Pinheiro Nathanael F, Hermida Micely D R, Macedo Mariana P, Mengel José, Bafica Andre, dos-Santos Washington L C
LPBI, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Rua Waldemar Falcão no. 121, Candeal, Salvador, BA 40296-710, Brazil.
Infect Immun. 2006 Jul;74(7):3912-21. doi: 10.1128/IAI.02103-05.
Leishmania spp. are intracellular parasites that cause lesions in the skin, mucosa, and viscera. We have previously shown that Leishmania infection reduces mononuclear phagocyte adhesion to inflamed connective tissue. In this study, we examined the role of adhesion molecules and chemokines in this process. Infection rate (r = -0.826, P = 0.003) and parasite burden (r = -0.917, P = 0.028) negatively correlated to mouse phagocyte adhesion. The decrease (58.7 to 75.0% inhibition, P = 0.005) in phagocyte adhesion to connective tissue, induced by Leishmania, occurred as early as 2 h after infection and was maintained for at least 24 h. Interestingly, impairment of cell adhesion was sustained by phagocyte infection, since it was not observed following phagocytosis of killed parasites (cell adhesion varied from 15.2% below to 24.0% above control levels, P > 0.05). In addition, Leishmania infection diminished cell adhesion to fibronectin (54.1 to 96.2%, P < 0.01), collagen (15.7 to 83.7%, P < 0.05), and laminin (59.1 to 82.2%, P < 0.05). The CD11b(hi) subpopulation was highly infected (49.6 to 97.3%). Calcium and Mg(2+) replacement by Mn(2+), a treatment that is known to induce integrins to a high state of affinity for their receptors, reverted the inhibition in adhesion caused by Leishmania. This reversion was completely blocked by anti-VLA4 antibodies. Furthermore, expression of CCR4 and CCR5, two chemokine receptors implicated in cell adhesion, was found to be downregulated 16 h after infection (2.8 to 4.1 times and 1.9 to 2.8 times, respectively). Together, these results suggest that mechanisms regulating integrin function are implicated in the change of macrophage adhesion in leishmaniasis.
利什曼原虫属是细胞内寄生虫，可导致皮肤、黏膜和内脏出现病变。我们之前已经表明，利什曼原虫感染会降低单核吞噬细胞对炎症结缔组织的黏附。在本研究中，我们研究了黏附分子和趋化因子在此过程中的作用。感染率（r = -0.826，P = 0.003）和寄生虫负荷（r = -0.917，P = 0.028）与小鼠吞噬细胞黏附呈负相关。利什曼原虫诱导的吞噬细胞对结缔组织的黏附减少（抑制率为58.7%至75.0%，P = 0.005），最早在感染后2小时出现，并持续至少24小时。有趣的是，吞噬细胞感染会持续损害细胞黏附，因为在吞噬杀死的寄生虫后未观察到这种情况（细胞黏附在低于对照水平15.2%至高于对照水平24.0%之间变化，P > 0.05）。此外，利什曼原虫感染会减少细胞对纤连蛋白（54.1%至96.2%，P < 0.01）、胶原蛋白（15.7%至83.7%，P < 0.05）和层粘连蛋白（59.1%至82.2%，P < 0.05）的黏附。CD11b(hi)亚群感染率很高（49.6%至97.3%）。用锰离子替代钙离子和镁离子（已知这种处理会诱导整合素对其受体处于高亲和力状态）可逆转利什曼原虫引起的黏附抑制。这种逆转被抗VLA4抗体完全阻断。此外，发现与细胞黏附有关的两种趋化因子受体CCR4和CCR5的表达在感染后16小时下调（分别下调2.8至4.1倍和1.9至2.8倍）。总之，这些结果表明，调节整合素功能的机制与利什曼病中巨噬细胞黏附的变化有关。
