Elsevier

Cellular Immunology

Volume 242, Issue 2, August 2006, Pages 61-71
Cellular Immunology

Acute cysticercosis favours rapid and more severe lesions caused by Leishmania major and Leishmania mexicana infection, a role for alternatively activated macrophages

https://doi.org/10.1016/j.cellimm.2006.09.006Get rights and content

Abstract

Parasitic helminths have developed complex mechanisms to modulate host immunity. In the present study we found that previous infection of mice with the cestode Taenia crassiceps favours parasitemia and induces larger cutaneous lesions during both Leishmania major and Leishmania mexicana co-infections. Analysis of cytokine responses into draining lymph nodes indicated that co-infection of T. crassicepsLeishmania did not inhibit IFN-γ production in response to Leishmania antigens, but significantly increased IL-4 production. Additionally, anti-Leishmania-specific IgG1 antibodies and total IgE increased in co-infected mice, whereas, IgG2a titers remained similar. Macrophages from Taenia-infected mice displayed increased mRNA transcripts of arginase-1, Ym1, and Mannose Receptor, as well as greater production of urea (all markers for an alternate activation state) compared to macrophages from Leishmania-infected mice. In contrast, lower mRNA transcripts for IL-12p35, IL-12p40, IL-23p19, and iNOS were detected in macrophages obtained from cestode-infected mice compared to uninfected and Leishmania-infected mice after LPS stimulation. The presence of cestode also generated impaired macrophage anti-leishmanicidal activity in vitro, as evidenced by the inability of these macrophages to prevent Leishmania growth compared to macrophages from uninfected mice. This was observed despite the fact that both groups of cells were exposed to IFN-γ. Flow cytometry showed high IFN-γR expression on Taenia-induced macrophages. Thus, lack of response to IFN-γ is not associated with the absence of its receptor. Our data suggest that cestode infection may favour Leishmania installation by inducing alternatively activated macrophages rather than inhibiting Th1-type responses.

Introduction

Parasitic helminths are an important group of large multicellular organisms that affect innumerable hosts. Most of them have developed complex mechanisms to both evade and modulate host immunity [1]. Helminths are known to induce immune anergy, anti-inflammatory responses and Th2 biased responses [1], [2]. Recent advances in our understanding of the immuno-regulatory capabilities of helminthic infections suggest that macrophages play a central role. They can become altered when hosts experience chronic exposure to helminth parasites or their products, which favours the induction of alternatively activated (AAMo) and/or suppressive macrophages [3]. For example, intraperitoneal injection of helminth parasites or their antigens led to the recruitment of a different cellular population of macrophages exhibiting a variety of activities [4], [5], [6], [7], [8].

In experimental cysticercosis, we first demonstrated that AAMo arise during the first weeks after infection and expresses typical markers such as CD23 and CCR5 [9]. In addition, they express high levels of specific genes, such as the lectin chitinase FIZZ1, Ym1, and arginase-1, as well as the inhibitory molecules PD-L1 and PD-L2 [10], [11].

Helminth infections can alter immunity and susceptibility to other pathogens [12], [13] or reduce the effectiveness of vaccines, such as tetanus vaccination during lymphatic filariasis [14]. However, the precise mechanism by which helminth infections affect concomitant immune responses remains to be determined.

Leishmania parasites are obligate intracellular organisms that infect and multiply within macrophages. Infection results in a localized cutaneous lesion the resolution of which is dependent on a strong Th1-type response and classical macrophage activation [15].

Concomitant infections are common in developing countries; in Latin America cysticercosis and leishmaniasis are co-endemic parasitic diseases, both considered to be of public interest. In the present study, we analyzed the interaction of these two infections in vivo by co-infecting mice with the cestode Taenia crassiceps and the protozoan Leishmania major or Leishmania mexicana, and comparing resultant immune responses by analyzing disease progression, parasite burden, subtypes of specific anti-Leishmania antibodies, cytokine responses, and macrophage activity. Our data suggest that established T. crassiceps infection have modulatory effects on the immune response elicited against Leishmaniasis, mainly by affecting macrophage activity rather than inhibiting Th1-type responses.

Section snippets

Mice

Six- to eight-week-old female BALB/cAnN mice were purchased from Harlan Laboratories (México) and maintained in a pathogen free environment at FES-Iztacala, UNAM animal facility in accordance with National and Institutional guidelines.

Parasites and parasite inoculation

(a) Metacestodes of T. crassiceps (ORF strain) were harvested from the peritoneal cavity of female BALB/c mice after 2–4 months of infection. Cysticerci were washed four times in phosphate-buffered saline (PBS, 0.15 M, pH 7.2). Experimental infection was achieved

Features of the cutaneous lesions that develop at site of inoculation of L. mexicana or L. major in BALB/c mice harboring the cestode T. crassiceps

In order to analyze how concurrent infection of T. crassiceps can affect disease progression of L. major and L. mexicana in anatomically distinct sites, mice were i.p. infected with 20 T. crassiceps cysticerci and co-infected 6 weeks later with L. major or L. mexicana. Following s.c. inoculation of 3 × 106L. mexicana promastigotes co-infected mice developed rapid and progressive non-healing lesions, reaching a size of almost 1 cm in diameter during the first 3 weeks after infection. Moreover, mice

Discussion

Among parasites, helminths are potent inducers of immune anergy and anti-inflammatory responses as well as important factors that drive a Th2 biased immune response [1]. Mechanisms involved in such immuno-modulatory effects are a focus of much attention since helminth infections can modulate vaccine effectiveness as well as host immune response to other pathogens [14], [25]. In general, the disease-exacerbating role of parasitic helminths has been attributed to their ability to promote Th2

Acknowledgments

Authors are grateful with M.Sc. Leticia Verdin by her help in histology images. This work was supported by PAPIIT-UNAM Grant # IN208606 to M.R.S., Grant # IN208706, Fundación Miguel Alemán A.C. and CONACYT Grant # 41584-M to L.I.T.

References (34)

  • W.C. Gause et al.

    Trends Immunol.

    (2003)
  • L.I. Terrazas et al.

    Int. J. Parasitol.

    (2005)
  • O.H. Lowry et al.

    J. Biol. Chem.

    (1951)
  • K.J. Livak et al.

    Methods

    (2001)
  • L.M. Sly et al.

    Immunity

    (2004)
  • C. Bogdan et al.

    Curr. Opin. Immunol.

    (2000)
  • R.J. Spolski et al.

    Vet. Parasitol.

    (2002)
  • A. Mantovani et al.

    Trends Immunol.

    (2004)
  • T. Kaisho et al.

    Microbes Infect.

    (2004)
  • R.M. Maizels et al.

    Immunol. Rev.

    (2004)
  • D.M. Mosser

    J. Leukoc. Biol.

    (2003)
  • M.G. Nair et al.

    Infect. Immunol.

    (2005)
  • O. Atochina et al.

    J. Immunol.

    (2001)
  • S. Donnelly et al.

    Infect. Immunol.

    (2005)
  • M. Rodriguez-Sosa et al.

    J. Immunol

    (2002)
  • J.E. Allen et al.

    Int. Immunol.

    (1996)
  • M. Rodriguez-Sosa et al.

    Infect. Immunol.

    (2002)
  • Cited by (0)

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