Abstract Acquired infections after spinal cord injury (SCI) constitute the main cause of death in patients. For those that survive, acute pneumonia has been associated with significantly reduced neurological recovery. However, proof of causality and the mechanisms underlying the blunted recovery triggered by infections remain elusive. To analyze whether pneumonia has a causal and direct effect on the lesioned spinal cord, we expose mice to a clinically relevant, controlled SCI-associated pneumonia (SCI-AP) embedded into a bed-to-bench translational approach. Our experimental data demonstrate that contracting pneumonia after subacute SCI with consecutive intraparenchymal iron deposition extending from the lesion site into spared tissue. Three aims are proposed to answer one main and novel question: does acute pneumonia exacerbate spinal cord -AP-triggered signaling as causal targets for neuroprotective intervention. Experiments in Aim 1 apply parabiosis models in conjunction with serum injections to identity circulatory, humoral factors underlying SCI-AP-induced injury/disrepair. Moreover, tracing bacterial fragments will detect passive shuttling of immunogenic bacterial material (Bright fluorescent S. pneumoniae) across a breached blood spinal cord barrier to study possible direct spinal cord lesion-pathogen interactions. Loss of vascular integrity will be detailed to the capillary level to detect features of capillary fragmentation by using spinal cord tissue clearing, intravascular tracing and 3-D imaging. Aim 2 targets and its underlying IFN-1 signaling via toxic CD11b+, CD206-- to propagate vascular damage and/or disrepair (STINGflox x LysMcre mice). Aim 3 captures SCI-AP-induced cell-specific transcriptional changes associated with anti-microbial immunity, such as myeloid cell-dependent effects on spinal cord endothelium to reveal novel targets for blocking or reversing SCI-AP-induced injury/disrepair. Clinically, SCI-AP typically emerges around day 2-3 days post SCI when the patient is in the hospital. This offers a more feasible and realistic time window for protective interventions compared to orthodox neuroprotective strategies which are limited to a short post- SCI time-window (golden first hour(s)). If successful, data from these experiments will directly inform effective strategies for SCI patients to i) reduce infection-associated disability and ii) protect outcome at risk.