Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level

Abstract

Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient's environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS ('immune paralysis'), sufficient to propagate clinically relevant infection in an injury level dependent manner.

miR-155 Deletion in Mice Overcomes Neuron-Intrinsic and Neuron-Extrinsic Barriers to Spinal Cord Repair

“…*p Ͻ 0.05 versus WT control. Scale bars: C, 100 m; F, 50 m; inset, 5 m. tive effects of miR-155 deletion may also benefit SCI-induced neuropathic pain or autonomic dysfunction (Gris et al, 2004;Detloff et al, 2008;Schwab et al, 2014;Allison and Ditor, 2015;Tan et al, 2015;Brommer et al, 2016;Offiah et al, 2016). Further studies may also incorporate male mice because miR-155 may have different effects on cell metabolism and host physiology in males and females (Sipski et al, 2004;Furlan et al, 2005;Swartz et al, 2007;Luchetti et al, 2010;.…”

“…For example, inflammatory macrophages can cause axonal injury or inhibit axon regeneration after spinal cord injury (SCI) (Popovich et al, 1997;Kigerl et al, 2006;Kigerl et al, 2009;Prüss et al, 2011;Pool et al, 2012;Kroner et al, 2014). Therefore, therapies that boost intrinsic axon growth programs or that limit macrophage inflammatory signaling could improve spinal cord repair (Kobayashi et al, 1997;Popovich et al, 1999;Ramer et al, 2000;Sun et al, 2011;Bartus et al, 2014).…”

Cell biology of spinal cord injury and repair

“…However, subacute phases after SCI may be amenable to delayed protective interventions that target and control peripheral infections and other peripheral sources of circulating inflammatory stimuli. Epidemiological studies show that comorbid infections such as pneumonia worsen functional outcome after human SCI (128)(129)(130). Potential cellular mechanisms may involve prolonged inflammation at the lesion site that results in increased tissue damage.…”

Journal Club: Long-term functional outcome in patients with acquired infections after acute spinal cord injury

“…3 In addition to increased morbidity and mortality, infections after SCI may affect neurologic recovery. 2,3 A recent study found that infections impaired the return of muscle strength up to 1 year postinjury; however, the long-term consequences remain uncertain.…”

“…3 In addition to increased morbidity and mortality, infections after SCI may affect neurologic recovery. 2,3 A recent study found that infections impaired the return of muscle strength up to 1 year postinjury; however, the long-term consequences remain uncertain. 2 The aim of this study was to investigate whether infections occurring in an acute care setting after SCI affected long-term functional recovery and survival.…”