Abstract
Restriction of nutrients to pathogens (nutritional immunity) is a critical innate immune response mechanism that operates when pathogens such as Mycobacterium tuberculosis have the potential to evade humoral immunity. Tuberculosis is of growing concern for zoological collections worldwide and is well-illustrated by infections of Asian and African elephants, where tuberculosis is difficult to diagnose. Here, we investigated hematological parameters and iron deposition in liver, lung, and spleen of three Asian elephants (Elephas maximus) infected with Mycobacterium tuberculosis. For reference purposes, we analyzed tissue samples from control M. tuberculosis-negative elephants with and without evidence of inflammation and/or chronic disease. Molecular analyses of bacterial lesions of post mortally collected tissues confirmed M. tuberculosis infection in three elephants. DNA sequencing of the bacterial cultures demonstrated a single source of infection, most likely of human origin. In these elephants, we observed moderate microcytic anemia as well as liver (mild), lung (moderate) and spleen (severe) iron accumulation, the latter mainly occurring in macrophages. Macrophage iron sequestration in response to infection and inflammation is caused by inhibition of iron export via hepcidin-dependent and independent mechanisms. The hepatic mRNA levels of the iron-regulating hormone hepcidin were increased in only one control elephant suffering from chronic inflammation without mycobacterial infection. By contrast, all three tuberculosis-infected elephants showed low hepcidin mRNA levels in the liver and low serum hepcidin concentrations. In addition, hepatic ferroportin mRNA expression was high. This suggests that the hepcidin/ferroportin regulatory system aims to counteract iron restriction in splenic macrophages in M. tuberculosis infected elephants to provide iron for erythropoiesis and to limit iron availability for a pathogen that predominantly proliferates in macrophages. Tuberculosis infections appear to have lingered for more than 30 years in the three infected elephants, and decreased iron availability for mycobacterial proliferation may have forced the bacteria into a persistent, non-proliferative state. As a result, therapeutic iron substitution may not have been beneficial in these elephants, as this therapy may have enhanced progression of the infection.
Highlights
Tuberculosis in zoological gardens is a major health concern, especially when it affects large land mammals, such as Asian or African elephants [1, 2]
We showed for the first time that iron storage disease (ISD) exist in elephants and in an exotic species is a matter of inadequate supply of a species-adapted diet but may be due to an underlying infectious disease, such as that caused by infection with M. tuberculosis
No iron deposits were observed in hepatocytes, enterocytes, or macrophages lining the inflammatory wall of the tubercles that host tuberculosis bacteria intracellularly
Summary
Tuberculosis in zoological gardens is a major health concern, especially when it affects large land mammals, such as Asian or African elephants [1, 2]. Diagnostic tests of live animals are usually limited to analyses of bodily fluids, which largely non-invasive for the elephant, are restricted in their ability to provide clinical insight [3] This is unfortunate as such insight would provide an improved understanding of host defenses to chronic mycobacterial infections and help improve assessment of the possible zoonotic risk, the latter a real risk due to the intimacy between elephants and caretakers or visitors of these highly valued and endangered species [4]. This capacity of M. tuberculosis to persist in the host is a major obstacle for tuberculosis treatment, since most antibiotics are inefficient at reaching and killing quiescent bacteria [5], thereby further complicating attempts to treat large animals
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