ETIOLOGY

The mycobacteria comprise the only genus in the family Mycobacteriaceae and are a large group of aerobic, non– spore-forming bacterial rods. The most salient feature of this group is their ability to retain arylmethane dyes such as fuschin when mixed with phenol to allow uptake of the dye (e.g., carbolfuschin), then resist decolorization with acid alcohols or inorganic acids. This is the basis for their designation as “acid-fast.” The ability to stain acid-fast results from the high cell wall content of hydrophobic mycolic acids and other complex lipids and waxes. Nutritionally, most mycobacteria are able to utilize simple substrates as sources of carbon and nitrogen, although some are fastidious and require supplemented media for growth in culture (e.g., mycobactin for Mycobacterium avium subspp., paratuberculosis). Growth in culture is generally stimulated by the presence of fatty acids, and thus many media for the culture of mycobacteria contain lipid sources such as egg yolk or oleic acid.¹

In general, mycobacteria have long generation times and thus are slow growing compared with other bacterial pathogens. Although growth rates vary widely, most of the significant human and veterinary mycobacterial pathogens take 14 to 60 days of culture to detect visible growth.^1,2 Some, such as Mycobacterium leprae and Mycobacterium lepraemurium, the cause of human and feline leprosy, respectively, effectively remain unculturable.³ Slow growth, groups or “complexes” of closely related organisms, and unreliable phenotypic or biochemical differentiation schemes have greatly complicated the diagnosis and taxonomic description of mycobacteria.^1,2,4 In recent years, however, genetic analysis of regions such as the 16S ribosomal ribonucleic acid (rRNA) or heat shock protein genes and biochemical analysis of fatty acids have resulted in great advances in both the identification and the taxonomy of mycobacteria.^4,5

EPIDEMIOLOGY

Mycobacterial infections generally result in either multifocal pulmonary or disseminated granulomatous disease (“tubercles”) or localized subcutaneous infections. Pulmonary or disseminated tuberculous disease is typically caused by the obligate pathogens Mycobacterium tuberculosis and Mycobacterium bovis, the classic agents of human and bovine tuberculosis.^1,6 Multifocal to infiltrative disease in ruminants is caused by another obligately pathogenic organism, Mycobacterium avium subsp. paratuberculosis, the causative agent of Johne’s disease.⁷ These particular mycobacteria are relatively unusual in that they are primary pathogens in mammalian hosts, and host immunodeficiency is not a prerequisite for disease.^1,6–8

In contrast, the other mycobacteria are environmental organisms that cause sporadic and opportunistic infections. They are ubiquitous in soil and water and typically cause either disseminated disease in immunocompromised hosts or localized infections in immunocompetent hosts. The only environmental mycobacterium frequently associated with disseminated granulomatous disease in veterinary medicine is Mycobacterium avium subsp. avium (MAA), sometimes referred to as “atypical tuberculosis” or “avian tuberculosis.” Pulmonary or disseminated MAA infections occur sporadically in a variety of domestic and nondomestic animals, as well as humans.^9–11 In humans, pulmonary mycobacterial infections are usually associated with underlying lung disease, and extrapulmonary disease is typically observed only in people with significant immunosuppressive conditions, most notably human immunodeficiency virus (HIV) infection.^1,6,9,12 Although MAA infections have been associated with immunosuppression in dogs and cats, in most cases of MAA disease in domestic animals, an obvious immunosuppressive condition is not recognized.^11,13 Birds are the only species in which epizootics of MAA disease occur. High challenge doses and virulence appear to play a role.^10,14 The other common form of mycobacterial disease in humans and veterinary species is localized infection that occurs opportunistically in immunocompetent hosts. These infections may be caused by a large number of environmental mycobacteria, including MAA.^1,5,15,16 Finally, many mycobacteria are entirely saprophytic and nonpathogenic. These become an issue when encountered in diagnostic samples, and caution needs to be used in ascribing significance to them.⁵

In horses, mycobacterial infections are rare. Although disease caused by M. bovis and to a lesser extent M. tuberculosis has been reported in horses, they appear to be inherently resistant based primarily on the observation that equine tuberculosis has remained uncommon even in areas where the disease is prevalent in humans and other animals.^17–19 In areas with effective control programs for M. bovis and M. tuberculosis, the incidence of these infections in horses has decreased correspondingly.¹⁷ In areas where these diseases occur, however, cases may still be seen in horses.²⁰ Moreover, with the continued presence in North America and Europe of M. bovis, particularly in wildlife,⁸ and the resurgence of M. tuberculosis in humans,²¹ the possibility of these infections in horses should not be disregarded.

