About

Nilam S. Mangalmurti, MD, is an Associate Professor of Medicine in the Pulmonary, Allergy, and Critical Care department at the Hospital of the University of Pennsylvania. She serves as an attending physician for the Medical Intensive Care Unit and the Procedure and Resuscitation Service at the Hospital of the University of Pennsylvania. Her clinical interests include acute lung injury and the management of critically ill patients. As a physician-scientist, her research program focuses on syndromes affecting the critically ill, such as sepsis and Acute Respiratory Distress Syndrome (ARDS). Her work emphasizes understanding the host response during sepsis, particularly how aberrant immune responses drive organ failure and mortality. She investigates the immunomodulatory functions of red blood cells (RBCs), exploring their capacity to influence inflammatory responses and innate immunity, especially in the context of infection and sterile injury. Her research themes are centered on innate immunity and inflammation within the vascular compartment, aiming to elucidate mechanisms that could inform therapeutic strategies for critical illnesses.

Research topics

• Pathology
• Medicine
• Immunology
• Biology
• Biochemistry
• Cell biology
• Virology
• Computational biology
• Intensive care medicine
• Internal medicine

Selected publications

• Extracellular Mitochondrial RNA is Elevated in Sepsis and Triggers Inflammation

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  articleSenior author

  Abstract Rationale: Damage-associated molecular patterns (DAMPs), endogenous immunostimulatory molecules, are elevated and pathogenic in sepsis, the dysregulated host response to infection. Among DAMPs, extracellular nucleic acids play a key role in triggering innate immune responses, and extracellular RNA is increasingly recognized as a DAMP. We hypothesize that extracellular mitochondrial RNA (mtRNA) functions as a DAMP and that extracellular mtRNA is elevated in sepsis. Methods: We used in vitro assays, a murine model of sepsis and plasma from patients with sepsis to determine if mtRNA triggers inflammation and is abundant in sepsis. For in vitro studies, mtRNA was extracted from wild-type mouse livers and Raw 264.7 cells were treated with 0.5µg, 1µg or 1.5µg/mL of mtRNA for 24 hours. Cytokines were measured by ELISA. Plasma mtRNA was measured in mice subjected to the cecal slurry model of sepsis. Whole blood was collected at 24 hours and spun at 1500g for 10 minutes. RNA was extracted from plasma and RTqPCR for the mitochondrial ribosomal 12S subunit was performed (mtRNR1). For mtRNA measurements in humans, plasma was obtained from sepsis patients on the day of admission to the ICU and healthy controls. Whole blood was spun at 3000g on collection and the plasma was stored at -80°C. RNA was extracted from the plasma and RTqPCR for the mitochondrial ribosomal 12S (mtRNR1) and 16S (mtRNR2) subunits was performed. Results: In vitro, mtRNA induced an inflammatory response in macrophages as measured by TNF⍺ release at 24 hours (p=0.02, 0.0003 and <0.0001 for 0.5µg, 1µg or 1.5µg/mL mtRNA v control ). In vivo, plasma levels of mtRNA were increased in murine sepsis (n=19) compared to controls (n=14) at 24 hours (p = 0.02). We also found that levels of mtRNA were elevated in the plasma of sepsis patients (n=15) on the day of ICU admission compared to healthy donors (n=8) (p<0.0001). Conclusions: mtRNA alone is sufficient to induce an inflammatory response in vitro. In both a murine model of sepsis and human sepsis we found that levels of mtRNA are elevated in plasma. These data suggest that mtRNA may function as a novel DAMP in the pathogenesis of sepsis. Further studies are needed to elucidate the mechanism of release from cells and the downstream pathway that results in inflammatory activation. Future studies will also be needed to determine whether mtRNA is sufficient to cause a sepsis phenotype in vivo.

  PublisherDOI

• Cell-free DNA methylomics identify tissue injury patterns in pediatric ARDS

  JCI Insight · 2025-09-02 · 1 citations

  articleOpen access

  Plasma cell-free DNA can ientify what tissues are damaged in children with severe lung injury, allowing us to identify new avenues to target therapies.

  PublisherOA PDFDOI

• Extracellular mtRNA Activates TLR7

  Scholarly Commons (University of Pennsylvania) · 2025-09-15

  otherOpen accessSenior author

  Cell-free nucleic acids are released following cell death and inflammation. We have shown that red blood cells (RBCs) express nucleic acid-sensing toll-like receptor 9 (TLR9) and scavenge mitochondrial DNA during homeostasis to prevent lung inflammation. Mitochondrial RNA (mtRNA) is also known as a damage-associated molecular pattern (DAMP) that triggers inflammatory states. Recently, we found that RBCs also express the RNA sensor toll-like receptor 7 (TLR7) on their surface. We hypothesize that RBCs bind and sequester exogenous mtRNA via TLR7, reducing inflammation. This study examines whether RBCs bind mtRNA and if mtRNA activates TLR7. A further understanding of RBCs’ novel role in inflammation could open new avenues to diagnostics and treatments for inflammatory diseases and cancer.

