Daily Sepsis Research Analysis
Three impactful studies advance sepsis science across mechanisms, epidemiology, and therapeutics. A mechanistic study identifies a CD47–amyloid-β–CD74 axis driving adaptive immunosuppression in sepsis with reversal by pathway blockade in mice. A large US Veterans cohort links COVID-19 to higher subsequent infections and sepsis, while a preclinical study shows linagliptin mitigates LPS-induced septic acute kidney injury via BDNF/TrkB/Nrf2 signaling.
Summary
Three impactful studies advance sepsis science across mechanisms, epidemiology, and therapeutics. A mechanistic study identifies a CD47–amyloid-β–CD74 axis driving adaptive immunosuppression in sepsis with reversal by pathway blockade in mice. A large US Veterans cohort links COVID-19 to higher subsequent infections and sepsis, while a preclinical study shows linagliptin mitigates LPS-induced septic acute kidney injury via BDNF/TrkB/Nrf2 signaling.
Research Themes
- Mechanisms of adaptive immunosuppression in sepsis
- Post-COVID-19 risk of infections and sepsis
- Preclinical therapeutic targeting of septic acute kidney injury
Selected Articles
1. CD47-amyloid-β-CD74 signaling triggers adaptive immunosuppression in sepsis.
Using scRNA-seq and transcriptomics across blood, spleen, lymph nodes, and bone marrow, the authors show pervasive suppression of adaptive immunity in sepsis. They uncover a CD47-driven amyloid-β signal that engages CD74 on B cells to suppress adaptive responses; pharmacologic blockade restores immune function, reduces organ injury, and improves survival in septic mice. Sepsis-related gene signatures also discriminated sepsis from common infections in clinical datasets.
Impact: Identifies a novel, targetable pathway (CD47–Aβ–CD74) driving sepsis-induced immunosuppression with cross-compartment human-mouse evidence. This advances mechanistic understanding and opens therapeutic avenues.
Clinical Implications: Suggests evaluating CD47 blockade, Aβ generation inhibitors, or CD74-targeted strategies to reverse sepsis-induced adaptive immunosuppression. Gene signatures may aid in distinguishing sepsis from common infections.
Key Findings
- scRNA-seq and RNA-seq reveal acute, systemic suppression of adaptive immunity across blood, spleen, lymph nodes, and bone marrow in sepsis.
- CD47 induces amyloid-β production that engages CD74 on B cells, suppressing B cells and adaptive immunity.
- Blocking CD47–Aβ signaling restores phagocyte function, reduces organ injury, and improves survival in septic mice.
- Adaptive immunity-related gene signatures distinguish sepsis from common infections in clinical datasets.
Methodological Strengths
- Multi-compartment human immune profiling with scRNA-seq integrated with bulk RNA-seq.
- Mechanistic validation with in vivo pathway blockade demonstrating survival benefit in septic mice.
Limitations
- Translational uncertainty from mouse models to human therapeutic efficacy.
- Specificity and safety of targeting CD47–Aβ–CD74 in heterogeneous sepsis populations remain to be established.
Future Directions: Evaluate CD47/Aβ/CD74-targeted therapeutics in translational models and early-phase trials; validate gene signatures for clinical sepsis diagnostics.
2. Rates of infection with other pathogens after a positive COVID-19 test versus a negative test in US veterans (November, 2021, to December, 2023): a retrospective cohort study.
In 836,913 US veterans, a positive COVID-19 test (vs negative) was associated with higher 12-month rates of multiple infections and hospitalizations for infectious illnesses, including sepsis. Non-hospitalized positives had increased outpatient infections (RR 1.17), respiratory infections (RR 1.46), and infection-related hospitalizations (RR 1.41); risks were greater among those hospitalized for COVID-19. Compared with seasonal influenza admissions, COVID-19 admissions had higher sepsis hospitalizations (RR 1.35).
Impact: Provides robust, large-scale evidence that COVID-19 is followed by sustained elevation in infection and sepsis risks, informing surveillance and prevention strategies.
Clinical Implications: Post-COVID patients warrant targeted infection prevention, vaccination optimization, and vigilance for sepsis; risk stratification may guide follow-up and early intervention.
Key Findings
- Compared with test-negative controls, non-hospitalized COVID-19 positives had increased outpatient infectious diagnoses (RR 1.17, 95% CI 1.15–1.19) and respiratory infections (RR 1.46, 95% CI 1.43–1.50).
- Hospitalizations for infectious illnesses, including sepsis and respiratory infections, were higher after COVID-19 (RR 1.41, 95% CI 1.37–1.45).
- Those hospitalized for acute COVID-19 had generally higher risks than non-hospitalized positives.
- Versus seasonal influenza admissions, COVID-19 admissions had higher hospitalizations for infectious illnesses (RR 1.24), sepsis (RR 1.35), and in-hospital antimicrobial use (RR 1.23).
Methodological Strengths
- Very large, spatiotemporally aligned cohort with inverse probability weighting to balance covariates.
- Comparator analysis versus seasonal influenza admissions to assess specificity.
Limitations
- Residual confounding and misclassification cannot be fully excluded in retrospective EHR-based analyses.
- Generalizability may be limited to US veterans; health-seeking behaviors could differ between groups.
Future Directions: Elucidate immunologic mechanisms underlying post-COVID susceptibility; test targeted prevention and surveillance strategies to reduce sepsis and infection burden.
3. Linagliptin mitigates lipopolysaccharide-induced acute kidney injury in mice: Novel renal BDNF/TrkB/NRF2-dependent antioxidant, anti-inflammatory, and antiapoptotic mechanisms.
In an LPS-induced septic AKI mouse model, the DPP-4 inhibitor linagliptin improved kidney function and histology, lowering creatinine, BUN, cystatin C, and KIM-1 while increasing albumin. Mechanistically, linagliptin enhanced GLP-1/BDNF/TrkB-mediated Nrf2 activation, reducing oxidative stress, inflammation (e.g., NLRP3, NF-κB, TNF-α, MCP-1), and apoptosis (↓Bax, ↑Bcl-2); TrkB antagonism (ANA-12) partially abrogated benefits.
Impact: Reveals a modifiable BDNF/TrkB/Nrf2 pathway for septic AKI and supports repurposing linagliptin, a clinically available agent, as a potential therapeutic.
Clinical Implications: Although preclinical, findings support exploring DPP-4 inhibition and BDNF/TrkB–Nrf2 modulation in early clinical studies of septic AKI. Not ready for off-label use without human data.
Key Findings
- Linagliptin ameliorated LPS-induced AKI with improved histology and function (↓serum creatinine, BUN, cystatin C, KIM-1; ↑serum albumin).
- Enhanced GLP-1/BDNF/TrkB-driven Nrf2 activation increased antioxidant defenses and reduced inflammation (↓MPO, MDA, NLRP3, NF-κB, TNF-α, MCP-1).
- Antiapoptotic effects observed (↓Bax, ↑Bcl-2); TrkB antagonist ANA-12 partially reversed renoprotection, supporting pathway specificity.
Methodological Strengths
- Use of a pathway-specific antagonist (ANA-12) to probe BDNF/TrkB causality.
- Comprehensive phenotyping across functional, histologic, oxidative stress, inflammatory, and apoptotic markers.
Limitations
- Single species LPS model may not capture the heterogeneity of human septic AKI.
- Dosing, timing, and safety of linagliptin in sepsis remain untested in humans.
Future Directions: Validate findings in polymicrobial sepsis models and larger animal studies; assess pharmacokinetics, safety, and efficacy of DPP-4 inhibition in early-phase clinical trials for septic AKI.