Infection with M. avium subspp., paratuberculosis (Johne’s disease) can be induced experimentally in horses.²² The recent literature also describes a single case in a Sicilian ass from North America, although the diagnosis was not confirmed by culture.²³ Consequently, naturally occurring equine Johne’s disease, if it truly occurs at all, appears to be exceedingly rare.

The most common mycobacterial disease currently seen in horses is disseminated disease caused by MAA, which has been reported sporadically from North America and Europe.^{13,17,24–30} These reports describe infection with MAA serotypes 1, 2, 4, 5, and 8, in some cases with multiple serotypes from a single horse. These serotypes indicate equine infections have been caused by MAA rather than the closely related Mycobacterium intracellulare (in human medicine often referred to as part of the “Mycobacterium avium complex”).¹ Interestingly, in humans, MAA infections are most often associated with disseminated disease in patients immunosuppressed by HIV infections,^1,12 whereas M. intracellulare infections predominate in patients with pulmonary disease.^31,32 Although completely speculative, this may suggest that horses with disseminated MAA infections have an underlying immune defect that predisposes them to this disease. Other than a single case in which MAA was associated with septic arthritis,¹⁶ all MAA infections described in horses have been disseminated disease. Although little is known about the source of equine MAA infections, the cases are very sporadic, and there is no evidence that these infections are contagious among horses. In other species, including humans, the source of infection is environmental.^{6,11,15,33,34}

Localized infections with other species of mycobacteria have also been described in horses but are surprisingly rare. These include a single case of abortion caused by Mycobacterium terrae,³⁵ a recent case of fetal disseminated granulomatous disease and abortion from which a pure culture of Mycobacterium holsaticum was obtained from fetal tissues (Slavic D, Shapiro J, Animal Health Laboratory, University of Guelph, unpublished data), and a single case of subcutaneous infection caused by Mycobacterium smegmatis.³⁶

PATHOGENESIS

No studies of MAA pathogenesis have been performed in horses, so information regarding the pathogenesis of this disease must be extrapolated from what is described in other species. However, because the lesions are so similar, it is reasonable to assume that at least the major features of pathogenesis in horses will be similar to other species. The predominant lesions in horses are respiratory and enteric, indicating that the entry of MAA is by aerosol or ingestion of environmental organisms, respectively. On ingestion, MAA has the ability to survive low pH conditions in the stomach and transit to the intestines.³⁷ Once in the intestine, MAA initially infects enterocytes, and to a lesser extent M cells, overlying intestinal lymphoid tissue. Although enterocyte infection is receptor mediated and a metabolically active process that blocks bacterial degradation in cellular vacuoles, MAA infection appears to be silent in that it elicits neither chemokine responses nor inflammation.³⁸

After extrusion from the intestinal epithelium into the submucosa, MAA is scavenged by local macrophages. MAA is a facultative intracellular parasite of macrophages, and the ability to infect and replicate within macrophages is the defining characteristic of pathogenic mycobacteria. Entry of MAA into macrophages is mediated primarily by complement receptors, including CR3 (CD11b/CD18 complex) and CR1. After uptake into the phagosome of a resting macrophage, MAA selectively upregulates gene expression³⁹ and is able to alter a number of host cell functions to prevent bacterial degradation and facilitate survival. These include blocking phagosome-lysosome fusion and acidification of the phagosome, upregulation of enzymes used in fatty acid metabolism, expression of MAA transcriptional regulators, and facilitation of iron transport.^38,40 Replication within macrophages appears to impart to progeny bacteria increased efficiency of infecting new macrophages, possibly by utilization of alternate receptors for entry, such as β₁-integrins and transferrin, as well an enhanced ability to block macrophage activation. This process may facilitate reinfection and dissemination.⁴¹

