University Clinics Tübingen, Institute for Tropical Medicine, Eberhard-Karls University, Tübingen, Germany.
Onchocerciasis Reference Laboratory, Institut National d'Hygiene, Centre Hospitalier Regional, Sokode, Togo.
PLoS Negl Trop Dis. 2022 May 3;16(5):e0010340. doi: 10.1371/journal.pntd.0010340. eCollection 2022 May.
Annual mass drug administrations (MDA) of ivermectin will strongly reduce Onchocerca volvulus microfilariae (mf) in the skin and in the onchocerciasis patients' eyes. Ivermectin treatment will also affect the expression of immunity in patients, such that activated immune defenses may help control and contribute to clearance of mf of O. volvulus. Longitudinal surveys are a prerequisite to determining the impact of ivermectin on the status of anti-parasite immunity, notably in risk zones where parasite transmission and active O. volvulus infections persist.
METHODOLOGY/PRINCIPAL FINDINGS: Onchocerciasis patients were treated annually with ivermectin and their Onchocerca volvulus antigen (OvAg) specific IgG and cellular responses were investigated before and at 30 years post initial ivermectin treatment (30yPT). Repeated annual ivermectin treatments eliminated persisting O. volvulus microfilariae (mf) from the skin of patients and abrogated patent infections. The OvAg-specific IgG1 and IgG4 responses were diminished at 30yPT to the levels observed in endemic controls. Prior to starting ivermectin treatment, OvAg-induced cellular productions of IL-10, IFN-γ, CCL13, CCL17 and CCL18 were low in patients, and at 30yPT, cellular cytokine and chemokine responses increased to the levels observed in endemic controls. In contrast, mitogen(PHA)- induced IL-10, IFN-γ, CCL17 and CCL18 cellular production was diminished. This divergent response profile thus revealed increased parasite antigen-specific but reduced polyclonal cellular responsiveness in patients. The transmission of O. volvulus continued at the patients' location in the Mô river basin in central Togo 2018 and 2019 when 0.58% and 0.45%, respectively, of Simulium damnosum s.l. vector blackflies carried O. volvulus infections.
CONCLUSIONS/SIGNIFICANCE: Repeated annual ivermectin treatment of onchocerciasis patients durably inhibited their patent O. volvulus infections despite ongoing low-level parasite transmission in the study area. Repeated MDA with ivermectin affects the expression of immunity in patients. O. volvulus parasite-specific antibody levels diminished to levels seen in infection-free endemic controls. With low antibody levels, antibody-dependent cellular cytotoxic responses against tissue-dwelling O. volvulus larvae will weaken. O. volvulus antigen inducible cytokine and chemokine production increased in treated mf-negative patients, while their innate responsiveness to mitogen declined. Such lower innate responsiveness in elderly patients could contribute to reduced adaptive immune responses to parasite infections and vaccines. On the other hand, increased specific cellular chemokine responses in mf-negative onchocerciasis patients could reflect effector cell activation against tissue invasive larval stages of O. volvulus. The annual Simulium damnosum s.l. biting rate observed in the Mô river basin was similar to levels prior to initiation of MDA with ivermectin, and the positive rtPCR results reported here confirm ongoing O. volvulus transmission.
每年一次的伊维菌素集体药物治疗（MDA）将强烈减少皮肤中的盘尾丝虫微丝蚴（mf）和盘尾丝虫患者眼中的微丝蚴。伊维菌素治疗还会影响患者的免疫表达，使激活的免疫防御有助于控制和有助于清除盘尾丝虫 mf。纵向调查是确定伊维菌素对寄生虫免疫状况影响的前提，特别是在寄生虫传播和活动性盘尾丝虫感染持续存在的风险区域。
方法/主要发现：盘尾丝虫病患者每年接受伊维菌素治疗，并在初次伊维菌素治疗后 30 年（30yPT）进行盘尾丝虫抗原（OvAg）特异性 IgG 和细胞反应的研究。反复的年度伊维菌素治疗从患者的皮肤中消除了持续存在的盘尾丝虫 mf，并消除了现症感染。30yPT 时，OvAg 特异性 IgG1 和 IgG4 反应降至与流行地区对照观察到的水平相当。在开始伊维菌素治疗之前，OvAg 诱导的细胞产生 IL-10、IFN-γ、CCL13、CCL17 和 CCL18 的水平较低，而在 30yPT 时，细胞因子和趋化因子反应增加到与流行地区对照观察到的水平。相反，丝裂原（PHA）诱导的 IL-10、IFN-γ、CCL17 和 CCL18 细胞产生减少。因此，这种发散的反应谱揭示了患者中寄生虫抗原特异性增加，但多克隆细胞反应性降低。2018 年和 2019 年，多哥中部莫河流域的盘尾丝虫病患者继续传播 O. volvulus，分别有 0.58%和 0.45%的 Simulium damnosum s.l. 传播媒介携带 O. volvulus 感染。
结论/意义：尽管在研究区域持续存在低水平的寄生虫传播，但反复的年度伊维菌素治疗持久地抑制了盘尾丝虫病患者的现症 O. volvulus 感染。重复的伊维菌素 MDA 治疗影响了患者的免疫表达。盘尾丝虫特异性抗体水平降至无感染流行地区对照观察到的水平。抗体水平较低时，针对组织内盘尾丝虫幼虫的抗体依赖性细胞细胞毒性反应将会减弱。在 mf 阴性的治疗患者中，O. volvulus 抗原诱导的细胞因子和趋化因子产生增加，而对丝裂原的先天反应性下降。老年患者较低的先天反应性可能导致对寄生虫感染和疫苗的适应性免疫反应降低。另一方面，mf 阴性盘尾丝虫病患者特异性细胞化学趋化因子反应的增加可能反映了针对组织侵袭性幼虫阶段的 O. volvulus 的效应细胞激活。莫河流域观察到的每年 Simulium damnosum s.l. 叮咬率与开始伊维菌素 MDA 之前的水平相似，这里报告的阳性 rtPCR 结果证实了 O. volvulus 的持续传播。
