The Study ofMycobacterium lepraeInfection in Interferon‐γ Gene–Disrupted Mice as a Model to Explore the Immunopathologic Spectrum of Leprosy

Abstract

Mycobacterium leprae infection was evaluated in interferon-gamma knockout (GKO) mice. At 4 months, growth of the bacilli in the footpads of GKO mice plateaued a log(10) higher than that in control mice. Control mice exhibited mild lymphocytic and histiocytic infiltrates, whereas GKO mice developed large, unorganized infiltrates of epithelioid macrophages and scattered CD4 and CD8 T cells. Flow cytometric analysis of popliteal lymph node cells demonstrated similar profiles of T cells; however, GKO cells exhibited an elevated proliferative response to M. leprae antigen. Expression of inducible nitric oxide synthase mRNA was decreased in GKO mice, whereas macrophage inflammatory protein-1alpha and interleukin-4 and -10 mRNA expression were augmented. Control and GKO activated macrophages inhibited bacterial metabolism and produced nitrite. Thus, although deficient in an important Th1 cytokine, GKO mice possess compensatory mechanisms to control M. leprae growth and feature elements resembling mid-borderline leprosy in humans.

Lymphotoxin-α and TNF Have Essential but Independent Roles in the Evolution of the Granulomatous Response in Experimental Leprosy

“…M. lepraeinfected IFN␥ Ϫ/Ϫ mice developed a large, unorganized cellular infiltration in the FP and a TH2-type cytokine profile. 29 In contrast, NOS2 Ϫ/Ϫ FP exhibited a granulomatous inflammation that infiltrated the musculature of the foot and a Th1-type cytokine and chemokine response. 28 Of note, as shown here, M. leprae-infected TNF-deficient mice generated an intense and diffuse T cell inflammation and growth of the bacilli was augmented throughout infection, phenomena quite different from those observed in the LT␣-deficient mice.…”

“…25,28,29 cB6 FPs exhibited scattered macrophage infiltration with a nil to mild lymphocyte response at 3 months (Figure 2A), which by 9 months (Figure 2, A and B) developed into a moderate to dense lymphocyte infiltration among plump histiocytes and macrophages ( Figure 2C) containing bacilli. In contrast, cLT␣ Ϫ/Ϫ mice exhibited very poor cellular infiltration throughout infection (Figure 2A).…”

“…Like B6 mice, 25,29 cB6 mice expressed Th1 cytokines, including interleukin (IL)-12/23p40, IL-12p35, IFN␥, IL-2, and TNF, as well as the activated macrophage product, NOS2 ( Figure 8A). In contrast, there was a 6-to 33-fold lower level of expression of all tested cytokine transcripts in the cLT␣ Ϫ/Ϫ FPs, with the exception of IL-12p35, which was expressed at a level similar to cB6 mice.…”

The First Probable Case of Leprosy in Southeast Italy (13th-14th Centuries AD, Montecorvino, Puglia)

“…It affects the peripheral nervous system primarily, especially the extremities (neural leprosy), and secondarily involves the skin, nasal tissues, and bones [1]. As is well known, Mycobacterium leprae is a highly infective bacterium with low pathogenicity; that is, its ability to induce clinical disease is low [2]. The bacteria affect the motor, sensory, and autonomic nervous systems.…”

Insights from animal models on the immunogenetics of leprosy: a review

“…In humans, an association between leprosy resistance and the single nucleotide polymorphism (SNP), IFNG + 874T, has been found (Cardoso et al 2011b). To study the role of IFNγ in experimental leprosy, control and IFNγ -/-mice were infected in the foot pads as per the Shepard model (Adams et al 2002). Initially, the rate of growth of M. leprae was similar in both strains of mice, but growth continued and plateaued at approximately one log higher in IFNγ -/-mice.…”