Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection

Abstract

Spinal cord injuries disrupt central autonomic pathways that regulate immune function, and increasing evidence suggests that this may cause deficiencies in immune responses in people with spinal cord injuries. Here we analyze the consequences of spinal cord injury (SCI) on immune responses following experimental viral infection of mice. Female C57BL/6 mice received complete crush injuries at either thoracic level 3 (T3) or 9 (T9), and 1 week post-injury, injured mice and un-injured controls were infected with different dosages of mouse hepatitis virus (MHV, a positive-strand RNA virus). Following MHV infection, T3- and T9-injured mice exhibited increased mortality in comparison to un-injured and laminectomy controls. Infection at all dosages resulted in significantly higher viral titer in both T3- and T9-injured mice compared to un-injured controls. Investigation of anti-viral immune responses revealed impairment of cellular infiltration and effector functions in mice with SCI. Specifically, cell-mediated responses were diminished in T3-injured mice, as seen by reduction in virus-specific CD4+ T lymphocyte proliferation and IFN-γ production and decreased numbers of activated antigen presenting cells compared to infected un-injured mice. Collectively, these data indicate that the inability to control viral replication following SCI is not level dependent and that increased susceptibility to infection is due to suppression of both innate and adaptive immune responses.

Spinal cord injury impacts B cell production, homeostasis, and activation

“…Decreases could reflect the loss of FO B cells observed following SCI, as there would be less initial cells able to respond to antigen encounter. Similarly, although total T cell numbers appear intact following SCI [92], the ability for T cells and specifically T follicular helper cells to interact with B cells and form sustained GCs could be inhibited. In either case, it appears that SCI dysregulation of either the HPA axis or SNS signaling could contribute to failed TD responses.…”

Immune dysfunction and chronic inflammation following spinal cord injury

“…There is ample evidence demonstrating that despite an elevated inflammatory state, SCI is associated with a state of immunosuppression and a heightened susceptibility to infection. [6][7][8][9] Suppressed function of natural killer cells, neutrophils, macrophages and lymphocytes have each been documented following SCI. 6,10,11 The loss of motor and sensory function also contribute to this population's greater susceptibility to a number of acute infections, including urinary tract infection (UTI) and pressure ulcers, as well as metabolic disorders associated with a more sedentary lifestyle such as obesity, atherosclerosis and type 2 diabetes.…”

“…9 Damage to the cervical spine would interfere with supraspinal control over preganglionic neurons below the injury, whereas damage at the mid-thoracic region would damage preganglionic sympathetic neurons directly. 7 Level-dependent impairment in B-cell function has been demonstrated in mice subjected to high (T3) versus mid-thoracic (T9) SCI. It was shown that only after high thoracic SCI (causing disruption of autonomic control of the spleen) was splenic norepinephrine elevated and immune function suppressed, 9 whereas mid-thoracic SCI (leaving autonomic control of the spleen intact) has been shown to induce B-cell activation, increase the synthesis of autoantibodies 19 and activate autoreactive T cells.…”

“…Similar alterations in natural killer cell and T-cell cytotoxic activity have been demonstrated in humans with both high-and low-level injuries, 11,23 as have elevations in viral load following infection in mouse models of high and low thoracic SCI. 7 It may be possible that the level of injury has a greater impact on certain aspects of immunity than others. Additional factors such as autonomic completeness of injury and time since injury may also explain some of the variability in findings.…”

Incidence of acute hepatitis B in patients with spinal cord injury

“…16 In our study, progression from acute to chronic hepatitis B was 50%. Held et al 17 reported that in mice, SCI is associated with the disruption of immune responses due to the interruption of neural pathways that regulate immune effectors functions required to control and eliminate the mouse hepatitis virus infection. These may be the cause of a high rate of progression to chronic HBV infection along with other mechanisms mentioned above.…”