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.
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. However, how this dysregulation occurs remains to be elucidated. In this study, we use single-cell RNA sequencing (scRNA-seq) and conventional RNA-seq to analyze the immune landscape of sepsis and observe that adaptive immunity is acutely and strongly suppressed. This systemic immunosuppression occurs not only in the peripheral blood but also in all other immune compartments, including the spleen, lymph nodes, and bone marrow. Clinical data show that these adaptive immunity-related genes may have the potential to be used to distinguish patients with sepsis from those with common infections. CD47 is found to play a pivotal role in this immunosuppression by inducing the production of amyloid-β (Aβ), which interacts with CD74 on B cells, leading to B-cell suppression and subsequent adaptive immunosuppression. Blocking CD47-Aβ signaling significantly reduces organ injury and improves the survival rate of septic mice by restoring phagocytic cell functions and alleviating B-cell suppression and adaptive immunosuppression.
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.
BACKGROUND: SARS-CoV-2 infection leads to post-acute sequelae that can affect nearly every organ system, including the immune system. However, whether an infection with SARS-CoV-2 is associated with increased risk of future infections with other pathogens is not yet fully characterised. In this study, we aimed to test the association between a positive test for COVID-19, compared with a negative test, and rates of future infections with other pathogens. METHODS: We used the US Department of Veterans Affairs health-care databases to build a spatiotemporally aligned cohort of 231 899 people with a positive COVID-19 test and 605 014 with a negative COVID-19 test (test-negative control group) between Nov 1, 2021, and Dec 31, 2023.
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.
Acute kidney injury (AKI) is a common complication associated with sepsis, yet no effective treatment is currently available. The primary mechanisms involved in lipopolysaccharide (LPS)-induced septic AKI are oxidative stress, inflammation, and apoptosis. This study aimed to investigate the potential renoprotective effects of linagliptin, an antidiabetic dipeptidyl peptidase (DPP)-4 inhibitor, against LPS-induced AKI with special emphasis on renal brain-derived neurotrophic factor (BDNF)/nuclear factor erythroid 2-related factor 2 (NRF2) axis. Mice were divided into control, LPS, LPS + linagliptin, and LPS + linagliptin+ANA-12 (tropomyosin receptor kinase B (TrkB) antagonist) groups. Our results revealed that linagliptin, partially through BDNF augmentation, ameliorated AKI, evidenced by the improved histological structure and function of the kidney where serum creatinine, blood urea nitrogen, cystatin C, and renal kidney injury molecule-1were decreased with increased serum albumin. These improvements result from glucagon-like peptide-1/BDNF/TrkB-mediated NRF2 activation, enhancing antioxidant, anti-inflammatory, and antiapoptotic pathways. Linagliptin, through NRF2 augmentation, suppressed renal myeloperoxidase, malondialdehyde, NLR Family pyrin domain-containing 3 inflammasome, nuclear factor-kappaB, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, B-cell lymphoma 2 (Bcl2)-associated X protein, while boosting the antioxidant glutathione and the antiapoptotic Bcl2 contents. The administration of ANA-12 before linagliptin partially reversed these beneficial effects. Accordingly, our results suggest that linagliptin has therapeutic potential in managing LPS-induced AKI. Furthermore, they provide insights into its underlying mechanisms, highlighting renal BDNF signaling as a potential therapeutic target through downstream NRF2 enhancement and its associated antioxidant, anti-inflammatory, and antiapoptotic effects.