Weathered Catherine, Wei Ning, Pienaar Elsje
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.
Department of Mathematics, Purdue University, West Lafayette, IN, USA.
Tuberculosis (Edinb). 2023 Mar;139:102304. doi: 10.1016/j.tube.2023.102304. Epub 2023 Jan 6.
Non-tuberculous mycobacterial (NTM) infections, and Mycobacterium avium Complex (MAC) in particular, affect women at nearly twice the rate of men, and post-menopausal patients are at higher risk than pre-menopausal patients. The reasons for the disproportionate number of cases in women and post-menopausal patients remain unclear. One possibility is that menopause-associated immunological changes contribute to higher MAC prevalence post-menopause compared to pre-menopause. Menopause-associated immune disruption includes increased cytokine and chemokine production, and reduced cytotoxicity and phagocytosis in macrophages. Here we use an agent-based model of bacterial and host immune interactions in the airway to translate the combined impact of menopause-associated cellular immune disruptions to tissue scale outcomes. Our simulations indicate that menopause-associated immune disruptions can result in increased macrophage recruitment. However, this increase in macrophage number is unable to overcome functional deficits in macrophage phagocytosis and killing, since the post-menopausal simulations also show increased bacterial loads. Post-menopausal conditions are also associated with a lower number of cleared infections, and more simulations that have predominantly extracellular bacteria. Taken together, our work quantifies the potential impact of menopause-associated disruptions of innate immune functions on early MAC infection progression. Our findings will support the development of new therapies targeted to this high-risk group of patients.
非结核分枝杆菌（NTM）感染，尤其是鸟分枝杆菌复合体（MAC）感染，影响女性的几率几乎是男性的两倍，且绝经后患者比绝经前患者风险更高。女性和绝经后患者中病例数不成比例的原因尚不清楚。一种可能性是，与绝经相关的免疫变化导致绝经后MAC患病率高于绝经前。与绝经相关的免疫紊乱包括细胞因子和趋化因子产生增加，以及巨噬细胞的细胞毒性和吞噬作用降低。在此，我们使用一种基于主体的气道细菌与宿主免疫相互作用模型，将与绝经相关的细胞免疫紊乱的综合影响转化为组织尺度的结果。我们的模拟表明，与绝经相关的免疫紊乱可导致巨噬细胞募集增加。然而，巨噬细胞数量的这种增加无法克服巨噬细胞吞噬和杀伤功能的缺陷，因为绝经后模拟结果还显示细菌载量增加。绝经后状况还与清除感染的数量减少以及更多主要为细胞外细菌的模拟结果相关。综上所述，我们的工作量化了与绝经相关的固有免疫功能紊乱对早期MAC感染进展的潜在影响。我们的研究结果将支持针对这一高危患者群体开发新疗法。