The host immune response to infected macrophages results in granuloma formation by activation and recruitment of macrophages into the affected area.⁴² Cell-mediated host responses that effectively activate and induce bactericidal mechanisms in MAA-infected macrophages are required to control infection. Neither CD8+ cytotoxic T lymphocytes nor specific antibodies appear to be important in control of MAA.^38,43 Key cytokines and cells involved in effective macrophage activation and anti-MAA immune responses include interferon gamma (IFN-γ) from natural killer (NK) cells and antigen-specific CD4+ T lymphocytes, tumor necrosis factor alpha (TNF-α) and granulocyte-monocyte colony-stimulating factor (GM-CSF) from macrophages, and interleukin-12 (IL-12) from macrophages, NK cells, and neutrophils.^32,38,43 TNF-α and IFN-γ in particular are key to granuloma formation.⁴³ TNF-α is one of the most critical cytokines for activation of bactericidal activity in infected macrophages, including production of antibacterial proteins, production of superoxide anions, inhibition of bacterial replication, and induction of apoptosis. Interference with TNF-α activity in infected mice leads to higher bacterial loads, and blocking TNF-α expression in infected macrophages is associated with increased MAA virulence.^44–46

To maintain infection, MAA is able to counter by interfering with host antibacterial responses. MAA increases production of transforming growth factor beta (TGF-β), IL-10, and IL-6, which suppresses macrophage function and responsiveness to IFN-γ and TNF-α.^38,43 MAA may also directly interfere with IFN-γ cell-signaling pathways in macrophages.⁴³ The lack of phagosome acidification and suppression of co-stimulatory molecules interfere with antigen presentation and prevent infected cells from initiating proinflammatory responses.^38,47

Clinical disease resulting from MAA is ultimately caused by organ dysfunction from infiltration and destruction of tissue by granulomatous inflammation. Weight loss is also frequently observed in MAA-infected horses. Although in many equine cases this is probably caused by intestinal involvement and malabsorption, in monkeys MAA also has the ability to cause cachexia directly by disruption of growth hormone and insulin-like growth factor regulation of metabolism.⁴⁸ In immunocompetent animals, antibacterial host responses are generally sufficient to control or eliminate infections. Because exposure is most likely ubiquitous and probably occurs routinely in all horses, the vast majority of MAA infections are eradicated subclinically. What tips the balance in some horses toward the inability to control infection is not known. Equine MAA infections are not associated with overt congenital or acquired immunodeficiency syndromes. However, more subtle defects that predispose horses to MAA infections may go unrecognized. For example, human susceptibility to disseminated MAA infections have been associated with genetic defects in IFN-γ and IL-12 immune responses.³²

CLINICAL FINDINGS

MAA infections in horses are typically diagnosed only after disease is highly advanced, and such infections have been uniformly fatal.^{13,17,24–30} As with most disseminated diseases, the clinical presentations may be quite variable depending on the organ system(s) affected and in which organ system(s) clinically significant pathology predominates. Cases of MAA have been described only in horses greater than 1 year of age. It is not known if the absence of disease in foals represents innate resistance, or if it means that MAA has a long incubation period. Interestingly however, cases do tend to occur in younger horses, with 13 of 21 horses in the series of cases reviewed being 6 years of age or younger.^{13,17,24–30} There does not appear to be a gender or breed predisposition.

MAA is a chronic disease, with most affected horses having clinical disease histories of 2 to 12 months. These horses likely were subclinically infected for some time before the onset of clinically apparent disease. Horses with MAA infections usually have many of the nonspecific signs of chronic bacterial infection, including depression, intermittent fever, and weight loss. Many, but not all, infected horses have mild neutrophilia. In some cases, anemia is present. One of the most consistent clinical presentations of equine MAA infections is chronic diarrhea caused by involvement of the small intestine, cecum, or colon.^* Many of these horses also have hypoalbuminemia from malabsorption and protein-losing enteropathy, which may result in ascites, pleural effusion, and edema. Although pulmonary involvement is common, overt respiratory signs such as dyspnea and coughing are uncommon. Similarly, although the liver is usually affected, and elevated liver function tests may be seen on clinical chemistries, overt liver disease is uncommon.^{13,17,24–30}

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