Integrin ?D?2 influences cerebral edema, leukocyte accumulation and neurologic outcomes in experimental severe malaria.

ABSTRACT: Malaria is an infectious disease of major worldwide clinical importance that causes a variety of severe, or complicated, syndromes including cerebral malaria, which is often fatal. Leukocyte integrins are essential for host defense but also mediate physiologic responses of the innate and adaptive immune systems. We previously showed that targeted deletion of the ?D subunit (?D-/-) of the ?D?2 integrin, which is expressed on key leukocyte subsets in mice and humans, leads to absent expression of the integrin heterodimer on murine macrophages and reduces mortality in mice infected with Plasmodium berghei ANKA (P. berghei ANKA). To further identify mechanisms involved in the protective effect of ?D deletion in this model of severe malaria we examined wild type C57BL/6 (WT) and ?D-/- mice after P. berghei ANKA infection and found that vessel plugging and leukocyte infiltration were significantly decreased in the brains of ?D-/- animals. Intravital microscopy demonstrated decreased rolling and adhesion of leukocytes in cerebral vessels of ?D-/- mice. Flow cytometry analysis showed decreased T-lymphocyte accumulation in the brains of infected ?D-/- animals. Evans blue dye exclusion assays demonstrated significantly less dye extravasation in the brains of ?D-/- mice, indicating preserved blood-brain barrier integrity. WT mice that were salvaged from P. berghei ANKA infection by treatment with chloroquine had impaired aversive memory, which was not observed in ?D-/- mice. We conclude that deletion of integrin ?D?2 alters the natural course of experimental severe malaria, demonstrating previously unrecognized activities of a key leukocyte integrin in immune-inflammatory responses that mediate cerebral involvement.

SUBMITTER: Azevedo-Quintanilha IG 

PROVIDER: S-EPMC6927624 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature