Insights into pathogen immune evasion mechanisms: Anaplasma phagocytophilum fails to induce an apoptosis differentiation program in human neutrophils

J Immunol. 2005 May 15;174(10):6364-72. doi: 10.4049/jimmunol.174.10.6364.

Abstract

Polymorphonuclear leukocytes (PMNs or neutrophils) are essential to human innate host defense. However, some bacterial pathogens circumvent destruction by PMNs and thereby cause disease. Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, survives within PMNs in part by altering normal host cell processes, such as production of reactive oxygen species (ROS) and apoptosis. To investigate the molecular basis of A. phagocytophilum survival within neutrophils, we used Affymetrix microarrays to measure global changes in human PMN gene expression following infection with A. phagocytophilum. Notably, A. phagocytophilum uptake induced fewer perturbations in host cell gene regulation compared with phagocytosis of Staphylococcus aureus. Although ingestion of A. phagocytophilum did not elicit significant PMN ROS, proinflammatory genes were gradually up-regulated, indicating delayed PMN activation rather than loss of proinflammatory capacity normally observed during phagocytosis-induced apoptosis. Importantly, ingestion of A. phagocytophilum failed to trigger the neutrophil apoptosis differentiation program that typically follows phagocytosis and ROS production. Heat-killed A. phagocytophilum caused some similar initial alterations in neutrophil gene expression and function, which included delaying normal PMN apoptosis and blocking Fas-induced programmed cell death. However, at 24 h, down-regulation of PMN gene transcription may be more reliant on active infection. Taken together, these findings suggest two separate antiapoptotic processes may work concomitantly to promote bacterial survival: 1) uptake of A. phagocytophilum fails to trigger the apoptosis differentiation program usually induced by bacteria, and 2) a protein or molecule on the pathogen surface can mediate an early delay in spontaneous neutrophil apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anaplasma phagocytophilum / growth & development
  • Anaplasma phagocytophilum / immunology*
  • Anaplasma phagocytophilum / pathogenicity*
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cell Separation
  • Gene Expression Profiling / methods
  • Growth Inhibitors / physiology
  • HL-60 Cells
  • Hot Temperature
  • Humans
  • Immunity, Innate / genetics
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Kinetics
  • Mice
  • Mice, SCID
  • NADPH Oxidases / biosynthesis
  • NADPH Oxidases / genetics
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Neutrophils / microbiology*
  • Neutrophils / pathology
  • Phagocytosis / genetics
  • Phagocytosis / immunology
  • Reactive Oxygen Species / metabolism
  • fas Receptor / physiology

Substances

  • Growth Inhibitors
  • Inflammation Mediators
  • Reactive Oxygen Species
  • fas Receptor
  • NADPH Oxidases