The biological basis of severe outcomes in Anaplasma phagocytophilum infection

Abstract

Anaplasma phagocytophilum causes granulocytic anaplasmosis, an acute disease in humans that is also often subclinical. However, 36% are hospitalized, 7% need intensive care, and the case fatality rate is 0.6%. The biological basis for severe disease is not understood. Despite A. phagocytophilum's mechanisms to subvert neutrophil antimicrobial responses, whether these mechanisms lead to disease is unclear. In animals, inflammatory lesions track with IFNγ and IL-10 expression and infection of Ifng(-/-) mice leads to increased pathogen load but inhibition of inflammation. Suppression of STAT signaling in horses impacts IL-10 and IFN-γ expression, and also suppresses disease severity. Similar inhibition of inflammation with infection of NKT-deficient mice suggests that innate immune responses are key for disease. With severe disease, tissues can demonstrate hemophagocytosis, and measures of macrophage activation/hemophagocytic syndromes (MAS/HPS) support the concept of human granulocytic anaplasmosis as an immunopathologic disease. MAS/HPS are related to defective cytotoxic lymphocytes that ordinarily diminish inflammation. Pilot studies in mice show cytotoxic lymphocyte activation with A. phagocytophilum infection, yet suppression of cytotoxic responses from both NKT and CD8 cells, consistent with the development of MAS/HPS. Whether severity relates to microbial factors or genetically determined diversity in human immune and inflammatory response needs more investigation.

Figure 1

Splenic histopathology from a patient who died after HGA. Note the hemo- and leukophagocytic cells denoted by the white arrows. Hematoxylin & eosin stain; original magnification x 400.

Figure 2

Splenic NKT cells from A. phagocytophilum-infected mice (Ap/HL-60 cells) have abrogated cytotoxic responses, based on reduced delivery of vesicles (CD107a) to membranes after degranulation stimulated by ionomycin C, as compared with mock-infected (HL-60 cells) mice at days 7 and 10 post-infection. P values were calculated using the Wilcoxon test for nonparametric analysis, and a value <0.05 was considered significant.