Abstract
Human granulocytic anaplasmosis, caused by the tick-transmitted Anaplasma phagocytophilum, is not controlled by innate immunity, and induces a proinflammatory disease state with innate immune cell activation. In A. phagocytophilum murine infection models, hepatic injury occurs with production of IFNγ thought to be derived from NK, NKT cells, and CD8 T lymphocytes. Specific A. phagocytophilum ligands that drive inflammation and disease are not known, but suggest a clinical and pathophysiologic basis strikingly like macrophage activation syndrome (MAS) and hemophagocytic syndrome (HPS). We studied in vivo responses of NK, NKT, and CD8 T lymphocytes from infected animals for correlates of lymphocyte-mediated cytotoxicity and examined in vitro interactions with A. phagocytophilum-loaded antigen-presenting cells (APCs). Murine splenocytes were examined and found deficient in cytotoxicity as determined by CD107a expression in vitro for specific CTL effector subsets as determined by flow cytometry. Moreover, A. phagocytophilum-loaded APCs did not lead to IFNγ production among CTLs in vitro. These findings support the concept of impaired cytotoxicity with A. phagocytophilum presentation by APCs that express MHC class I and that interact with innate and adaptive immune cells with or after infection. The findings strengthen the concept of an enhanced proinflammatory phenotype, such as MAS and HPS disease states as the basis of disease and severity with A. phagocytophilum infection, and perhaps by other obligate intracellular bacteria.
Highlights
Human granulocytic anaplasmosis, caused by the tick-transmitted Anaplasma phagocytophilum, is the third most common human vector-borne infection in the U.S, where 1% die and 7% require ICU admission [1,2,3]
To better understand the nature of macrophage activation syndrome (MAS)/hemophagocytic syndrome (HPS) induced by A. phagocytophilum infection, we studied in vivo and in vitro responses of NK, NKT, and CD8 T lymphocytes from infected animals to determine if their interactions with A. phagocytophilum-loaded antigen-presenting cells (APCs) results in delivery of cytotoxic cargo dissociated from intracellular production of IFNγ
CD107a expression on NKT cells was generally unchanged among infected animals over the 14-day experiment, whereas control mice who received uninfected HL-60 cells, a xenogeneic cell line anticipated to stimulate cytotoxic responses, demonstrated a slow increase in CD8 and NK T lymphocyte cytotoxicity (CD107a expression) as early as day 7 p.i., peaking at day 14 at the experiment’s conclusion by contrast, demonstrating significant suppression of responses in cells from infected animals at days 10 and 14 (p = 0.048 and 0.049, respectively; Mann–Whitney test) (Figure 1B)
Summary
Human granulocytic anaplasmosis, caused by the tick-transmitted Anaplasma phagocytophilum, is the third most common human vector-borne infection in the U.S, where 1% die and 7% require ICU admission [1,2,3]. A. phagocytophilum is not controlled by innate immunity, but induction of a proinflammatory disease state occurs with innate immune cell activation via TLR2 and the inflammasome to achieve STAT1-mediated IFNγ and NF-κB-mediated proinflammatory gene transcription [4,5,6,7,8]. TLR2-activation implies a role for A. phagocytophilum lipoproteins as a ligand, and induction of the inflammasome via NLRC4 relates to endogenous host cell eicosanoid production following infection. The specific A. phagocytophilum ligands that drive inflammation and disease are not known [4, 17] Regardless, these observations secure an inflammatory basis for A. phagocytophilum-induced septic or toxic shock-like manifestations and imply that severity has its pathophysiologic basis in MAS and hemophagocytic syndrome (HPS) [11, 18]
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