Central nervous system (CNS) injury such as spinal cord injury (SCI) disrupts the crosstalk between the CNS and the immune system resulting in a syndrome called “CNS Injury-Induced Immuno-depression” (CIDS) characterized by increased susceptibility to infections, worse neurological outcome, and oftentimes death [
1,
2]. In fact, more than 50 % of deaths following SCI result from infection [
1,
3‐
5]. Investigations on the effects of SCI on peripheral immune function have yielded valuable insights regarding the negative impact of loss of proper regulation by peripheral nerves on primary and secondary lymphoid tissues. Inflammation and stress responses initiated soon after injury can cause an early deficit in leukocyte number and function [
6]. Clinical and experimental models of SCI have validated that during the acute phase of injury, post-SCI both innate and adaptive immunity are severely compromised [
6‐
8] and can persist into the chronic phase [
4,
9‐
11]. While most studies investigating the impact of acute or chronic SCI on immune dysfunction have focused on high thoracic (T3) injury, studies by Held and colleagues have concluded that increased sensitivity to viral infection due to SCI-induced immune depression is level independent [
4]. Therefore, it is critical to better understand mechanisms through which SCI mediates systemic immune depression so that complications arising from secondary infections (e.g., chronic hospitalization, worse neurological outcome, and death) can be reduced or alleviated altogether. A number of studies examining SCI-induced immune depression have shown an increase in the susceptibility to microbial infections such as mouse hepatitis virus [
4] and
Streptococcus pneumoniae [
12]. However, few have examined the impact of SCI on antiviral immunity using a clinically relevant respiratory virus infection model. For example, SCI patients are at high risk of developing complications of influenza infection followed by secondary pneumonia due to their reduced respiratory function and mobility after injury [
3,
13‐
15]. Influenza A virus is a major respiratory pathogen that causes high morbidity and accounts for a significant number of deaths in both the very young and elderly people (
www.cdc.gov). Furthermore, the emergence of new pandemic strains in the past decade have heightened the awareness that immune-compromised patients such as those suffering from SCI are most susceptible to new viruses [
16]. In immunocompetent individuals, primary infection generates a robust immunity and requires generation of both virus-specific antibodies and an effector T cell response [
17]. This establishes an immunological memory and an immune protection over an individual’s lifespan that can protect against re-infection with the same virus. This response can also be mimicked by proper immunization.
Thus, the goal of this study was to characterize how chronic SCI affects immunity acquired after influenza infection. We used a well-characterized mouse model of influenza virus infection in C57Bl/6J mice [
18] to investigate the mechanisms of protective immunity in chronic SCI during primary and secondary viral infections. Intranasal inoculation with type A influenza virus results in a lower respiratory tract infection and induction of both innate and adaptive responses necessary to clear the viral infection. Because of the complex nature of SCI and the finding that high-level injury affects immune function through complete deregulation of the sympathetic nervous system, we chose to investigate SCI-induced immune dysfunction using a low thoracic level (T9) contusion injury model that mostly maintains the central sympathetic regulation to the peripheral lymphoid organs [
6,
12]. Six to seven weeks following a thoracic (T9) SCI contusion, mice were intranasally infected with H3N2 influenza A virus. A comprehensive analysis of virus-specific immunity was performed at various time points after infection and compared to uninjured controls. We demonstrate that chronic SCI causes severe morbidity and mortality in mice infected with influenza A virus. Analysis of innate immune gene expression and recruitment of inflammatory cells to the lungs during the initial phase did not show significant differences between uninjured and chronic SCI mice. In contrast, both virus-specific antibody production and CD8
+ T cell responses were severely compromised in chronically injured mice. Vaccination against influenza prior to injury protected mice from a homologous influenza virus challenge but did protect against infection with a different strain of type A influenza, H1N1 (PR8), pointing to a deficit in CD8
+ T memory cells. These studies will have broad application to our mechanistic understanding to CIDS and may contribute to novel therapeutic strategies to both improve neurological outcome and reduce death related to immune-mediated complications often seen following CNS injury.