Harpur Christopher M, West Alison C, Le Page Mélanie A, Lam Maggie, Hodges Christopher, Oseghale Osezua, Gearing Andrew J, Tate Michelle D
Centre for Innate Immunity and Infectious Diseases Hudson Institute of Medical Research Clayton VIC Australia.
Department of Molecular and Translational Sciences Monash University Clayton VIC Australia.
Clin Transl Immunology. 2023 Mar 23;12(3):e1443. doi: 10.1002/cti2.1443. eCollection 2023.
Novel host-targeted therapeutics could treat severe influenza A virus (IAV) infections, with reduced risk of drug resistance. LAT8881 is a synthetic form of the naturally occurring C-terminal fragment of human growth hormone. Acting independently of the growth hormone receptor, it can reduce inflammation-induced damage and promote tissue repair in an animal model of osteoarthritis. LAT8881 has been assessed in clinical trials for the treatment of obesity and neuropathy and has an excellent safety profile. We investigated the potential for LAT8881, its metabolite LAT9991F and LAT7771 derived from prolactin, a growth hormone structural homologue, to treat severe IAV infection.
LAT8881, LAT9991F and LAT7771 were evaluated for their effects on cell viability and IAV replication , as well as their potential to limit disease in a preclinical mouse model of severe IAV infection.
LAT8881 treatment enhanced cell viability, particularly in the presence of cytotoxic stress, which was countered by siRNA inhibition of host lanthionine synthetase C-like proteins. Daily intranasal treatment of mice with LAT8881 or LAT9991F, but not LAT7771, from day 1 postinfection significantly improved influenza disease resistance, which was associated with reduced infectious viral loads, reduced pro-inflammatory cytokines and increased abundance of protective alveolar macrophages. LAT8881 treatment in combination with the antiviral oseltamivir phosphate led to more pronounced reduction in markers of disease severity than treatment with either compound alone.
These studies provide the first evidence identifying LAT8881 and LAT9991F as novel host-protective therapies that improve survival, limit viral replication, reduce local inflammation and curtail tissue damage during severe IAV infection. Evaluation of LAT8881 and LAT9991F in other infectious and inflammatory conditions of the airways is warranted.
新型宿主靶向疗法可治疗严重甲型流感病毒（IAV）感染，且耐药风险降低。LAT8881是人生长激素天然存在的C末端片段的合成形式。它独立于生长激素受体发挥作用，在骨关节炎动物模型中可减少炎症诱导的损伤并促进组织修复。LAT8881已在治疗肥胖症和神经病变的临床试验中进行了评估，且具有良好的安全性。我们研究了LAT8881、其代谢产物LAT9991F以及源自催乳素（一种生长激素结构同源物）的LAT7771治疗严重IAV感染的潜力。
评估LAT8881、LAT9991F和LAT7771对细胞活力和IAV复制的影响，以及它们在严重IAV感染的临床前小鼠模型中限制疾病的潜力。
LAT8881处理可提高细胞活力，尤其是在存在细胞毒性应激的情况下，而宿主类似兰硫氨酸合成酶C蛋白的siRNA抑制可抵消这种作用。感染后第1天起，每天对小鼠进行鼻内给予LAT8881或LAT9991F（而非LAT7771）治疗，可显著提高流感抗病能力，这与传染性病毒载量降低、促炎细胞因子减少以及保护性肺泡巨噬细胞数量增加有关。LAT8881与抗病毒药物磷酸奥司他韦联合治疗比单独使用任何一种化合物治疗导致疾病严重程度标志物的降低更为显著。
这些研究提供了首个证据，确定LAT8881和LAT9991F为新型宿主保护疗法，可提高严重IAV感染期间的存活率、限制病毒复制、减少局部炎症并减轻组织损伤。有必要在气道的其他感染和炎症性疾病中评估LAT8881和LAT9991F。
