Iron Regulation in Elderly Asian Elephants (Elephas maximus) Chronically Infected With Mycobacterium tuberculosis

Maja Ruetten; Hanspeter W Steinmetz; Markus Thiersch; Marja Kik; Lloyd Vaughan; Sandro Altamura; Martina U Muckenthaler; Max Gassmann

doi:10.3389/fvets.2020.596379

Iron Regulation in Elderly Asian Elephants (Elephas maximus) Chronically Infected With Mycobacterium tuberculosis

Front Vet Sci. 2020 Oct 30:7:596379. doi: 10.3389/fvets.2020.596379. eCollection 2020.

Authors

Maja Ruetten¹, Hanspeter W Steinmetz², Markus Thiersch³, Marja Kik⁴, Lloyd Vaughan¹, Sandro Altamura⁵, Martina U Muckenthaler^{5

6

7}, Max Gassmann^{3

8}

Affiliations

¹ PathoVet AG, Pathology Diagnostic Laboratory, Lindau, Switzerland.
² Tierpark Hellabrunn, München, Germany.
³ Institute of Veterinary Physiology, and Center for Clinical Studies, Vetsuisse Faculty Zurich, and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
⁴ Pathology Division, Department of Biomedical Health Sciences, Veterinary Medicine, Utrecht University, Utrecht, Netherlands.
⁵ Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Children's Hospital, Heidelberg University Medical Center, Heidelberg, Germany.
⁶ Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
⁷ Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany.
⁸ Universidad Peruana Cayetano Heredia (UPCH), Lima, Peru.

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.

Keywords: anemia; ferritin; hepcidin-ferroportin axis; interleukin-6; iron storage disease; nutritional immunity; secondary hemosiderosis; transferrin receptor.