Sepsis is the leading cause of death in most ICU’s, and patients who survive the hyper-inflammation that develops early during sepsis later display severely compromised immunity. Not only is there apoptosis of lymphoid and myeloid cells during sepsis that depletes these critical cellular components of the immune system, but the remaining immune cells also show decreased function. Using a cecal-ligation and puncture (CLP) model to induce intra-abdominal polymicrobial peritonitis, we recently established a link between the apoptotic cells generated during sepsis and induction of sepsis-induced suppression of delayed-type hypersensitivity. The present study extends this earlier work to include a secondary heterologous bacterial infection (OVA-expressing Listeria monocytogenes; LM-OVA) subsequent to sepsis initiation to investigate sepsis-induced alterations in the control of this secondary infection and the associated naïve Ag-specific CD8 T cell response. We found that CLP-treated WT mice had a reduced ability to control the LM-OVA infection, which was paralleled by suppressed T cell responses, versus sham-treated WT mice. In contrast, CLP-treated Trail−/− and Dr5−/− mice were better able to control the secondary bacterial infection and the Ag-specific CD8 T cell response was similar to that seen in sham-treated mice. Importantly, administration of a blocking anti-TRAIL mAb to CLP-treated WT mice was able to restore the ability to control the LM-OVA infection and generate Ag-specific CD8 T cell responses like those seen in sham-treated mice. These data further implicate TRAIL-dependent immune suppression during sepsis, and suggest TRAIL neutralization may be a potential therapeutic target to restore cellular immunity in septic patients.

Transient lymphopenia is one hallmark of sepsis, and emergent data indicates the CD4 T cell compartment in sepsis survivors is numerically and functionally altered (when examined at the Ag-specific level) compared to non-septic controls. Previous data from our laboratory demonstrated Ag-independent, lymphopenia-induced homeostatic proliferation to be a contributing mechanism by which CD4 T cells numerically recover in sepsis survivors. However, we reasoned it is also formally possible that some CD4 T cells respond directly to Ag expressed by gut resident microbes released during polymicrobial sepsis. The effect of gut microbiome leakage on CD4 T cells is currently unknown. In this study, we explored the number and function of endogenous CD4 T cells specific for segmented filamentous bacterium (SFB) after cecal ligation and puncture (CLP)-induced sepsis using mice that either contained or lacked SFB as a normal gut resident microbe. Interestingly, SFB-specific CD4 T cells underwent Ag-driven proliferation in CLP-treated SFB+, but not in SFB−, mice. Moreover, CLP-treated SFB+ mice showed resistance to secondary lethal infection with recombinant SFB Ag-expressing virulent Listeria (but not wildtype virulent Listeria) suggesting the CLP-induced polymicrobial sepsis primed for a protective response by the SFB-specific CD4 T cells. Thus, our data demonstrate that the numerical recovery and functional responsiveness of Ag-specific CD4 T cells in sepsis survivors is, in part, modulated by the intestinal barrier’s “health” discreetly defined by individual bacterial populations of the host’s microbiome.

BACKGROUND AND PURPOSE: Diagnosing spontaneous intracranial hypotension and associated CSF leaks can be challenging, and additional supportive imaging findings would be useful to direct further evaluation. This retrospective study evaluated whether there was a difference in the prevalence of calvarial hyperostosis in a cohort of patients with spontaneous intracranial hypotension compared with an age-and sex-matched control population. MATERIALS AND METHODS:Cross-sectional imaging (CT of the head or brain MR imaging examinations) for 166 patients with spontaneous intracranial hypotension and 321 matched controls was assessed by neuroradiologists blinded to the patient's clinical status. The readers qualitatively evaluated the presence of diffuse or layered calvarial hyperostosis and measured calvarial thickness in the axial and coronal planes.RESULTS: A significant difference in the frequency of layered hyperostosis (31.9%, 53/166 subjects versus 5.0%, 16/321 controls, P , .001, OR ¼ 11.58) as well as the frequency of overall (layered and diffuse) hyperostosis (38.6%, 64/166 subjects versus 13.2%, 42/ 321 controls, P , .001, OR ¼ 4.66) was observed between groups. There was no significant difference in the frequency of diffuse hyperostosis between groups (6.6%, 11/166 subjects versus 8.2%, 26/321 controls, P ¼ .465). A significant difference was also found between groups for calvarial thickness measured in the axial (P , .001) and coronal (P , .001) planes.CONCLUSIONS: Layered calvarial hyperostosis is more prevalent in spontaneous intracranial hypotension compared with the general population and can be used as an additional noninvasive brain imaging marker of spontaneous intracranial hypotension and an underlying spinal CSF leak.

Sepsis changes the composition and functional potential of the naïve CD4 T cell repertoire, but the mechanism(s) that control such changes are unknown. We posited that the constituents of the gut flora play an important role in defining the responsiveness of CD4 T cell populations specific for Ag present in the commensal bacterial species that establish polymicrobial sepsis after cecal-ligation and puncture (CLP) versus those CD4 T cells undergoing sepsis-induced Ag-independent homeostatic proliferation. To test this hypothesis, we tracked the loss/recovery and function of CD4 T cells specific for an Ag present in segmented filamentous bacteria (SFB) in mice containing or devoid of this bacteria in their gut. SFB-specific CD4 T cells underwent Ag-driven proliferation in CLP-treated SFB+ mice, but not in SFB- mice. This correlated with their functional ability after secondary infection with SFB Ag-expressing Listeria. Interestingly, we found that a second CD4 T cell population specific for the influenza NP311 epitope underwent differential recovery and function depending on the mouse vendor, suggesting antigenic stimulation as a result of cross-reactivity with some yet-to-be defined epitope expressed by the gut commensal bacteria. Our data suggest the extent of recovery and function of a particular Ag-specific T cell population during sepsis can determined by the intestinal “health” of the individual, regardless of possible genetic similarities.