  Publisher

• Detection of Human Papillomavirus DNA on Red Blood Cells in Patients With Cervical Cancer

  Obstetrics and Gynecology · 2025-05-15 · 2 citations

  articleSenior author

  Red blood cells (RBCs) have the potential to bind and harbor viral DNA, providing a novel approach to detecting human papillomavirus (HPV). Red blood cells incubated with fluorescently labeled HPV CpG acquired HPV DNA in a concentration-dependent manner. Red blood cells incubated with HPV-positive cervical cancer cells (CaSki cell line) acquired HPV 16 DNA detected by quantitative polymerase chain reaction (PCR). Consistent with these results, HPV 16 DNA was detected by quantitative PCR on RBCs from five patients with cervical cancer or dysplasia but not on healthy control RBCs. Detection of HPV 16 DNA on RBCs from patients with cervical cancer underscores the potential of RBC-bound DNA as a substrate for future blood-based HPV screening.

  PublisherDOI

• Systematic data capture reduces the need for source data verification: exploratory analysis from a phase 2 multicenter randomized controlled platform trial

  Communications Medicine · 2025-10-29

  articleOpen access

  BACKGROUND: The COVID-19 pandemic gave rise to clinical trials focused on systematic, accurate primary data capture, and reduced reliance on source data verification (SDV). Here, we report on a natural experiment that allowed us to assess the quality, cost, and impact of this approach compared to traditional SDV. METHODS: The I-SPY COVID trial (NCT04488081) was a multicenter, open-label, platform trial that employed a streamlined daily checklist, daily capture of labs and medications, and centralized monitoring to ensure accurate data collection in lieu of SDV. The trial enrolled 1,111 patients in 11 drug arms with severe COVID-19. After the trial arms were closed, extensive retrospective SDV was performed on 333 (30.0%) patients, including 10,101 of 44,486 (23%) electronic case report forms (eCRFs), allowing us to evaluate the impact of our strategy on data integrity, outcomes, and costs. RESULTS: We find that retrospective SDV results in changes to 0.36% (1,234 / 340,532) of data fields. It results in no changes to the type of outcome recorded (death, recovery, or censored), but changes in the day of recovery in 9 instances, by a median of 2 days (range 1-7). Two additional AEs are added during SDV that had not previously been captured. Costs associated with retrospective SDV of 23% eCRFs are 61,073 person-hours at a cost of $6.1 M. CONCLUSIONS: Extensive SDV does not change any results or conclusions of the I-SPY COVID trial, which was designed with a systematic strategy for data capture, monitoring, and safety. This strategy could improve the efficiency of clinical trials and eliminate the need for manual SDV.

  PublisherOA PDFDOI

• Acute Respiratory Distress Syndrome in Veterinary Medicine—The ARDSVet Definitions

  Journal of Veterinary Emergency and Critical Care · 2025-07-01 · 5 citations

  articleOpen access

  OBJECTIVE: To use a systematic, evidence-based consensus process to develop updated definitions for acute respiratory distress syndrome (ARDS) in veterinary medicine to facilitate its recognition and diagnosis. DESIGN: International consensus conference series involving 12 multidisciplinary international content experts from three countries, using consensus conference methodology and implementation science. A systematic review of the literature was carried out for ARDS and acute lung injury in veterinary medicine. Updated definitions of ARDS were generated based on synthesis of human and veterinary literature. Consensus on the definitions was achieved through Delphi-style surveys involving the above subject matter experts. Draft recommendations were made available through industry specialty listservs for feedback, which was incorporated in the final definitions. RESULTS: Updated definitions were developed for Veterinary Acute Respiratory Distress Syndrome (ARDSVet) in small animals (dogs and cats) and large animals (equids). For small animals, 690 publications were identified for dogs and 99 were identified for cats in the initial literature search. Seventeen cats and 103 dogs with ARDS were represented across these publications. For the initial literature search in large animals, there were 83 equid, five camelid, 158 pig, 714 sheep and goat, and 270 cattle publications identified. Additionally, 1084 publications were found across all large animals that addressed interstitial lung disease. Five adult equids and 136 foals with ARDS were represented across these publications. The updated ARDSVet definitions incorporate criteria for risk factors, origin and timing of pulmonary edema, and impaired oxygenation, with severity stratified by oxygenation and definitions for both intubated and nonintubated animals. CONCLUSIONS: The evidence review and consensus process resulted in updated definitions that can be used to improve the recognition of veterinary ARDS as well as facilitate and standardize future research, including the development of an ARDS registry and eventual treatment recommendations.

