Malnutrition Alters the Innate Immune Response and Increases Early Visceralization followingLeishmania donovaniInfection

Abstract

Malnutrition is a risk factor for the development of visceral leishmaniasis. However, the immunological basis for this susceptibility is unknown. We have developed a mouse model to study the effect of malnutrition on innate immunity and early visceralization following Leishmania donovani infection. Three deficient diets were studied, including 6, 3, or 1% protein; these diets were also deficient in iron, zinc, and calories. The control diet contained 17% protein, was zinc and iron sufficient, and was provided ab libitum. Three days after infection with L. donovani promastigotes, the total extradermal (lymph nodes, liver, and spleen) and skin parasite burdens were equivalent in the malnourished (3% protein) and control mice, but in the malnourished group, a greater percentage (39.8 and 4.0%, respectively; P ‫؍‬ 0.009) of the extradermal parasite burden was contained in the spleen and liver. The comparable levels of parasites in the footpads in the two diet groups and the higher lymph node parasite burdens in the well-nourished mice indicated that the higher visceral parasite burdens in the malnourished mice were not due to a deficit in local parasite killing but to a failure of lymph node barrier function. Lymph node cells from the malnourished, infected mice produced increased levels of prostaglandin E 2 (PGE 2 ) and decreased levels of interleukin-10. Inducible nitric oxide synthase activity was significantly lower in the spleen and liver of the malnourished mice. Thus, malnutrition causes a failure of lymph node barrier function after L. donovani infection, which may be related to excessive production of PGE 2 and decreased levels of IL-10 and nitric oxide.Globally, protein-energy malnutrition is the most frequent cause of immunodeficiency (58). Epidemiologic and experimental studies have documented an increased risk for visceral leishmaniasis, caused by intracellular protozoan parasites of the Leishmania donovani complex, in the malnourished host (1, 2, 26). However, the immunologic basis for this association has not been established and standardized experimental models have not addressed this important issue.In this study, our goal was to investigate the mechanisms of the malnutrition-related susceptibility to visceral leishmaniasis. There were three components of the study. First, we needed to create a murine model of malnutrition that was relevant to human malnutrition in developing countries. Although the mouse has been extensively used in animal models of malnutrition, there is no standard murine model of protein-energy malnutrition (69). Human malnutrition is complex, typically involving deficiency of protein and energy with superimposed deficits of other nutrients. Zinc deficiency usually accompanies protein-energy malnutrition (19). Iron deficiency is highly prevalent in developing countries and may accompany zinc deficiency due to a common risk factor, cereal-based diets with little meat (61). Thus, in this model, in addition to protein and energy, zinc and iron were selected as deficient nutrients.M...

Immune response to Leishmania (Leishmania) chagasi infection is reduced in malnourished BALB/c mice

“…Despite the evidence provided by Anstead et al (2001) indicating that PEM affects the innate immune response in mice infected with L. donovani, little is known about the effects of PEM on the adaptive immune response in mice infected with L. chagasi. Thus, in the present study, a murine model of PEM was created based on that described by Anstead et al (2001) to evaluate the effects of combined protein, iron and zinc deficiencies on some aspects of the adaptive immune response against L. chagasi, the causative agent of VL in the New World.…”

“…The impact of PEM specifically on immune response against Leishmania infection is not totally understood and the nutritional status of the host is often neglected (Malafaia 2009). Anstead et al (2001) studied the effects of malnutrition on innate immunity and early visceralization following L. donovani infection and observed that malnutrition causes a failure of lymph node barrier function after L. donovani infection, which may be related to excessive production of prostaglandin E 2 and decreased levels of interleukin (IL) 10 and nitric oxide (NO). In this study, a murine model of polynutrient deficiency (diets deficient in iron, zinc and protein) was established and demonstrated that malnourished mice have an altered innate immune defence and an increased risk of visceralization following cutaneous L. donovani infection.…”

“…Thus, in the present study, a murine model of PEM was created based on that described by Anstead et al (2001) to evaluate the effects of combined protein, iron and zinc deficiencies on some aspects of the adaptive immune response against L. chagasi, the causative agent of VL in the New World. Many experimental animal models have been used to study VL, but few studies investigated the evolution of infection in malnourished mice.…”

Who Is a Typical Patient with Visceral Leishmaniasis? Characterizing the Demographic and Nutritional Profile of Patients in Brazil, East Africa, and South Asia

“…[7][8][9][10][11][12] VL is often associated with malnutrition, which is also a symptom of more severe infection and a major risk factor for poorer clinical and treatment outcomes. [13][14][15][16][17][18][19] The precise mechanisms of the interaction between VL and malnutrition are not well-understood, 19,20 partly because of limited epidemiological data on patient populations. 21 This lack of basic information on VL, particularly demographic and anthropometric data, hinders (1) the ability of health providers to properly prepare for patient management, (2) an informed drug procurement for disease control, and (3) the design of clinical trials and development of new drug therapies in the different endemic areas.…”

Unchanged interleukin 6 level of protein and energy restricted goats during late gestation: the role of elevated blood nitric oxide

“…In previous experiments, there have been variable inflammatory immune responses to malnutrition. Decreased plasma TNFa production has been reported in rodent models of protein-energy malnutrition (Chan et al 1996, Schaffer et al 1997, Anstead et al 2001, but increased plasma IL6 concentration has been observed in malnourished patients (Malave et al 1998, Johann-Liang et al 2000, de Martino et al 2000. In addition, maternal dietary protein restriction decreased NO synthase (NOS) in endometrium and placenta of pigs during early gestation (Wu et al 1998).…”