Flu Induced Acute Chest Syndrome in Sickle Cell Disease Mice

Background: Sickle cell disease (SCD) affects over ~8 million people world-wide. Acute chest syndrome, a type of acute lung injury (ALI) is a major cause of mortality among SCD patients. Flu is an acute respiratory disease primarily caused by the influenza A virus (IAV), which is typically a self-resolving upper airway inflammation. However, epidemiological evidence suggests that flu can result in severe ACS in SCD patients. Although flu associates with a 50-fold higher risk of ICU admission among SCD than non-SCD humans, the etiological mechanism underlying the flu severity in SCD remains unknown.

Aim: To determine whether a mild dose of IAV promotes severe lung injury in SCD mice.

Methods: We have developed a model of A/PR/8/34 (H1N1) IAV induced respiratory infection in knock-in, humanized SCD mice. Mice were intranasally inoculated with a mild dose of IAV. The body weight was measured every day for three weeks after intranasal IAV administration followed by assessment of lung injury at day 10 and 14 post infection. Severity of lung injury was evaluated using histological scoring and oxygen saturation measurements. Real-time intravital ( in vivo) multi-photon-excitation fluorescence microscopy (MPE) was used to assess thrombo-inflammation and vascular leakage in the lung of mice at 10 and 14 days post IAV-infection.

Results: Over the first 8 days post-IAV infection, both SCD and control mice manifested comparable levels of mild lung injury and a mild drop in body weight (15%). Unlike the control mice that started to recover, the lung injury and drop in body weight continued to worsen in SCD mice at 8-10 days post IAV infection. By day 14 post IAV infection, the lung injury was resolved and body weight was recovered in control mice, while SCD mice still manifested severe lung injury and ~20% drop in body weight. Intravital lung microscopy revealed large areas with vascular occlusion, ischemia, neutrophil infiltration and vascular leakage in the lung of SCD mice 10 days post infection, however, such pathophysiology was rarely present in the lung of control mice at 10 days post infection.

Conclusions: Our current findings are the first to suggest that the inflammatory milieu in SCD mice promotes a severe non-resolving ALI following an IAV infection, which otherwise leads to a mild self-resolving lung inflammation in control mice.