Comparative Functional Genomics and the Bovine Macrophage Response to Strains of the Mycobacterium Genus

Abstract

Mycobacterial infections are major causes of morbidity and mortality in cattle and are also potential zoonotic agents with implications for human health. Despite the implementation of comprehensive animal surveillance programs, many mycobacterial diseases have remained recalcitrant to eradication in several industrialized countries. Two major mycobacterial pathogens of cattle are Mycobacterium bovis and Mycobacterium avium subspecies paratuberculosis (MAP), the causative agents of bovine tuberculosis (BTB) and Johne’s disease (JD), respectively. BTB is a chronic, granulomatous disease of the respiratory tract that is spread via aerosol transmission, while JD is a chronic granulomatous disease of the intestines that is transmitted via the fecal-oral route. Although these diseases exhibit differential tissue tropism and distinct complex etiologies, both M. bovis and MAP infect, reside, and replicate in host macrophages – the key host innate immune cell that encounters mycobacterial pathogens after initial exposure and mediates the subsequent immune response. The persistence of M. bovis and MAP in macrophages relies on a diverse series of immunomodulatory mechanisms, including the inhibition of phagosome maturation and apoptosis, generation of cytokine-induced necrosis enabling dissemination of infection through the host, local pathology, and ultimately shedding of the pathogen. Here, we review the bovine macrophage response to infection with M. bovis and MAP. In particular, we describe how recent advances in functional genomics are shedding light on the host macrophage–pathogen interactions that underlie different mycobacterial diseases. To illustrate this, we present new analyses of previously published bovine macrophage transcriptomics data following in vitro infection with virulent M. bovis, the attenuated vaccine strain M. bovis BCG, and MAP, and discuss our findings with respect to the differing etiologies of BTB and JD.

Comparative ‘omics analyses differentiateMycobacterium tuberculosisandMycobacterium bovisand reveal distinct macrophage responses to infection with the human and bovine tubercle bacilli

“…The comparison of M. bovis- or M. tuberculosis-infected macrophages with respect to non-infected macrophages revealed a sequential increase in the number of DE genes across the infection time-course, which peaked at 48 hpi and a larger number of DE genes were seen in M. bovis -infected macrophages with the exception of 6 hpi (Fig.3A, B, C, Supp_VI.csv); similar temporal expression profiles were previously reported in other in vitro bovine and human macrophage infection studies (42, 72-74). Comparison of these DE gene lists identified a subset of genes that displayed the same directionality and a similar magnitude of expression (Fig.4A) (Supp_VII.csv).…”

Divergent macrophage responses to Mycobacterium bovis among naturally exposed uninfected and infected cattle

“…It has been shown that pathogenic M. bovis may survive during a stage where neither growth nor killing is seen within macrophages, suggesting a ‘latent’ infection; it has also been speculated that M. bovis may infect an animal and persist in this stage without progression until reactivation 8 , 9 . The successful survival of M. bovis within bovine macrophages may rely on a diverse succession of immunomodulatory mechanisms, including the blockade of bactericidal nitric oxide (NO) production and apoptosis, leading to a strong generation of necrosis 10 , 11 , 12 …”

“…8,9 The successful survival of M. bovis within bovine macrophages may rely on a diverse succession of immunomodulatory mechanisms, including the blockade of bactericidal nitric oxide (NO) production and apoptosis, leading to a strong generation of necrosis. [10][11][12] Susceptible cattle become infected with M. bovis when housed with infective cattle, by contact with wildlife reservoirs or when exposed to a contaminated environment with favourable conditions for the pathogen, such as slow air exchange, large herd size or overcrowding and warm weather. 1, [13][14][15] Whatever the source of M. bovis, infection of cattle and spread within the herd is highly probable when it is endemic, especially when it is highly prevalent.…”

Mycobacterium bovis hosted by free‐living‐amoebae permits their long‐term persistence survival outside of host mammalian cells and remain capable of transmitting disease to mice

“…Macrophages provide a safe niche for long‐term survival within mammals (Andrade et al ., ), however, within the lower eukaryotes organisms, FLA are also hosts to several Mycobacterium species, including M. bovis (Mardare et al ., ). The current growing interest in amoebae as important mediators of emerging epidemics of human and animal diseases (Rue‐Albrecht et al ., ; Scheid, ) stimulated these studies on the persistence of M. bovis within amoebae as a potential environmental source of TB infection.…”

“…including M. bovis (Taylor et al, 2003;Greub et al, 2004;Mba Medie et al, 2011). There are striking similarities in the biology of FLA and macrophages, the established eukaryotic intracellular niche within host organisms of mycobacteria (Rue-Albrecht et al, 2014). Trophozoites are the actively replicating and feeding form of FLA with similar phagocytic capacity to macrophages (they can uptake particles and microorganisms larger than 0.5 lm) and are capable of forming enveloping phagocytic vacuoles followed by formation of phagolysosomes which, in some cases, kill and digest both pathogenic and nonpathogenic microbes (Guimaraes et al, 2016).…”