Chapter 5 : Murine Leishmaniasis

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In human visceral leishmaniasis (VL), granuloma formation typifies the reactions seen in individuals with subclinical VL; however, acute clinical disease (kala-azar) typically presents as a complete failure in granuloma formation. Thus, mouse models may also provide a setting for the development of therapies aimed at initiating or enhancing granuloma formation. Although the focus of this chapter is the development, structure, and formation of granulomas in murine VL, a brief consideration of the natural history of infection is helpful to understand potential limitations in the models used. Importantly, unlike most intracellular pathogens, spp. may not readily trigger conventional Toll-like receptor activation. Immune responses to infection are often classified as being Th1 or Th2 type, reflecting polarized differentiation of CD4T-cell subsets. One of the most striking observations when examining the maturation of tissue granulomas, clearly evident following infection but by no means unique to this infection, is that granuloma formation is asynchronous. IL-2 and granulocyte-macrophage colony-stimulating factor treatment of infected mice also promotes granuloma assembly, though with various alterations to the histological characteristics. Promotion of the granulomatous response may be beneficial in the murine host and may also indicate possible avenues for the establishment of the tissue response in humans developing VL.

Citation: Kaye P, Engwerda C. 2003. Murine Leishmaniasis, p 117-146. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch5
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Figure 1

Major factors influencing hepatic growth of The graph illustrates a stylized growth curve for infection in mice, established after intravenous inoculation of 10 amastigotes. Parasite burden is measured as Leishman Donovan units (LDU) ( ). Parasites initially replicate in Kupffer cells at approximately equal rates in all strains examined. After day 3, the impact of the Gly → Asp mutation in the Slc11a1 protein becomes apparent. In Slc11a1 mutant strains (e.g., BALB/c, C57BL/6, and C57BL/10), rapid multiplication of amastigotes is also controlled by endogenous oxygen and nitrogen intermediates. Between day 14 and day 28 postinfection, the influence of MHC genes on rate of cure becomes apparent, and at this time, both CD4and CD8T cells cooperate to induce NO-dependent leishmanicidal activity in macrophages. The dotted line parallel to the axis represents the limit of detection.

Citation: Kaye P, Engwerda C. 2003. Murine Leishmaniasis, p 117-146. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch5
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Figure 2

Defined stages in granuloma "maturation." Photomicrographs showing infected Kupffer cell (A), Kupffer cell fusion with minimal associated inflammation (B), immature granuloma (C), mature granuloma (D), and sterile, involuted granuloma (E). Lower magnification reveals that many stages of granuloma maturation are evident in the same field of view (F). Amastigotes are seen as small dots in the micrographs. For additional details, see text.

Citation: Kaye P, Engwerda C. 2003. Murine Leishmaniasis, p 117-146. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch5
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Figure 3

Chemokine regulation of hepatic granuloma formation. Infected Kupffer cells rapidly express chemokines (CK), but these fail to induce local recruitment of inflammatory cells in immunodeficient mice (left panels). In the presence of resident hepatic TCRγδor TCRαβT cells, chemokine production, notably of γIP-10 (CXCL10), is sustained and serves to initiate a local inflammatory focus with Kupffer cell fusion (center panel). However, TCRαβT cells are required to mount an organized granulomatous response (right panel).

Citation: Kaye P, Engwerda C. 2003. Murine Leishmaniasis, p 117-146. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch5
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Figure 4

Models for asynchronous granuloma development following infection. In panel 1, Kupffer cells (KC) are either heterogeneous or respond in a heterogeneous manner to infection, with qualitative or quantitative differences in chemokine (CK) synthesis. In panel 2, heterogeneity results from the random distribution of resident hepatic T cells, necessary to sustain CK production. In panel 3, the stimulus for inflammation is uniform, but the availability of TCRαβT cells derived from the periphery is limiting.

Citation: Kaye P, Engwerda C. 2003. Murine Leishmaniasis, p 117-146. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch5
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Figure 5

Cytokine regulation of hepatic granuloma formation. Chemokines attract TCRαβT cells to infected Kupffer cells where they produce cytokines essential for generation of the full granulomatous response. Chemokines also attract monocytes and neutrophils, which may supplement the local cytokine environment. Autocrine and paracrine responses to these cytokines likely occur within the granuloma, which cannot be readily dissected with current methodology.

Citation: Kaye P, Engwerda C. 2003. Murine Leishmaniasis, p 117-146. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch5
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Figure 6

Enhancing granuloma formation using costimulation-based therapy. The early immature granulomatous response seen in normal mice at day 14 postinfection (A) can be substantially enhanced in both maturity and size by interfering with the negative regulatory function of CTLA-4 (B and C). Extensive epithelioid cell generation, with minimal additional mononuclear cell recruitment, is also a characteristic of sterile granulomas seen following this intervention (C). Reprinted from reference 64 with permission. Copyright 1998. The American Association of Immunologists, Inc.

Citation: Kaye P, Engwerda C. 2003. Murine Leishmaniasis, p 117-146. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch5
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Table 1

Structure-function relationships of granulomas formed during experimental infection

Citation: Kaye P, Engwerda C. 2003. Murine Leishmaniasis, p 117-146. In Boros D (ed), Granulomatous Infections and Inflammations. ASM Press, Washington, DC. doi: 10.1128/9781555817879.ch5

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