disease. Indeed, McLoughlin
et al. used multi-dimensional scaling to unambiguously classify peripheral blood leukocyte
transcriptomic profiles from Mycobacterium bovis infected and healthy cattle, thereby
uncovering potential biomarkers for M. bovis infection (4). This technology is a powerful
tool for unraveling the complexities of host immune response and provides new layers
of information, which deepens our understanding of host–pathogen interactions that
underlie Mycobacterial disease pathogenesis. The macrophage is recognized as the key
effector cell driving anti-mycobacterial immunity but which can be hijacked by mycobacteria,
thereby contributing to suboptimal bacterial clearance and disease chronicity. Using
the macrophage as a model, RNA-seq was performed after challenge with Mycobacterium
avium subspecies paratuberculosis (MAP), which has uncovered novel genes that have
not previously been associated with the host response to MAP infection (5). One of
the key challenges with NGS technologies is the bioinformatic analysis to extract
meaningful and biologically relevant findings from the wealth of data generated. Sophisticated
system-biology tools have been employed by Killick et al. to generate biological interaction
networks that usefully identify key hub and bottleneck genes that are central to the
immune response and thereby potential targets for immunomodulation – either naturally
by pathogens in their eternal quest for survival, or therapeutically with the development
of new intervention strategies (6). Furthermore, a comparative analysis of the macrophage
response to various strains of mycobacteria has been reviewed; M. bovis induced a
distinct transcriptional profile in monocyte-derived macrophages compared to the more
similar profiles of both M. bovis BCG and MAP (7). The authors describe how differential
expression of type-I interferon genes were specific to the virulent M. bovis strain
supporting a role for these genes in the establishment of active tuberculosis in cattle.
The identification of the genes and pathways involved in orchestration of the immune
response is not merely of fundamental importance but differentiating between the immune
responses to closely related bacterial species can have very real implications for
the success of current generation diagnostics. The study by Kennedy et al., examines
the effects of annual mandatory testing for M. bovis infection on the ELISA performance
routinely used for the diagnosis of MAP (8). In one herd, prior to testing for bovine
tuberculosis (BTB), 7.9% of cattle serum samples and 5.8% of milk samples were positive
for MAP antibodies. Shortly after the BTB test, the MAP ELISA positive rate increased
to 39% in both sample types, clearly showing BTB test interference in MAP ELISA performance.
Exploiting differences in host immunity induced in response to these closely related
strains of mycobacteria could yield significant dividends in terms of increased specificity
of diagnostics.
An optimal and effective host immune response must overcome pathogen-mediated efforts
to subvert it while minimizing tissue damage and, therefore, the regulation of the
immune response is critical. Furthermore, shedding light on the differential dialog
between the host and pathogenic or comensal bacterial strains is a very exciting area
of research. It is of interest, therefore, that Villena et al. review how immunobiotics
can dampen TLR-mediated inflammation in an intestinal cell line, and postulate how
immunoregulatory feeds could be developed in the future (9). Inflammation is a feature
of most diseases, and detailed knowledge on the pathways regulating it is critical
toward developing effective immunoregulatory approaches in cattle. MiRNAs have also
been shown to be powerful regulators of immunity and as reviewed by Lawless et al.,
793 miRNAs have been identified to date in the bovine genome (10). Their rapid induction
in response to challenge and the tissue-specific expression pattern of some has led
to speculation on their potential use as diagnostics. Work by the same group has identified
miRNA signatures of infection in mammary epithelial cells in response to a common
mastitis-causing pathogen. The review highlights relevant studies on how miRNAs regulate
the production of IFN-y and TNF, key cytokines in the immune response to TB.
In a comprehensive review, Thompson-Crispi et al. integrates multiple studies on the
genetic regulation of the bovine immune response, particularly in relation to mastitis
(11). Interestingly, the review discusses earlier work by the same group in which
their High Immune Response (HIR) technology was used to identify Immunity+ sires,
daughters of which showed a 44% reduction in mastitis as well as reduced susceptibility
to other diseases. The potential consequences of selection for a specific immune phenotype
are discussed, and the review signposts how integration of complementary genetic,
genomic, and epigenetic data – supplemented with accurate disease and health phenotype
information – will enhance our ability to breed cattle with superior disease resistance
in the future.
Early fetal mortality is a major contributory factor to poor reproductive outcomes
and increased costs, especially in high producing dairy cows. In that regard, the
review by Fair is a relevant one. Although immunological analyses in the cow during
pregnancy are growing, attempts to evaluate the interaction between the cow and the
developing fetus are few. While comparative immunology can shed some light, Fair argues
that basic understanding in the bovine are required to more comprehensively understand
the complex regulation of local and systemic immunity in the pregnant cow and thereby
yield novel solutions to fertility problems (12). Understanding the immune shifts
that occur during pregnancy is also critical to understanding the windows of susceptibility
that may exist through which susceptibility to infectious diseases could be increased.
Multi-factorial challenges, for example achieving and sustaining excellent animal
health, require multifaceted solutions that can only be achieved through intensive
integration of knowledge and expertise from a diverse spectrum of research efforts
(13). As the physicist Richard J. Feynman once wrote “In order to make progress, one
must leave the door to the unknown ajar.” There is a lot yet to learn in relation
to bovine immunity and, therefore, this e-book is a timely integration of the most
current research and scientific thinking on these critical issues and will contribute
to the direction of future research in these areas. When dealing with infectious diseases,
the old truism is perfectly apt – ipsa scientia potestas est. New knowledge also prepares
us for the unforeseen challenges of the future.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.