ABSTRACT

Anaplasma phagocytophilum infects neutrophils to cause granulocytic anaplasmosis. It poorly infects mice deficient in acid sphingomyelinase (ASM), a lysosomal enzyme critical for cholesterol efflux, and wild-type mice treated with desipramine that functionally inhibits ASM. Whether inhibition or genetic deletion of ASM is bacteriostatic or bactericidal for A. phagocytophilum and desipramine's ability to lower pathogen burden requires a competent immune system were unknown. Anaplasma phagocytophilum-infected severe combined immunodeficiency disorder (SCID) mice were administered desipramine or PBS, followed by the transfer of blood to naïve wild-type mice. Next, infected wild-type mice were given desipramine or PBS followed by transfer of blood to naïve SCID mice. Finally, wild-type or ASM-deficient mice were infected and blood transferred to naïve SCID mice. The percentage of infected neutrophils was significantly reduced in all desipramine-treated or ASM-deficient mice and in all recipients of blood from these mice. Infection was markedly lower in ASM-deficient and desipramine-treated wild-type mice versus desipramine-treated SCID mice. Yet, infection was never ablated. Thus, ASM activity contributes to optimal A. phagocytophilum infection in vivo, pharmacologic inhibition or genetic deletion of ASM impairs infection in a bacteriostatic and reversible manner and A. phagocytophilum is capable of co-opting ASM-independent lipid sources.

中文翻译：

---

酸性鞘磷脂酶的功能抑制或基因缺失抑菌抑制体内无形体吞噬细胞感染

摘要

无形体吞噬细胞感染中性粒细胞引起粒细胞无形体病。它对缺乏酸性鞘磷脂酶 (ASM)（一种对胆固醇流出至关重要的溶酶体酶）的小鼠和用功能性抑制 ASM 的地昔帕明治疗的野生型小鼠的感染效果不佳。ASM 的抑制或基因缺失对嗜噬菌体是抑菌还是杀菌，而地昔帕明降低病原体负担的能力需要有能力的免疫系统尚不清楚。无形体吞噬细胞感染严重联合免疫缺陷疾病 (SCID) 的小鼠被给予地昔帕明或 PBS，然后将血液转移到幼稚的野生型小鼠。接下来，给受感染的野生型小鼠注射去昔帕明或 PBS，然后将血液转移到幼稚的 SCID 小鼠中。最后，感染野生型或缺乏 ASM 的小鼠，并将血液转移到幼稚的 SCID 小鼠中。在所有地昔帕明治疗或 ASM 缺陷小鼠以及所有这些小鼠血液接受者中，受感染的中性粒细胞百分比显着降低。与地昔帕明治疗的 SCID 小鼠相比，ASM 缺陷型和地昔帕明治疗的野生型小鼠的感染率显着降低。然而，感染从未被消除。因此，ASM 活性有助于优化A. phagocytophilum体内感染，ASM 的药理学抑制或基因缺失以抑菌和可逆的方式损害感染，并且A. phagocytophilum能够选择不依赖 ASM 的脂质来源。