Sharing essential knowledge with health researchers and policy makers

Communities of practice

Age-related alteration of arginase activity impacts on severity of leishmaniasis

25 Jun 2008

Maria Victoria Valero

Source: PLoS Neglected Tropical Diseases (see original article)

Citation: Müller I, Hailu A, Choi B-S, Abebe T, Fuentes JM, et al. (2008) Age-Related Alteration of Arginase Activity Impacts on Severity of Leishmaniasis. PLoS Negl Trop Dis 2(5): e235. doi:10.1371/journal.pntd.0000235

Leishmaniasis remains a severe public health problem, with an estimated global prevalence of 12 million and a yearly incidence of 1.5–2 million cases: 1–1.5 million for cutaneous leishmaniasis and 500,000 for the visceral form VL (1). Multiple risk factors such as environmental changes and human behaviour are making leishmaniasis a neglected disease of growing importance. One of the key underlying issues is the unplanned displacement of populations. Socio-economic, demographic, cultural, religious, political and environmental determinants force people to migrate and to find new means to supply their basic needs. Due to these factors and to the social exclusion of migrant populations, there is according to recent evidence an increasing geographical overlap between VL and HIV/AIDS. This newly emerging co-infection pattern currently affects 34 countries around the world, leading to new challenges for the design and implementation of integrated control strategies (2).

Müller and colleagues tested the hypothesis that arginase mediated L-arginine metabolism is altered with age and in this manner modulates the capacity of macrophages to control parasite growth. The study evaluated the impact of ageing on the development of experimental leishmaniasis in genetically susceptible young (6–8 weeks) and older (12 monthss) BALB/c mice. The mice were infected with Leishmania major then parasite and lesion development, and parasite load were determined. The laboratory findings were compared with data from an endemic area in Ethiopia. Data from 37 patients with visceral leishmaniasis (VL) were used to determine the age distribution of VL.

The results showed that, after three weeks of infection, the disease pathology was exacerbated in young BALB/c mice. The parasite loads and arginase activities at the site of infection were significantly increased in both pre-pubertal and adult mice, as compared with aged mice. The authors also suggest that the level of arginase activity correlates with disease severity. Finally, activated macrophages from young mice provide a more permissive environment for parasite growth, directly linking the higher arginase activity to increased parasite replication. These findings were also reflected in the limited data from patients.

A variety of immunological, nutritional and genetic factors are associated with frequency and severity of infectious diseases at different stage of life (3). In young populations the susceptibility to diseases is higher, owing to the still maturing immune system. Exposure to diseases and successful treatments contribute to the development of acquired immunity with age. Therefore, infection load and disease are often the result of the dynamic interplay of environmental factors – i.e. exposure, parasite biology including resistance dynamics and host susceptibility.

The findings of this paper offer a basis for research seeking to develop new strategies to interrupt the process of Leishmania colonization of the macrophages, using a murine model as the basis for young human populations. It is hoped that these experimental and descriptive epidemiological studies are followed-up by thorough additional preclinical, clinical and field studies to establish the potential of new intervention strategies. Finally, such new approaches should not neglect the fact that leishmaniasis is a zoonosis.

References

1. Desjeux P (2001) .The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg; 95:239–243.

2. Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, et al (2002). Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis; 2:494-501

2. Raguenaud M-E, Jansson A, Vanlerberghe V, Van der Auwera G, Deborggraeve S, et al (2007). Epidemiology and clinical features of patients with Visceral Leishmaniasis treated by an MSFClinic in Bakool Region, Somalia, 2004–2006. PLoS Negl Trop Dis; 1(1): e85. doi:10.1371/journal.pntd.0000085.

© 2008 Müller et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Source

Title:
Age-related alteration of arginase activity impacts on severity of leishmaniasis.

Authors:
Müller I, Hailu A, Choi BS, Abebe T, Fuentes JM, Munder M, Modolell M, Kropf P

References:
PLoS Negl Trop Dis 2008: Vol. 2 no. 5, pp. e235

Abstract:
BACKGROUND: The leishmaniases are a group of vector-borne parasitic diseases that represent a major international public health problem; they belong to the most neglected tropical diseases and have one of the highest rates of morbidity and mortality. The clinical outcome of infection with Leishmania parasites depends on a variety of factors such as parasite species, vector-derived products, genetics, behaviour, and nutrition. The age of the infected individuals also appears to be critical, as a significant proportion of clinical cases occur in children; this age-related higher prevalence of disease is most remarkable in visceral leishmaniasis. The mechanisms resulting in this higher incidence of clinical disease in children are poorly understood. We have recently revealed that sustained arginase activity promotes uncontrolled parasite growth and pathology in vivo. Here, we tested the hypothesis that arginase-mediated L-arginine metabolism differs with age. METHODOLOGY: The age distribution of patients with visceral or cutaneous leishmaniasis was determined in cohorts of patients in our clinics in endemic areas in Ethiopia. To exclude factors that are difficult to control in patients, we assessed the impact of ageing on the manifestations of experimental leishmaniasis. We determined parasite burden, T cell responses, and macrophage effector functions in young and aged mice during the course of infection. RESULTS: Our results show that younger mice develop exacerbated lesion pathology and higher parasite burdens than aged mice. This aggravated disease development in younger individuals does not correlate with a change in T helper cytokine profile. To address the underlying mechanisms responsible for the more severe infections in younger mice, we investigated macrophage effector functions. Our results show that macrophages from younger mice do not have an impaired capacity to kill parasites; however, they express significantly higher levels of arginase 1 than aged mice and promote parasite growth more efficiently. Thus, our results demonstrate that ageing differentially impacts on L-arginine metabolism and subsequent effector functions of physiologically distinct macrophage subsets. CONCLUSIONS: Here, we show that arginase-mediated L-arginine metabolism is modulated with age and affects the capacity of macrophages to express arginase; the increased capacity to upregulate this enzyme in younger individuals results in a more permissive environment for parasite growth, increased disease severity and pathology. These results suggest that the difference in arginase-mediated L-arginine catabolism is likely to be an important factor contributing to the increased incidence of clinical cases in children. Thus, targeting L-arginine metabolism might be a promising therapeutic strategy against leishmaniasis, especially in children and young adults.

PMID: 18478052
Full text: HTML

Comments | Related Articles