The pathogenesis of Anaplasma phagocytophilum infections

Abstract

Anaplasma phagocytophilum is a tick-borne, granulocytotropic bacterium causing a nonspecific febrile illness in humans and multiple domestic animals including cattle, sheep, horses and dogs. Since the discovery of A. phagocytophilum as a human pathogen approximately 15 years ago, a large effort has been made to investigate the pathogenesis of this intriguing bacterium. Making use of different leukemic cell lines and knock-out mouse models many cellular and molecular pathogenic mechanisms have been unearthed. The picture arising from this research is one of a bacterium employing unique mechanisms to survive in its dangerous neutrophilic host cell. By entering via receptor-mediated endocytosis and residing in a vacuole which does not fuse with lysosomes, A. phagocytophilum evades the default pathway of bacterial phagocytosis and lysosomal destruction. Subsequently, the bacterium downregulates microbicidal functions of the neutrophil, while at the same time prolonging its life span and using some activated functions for its own benefit. This leaves the infected host with dysregulated neutrophils, on the one hand unable to act as microbial killers, while on the other hand participating in proinflammatory reactions. Also beyond the neutrophil, infection with A. phagocytophilum causes disorder. Both hematological pathology and inflammatory tissue lesions seem to be caused by a poorly regulated inflammatory process. Bacterial burden does not directly correlate with severity of pathology, therefore the question arises to what degree disease in A. phagocytophilum infection is caused by direct bacterial mechanisms or the host’s own immune responses. Most likely, cytokine secretion of infected neutrophils plays an initiatory role in pathology, with subsequent steps in pathogenesis being caused by the dysregulated immune system of the host.