LeishmaniaInfection Impairs β₁-Integrin Function and Chemokine Receptor Expression in Mononuclear Phagocytes

Abstract

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.

The Chemokine Receptor CCR5 Plays a Key Role in the Early Memory CD8+ T Cell Response to Respiratory Virus Infections

“…Although we cannot yet offer a formal explanation for the inability of CXCR3 to compensate for CCR5 in this process, there does not appear to be any differences in the expression of the adhesion molecules VLA-1, -2, -4, -5, ICAM-1, or PSGL-1 between CXCR3 + and CCR5 + memory T cells in resting mice (data not shown). One possibility is that ligation of CCR5 may promote changes in intergrin affinity that are necessary for lymphocyte arrest within the pulmonary vasculature, but this hypothesis remains to be tested in the context of respiratory infections (Constantin et al, 2000; Mukai et al, 2001; Pinheiro et al, 2006). In addition, it is unclear whether CCR5, or CXCR3, is also important for secondary effector CD8 + T cells to traffic from local lymphoid tissues back to the lung airways during the latter stages of a recall response.…”

Leishmaniainfection inhibits macrophage motility by altering F-actin dynamics and the expression of adhesion complex proteins

“…Infection with Leishmania has been shown to modulate phagocyte functions associated with cell migration such as signaling, spreading, and adhesion to the substrate (Bray, Heikal, Kaye, & Bray, ; De Almeida, Cardoso, & Barral‐Netto, ; Carvalhal et al, ; Pinheiro, Hermida, Macedo, Mengel, & Bafica, ). Some of these studies suggested that Leishmania ‐induced defects in substrate adhesion might facilitate macrophage migration after infection, promoting parasite dissemination in vivo (Carvalhal et al, ; Pinheiro et al, ; Figueira et al, ). However, other authors have reached the opposite conclusion, proposing that infection with Leishmania impairs the ability of macrophages to migrate (Bray et al, ).…”

Degranulating Neutrophils Promote Leukotriene B4 Production by Infected Macrophages To Kill Leishmania amazonensis Parasites

“…Sterile 96-well tissue culture plates were coated with ECM proteins diluted in RPMI 1640 (14). After protein coating, 5 3 10 5 neutrophils in RPMI 1640 supplemented medium were added for 1 h at 37˚C and 5% CO 2 .…”