  PublisherOA PDFDOI

• Red Blood Cell Analysis Identifies Trypanosoma cruzi in Wild Pennsylvania Bats

  Physiology · 2025-05-01

  articleSenior author

  Rationale: We have previously identified nucleic acid sensors on bat red blood cells (RBCs) and demonstrated that human RBCs can bind and harbor microbial genetic material, providing diagnostic insights into pathogen presence. Based on these findings, we hypothesized that bat RBCs could serve as a reservoir for pathogen nucleic acids. Chagas disease, caused by Trypanosoma cruzi ( T. cruzi ), is a leading cause of heart failure worldwide. While primarily endemic to Central and South America, its incidence in the United States is increasing due to both immigration from endemic regions and local transmission. Here, we report the presence of T. cruzi in wild big brown bats of Pennsylvania and demonstrate the feasibility of using bat RBCs for pathogen RNA detection. Methods: All studies were approved by the Institutional Animal Care and Use Committee. Terminal blood samples were obtained from wild-caught big brown bats ( Eptesicus fuscus ) admitted to Pennsylvania wildlife rehabilitators and deemed non-releasable. RBCs were isolated by centrifugation, washed in PBS, and preserved in RNA/DNA shield (Zymo Research). Total nucleic acid was extracted using the Quick-DNA/RNA Pathogen Magbead kit (Zymo Research), followed by RNA extraction of a 20uL aliquot using DNase according to the manufacturer's protocol. The NEBNext Ultra II Library Prep kit (New England Biolabs) was used to reverse transcribe RNA into cDNA which was used to construct and barcode metagenomic libraries for paired-end sequencing on a NextSeq2000 (Illumina). To confirm the presence of T. cruzi, DNA was extracted from distinct RBC aliquots from four bats with and without sequencing-confirmed T. cruzi (n=2/group). Quantitative PCR (qPCR) using T. cruzi -specific primers and probes was conducted, followed by gel electrophoresis to isolate amplicons followed by Sanger sequencing. Histological analysis of cardiac tissue was performed to assess the presence of T. cruzi parasites. Results: Metagenomic sequencing identified partial T. cruzi genomes in 5 of 10 bat RBC samples. DNA extraction and qPCR from packed RBCs showed amplification with T. cruzi -specific primers and probes in bats previously identified as T. cruzi-positive by RNA sequencing. Sanger sequencing of the amplicons showed the highest alignment with the T. cruzi CL strain, the causative agent of Chagas disease. Histological evaluation of cardiac tissue from one study bat confirmed the presence of a T. cruzi amastigote nest. Conclusion: The identification and confirmation of T. cruzi in wild Pennsylvania bats suggest a shift in the perceived geographic distribution of this pathogen. However, whether bats contribute to human transmission remains unclear. These findings underscore the need for increased Chagas disease screening in regions as far north as Pennsylvania. Additionally, this study reinforces the concept that RBCs serve as a reservoir for pathogen detection, suggesting that DNA extraction from small RBC volumes could be a valuable surveillance tool for Chagas and other diseases. ITMAT Pilot PiCAB grant (JCE, NSM)- NIH/NCATS UL1TR001878 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

  PublisherDOI

• Cell-free DNA Methylomics Identify Tissue Injury Patterns in Pediatric ARDS

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract Rationale: Cell-free DNA (cfDNA) is released into the circulation from dead and dying cells, and is elevated in critical illness syndromes including sepsis and acute respiratory distress syndrome (ARDS). Plasma cfDNA has been implicated as a damage-associated molecular pattern (DAMP) that propagates ongoing inflammation. However, the tissue source of circulating cfDNA has not been fully elucidated, and identification of the cellular origin of cfDNA may provide insight into the mechanisms underlying the early inflammatory response. As cfDNA retains the unique methylation pattern of its tissue of origin, we can leverage cfDNA methylomics to map presumed tissue of origin of these DAMPs. Therefore, we conducted a pilot study to assess the cfDNA methylation and tissue origin in pediatric ARDS. Methods: This was a secondary analysis of a cohort of children with ARDS (total n = 333) from the Children's Hospital of Philadelphia enrolled between 2014 and 2019, with plasma collected within 24 hours of ARDS onset. We aimed to recruit subjects with higher levels of plasma cfDNA to assess feasibility. We randomly selected 24 children with cfDNA levels above the median value and 6 intubated non-ARDS controls. We isolated and quantified cfDNA from plasma, and performed methylation analysis using the Infinium MethylationEPIC v2.0 BeadChip. Methylation patterns were deconvoluted by mapping against known cell methylation patterns to identify tissues of origin. Hypo- and hyperinflammatory ARDS were defined using a previously published parsimonious algorithm of protein biomarkers and clinical variables. Our primary comparison was between hypoinflammatory ARDS, hyperinflammatory ARDS, and non-ARDS controls using non-parametric statistics. Results: Total plasma cfDNA levels were higher in hyperinflammatory ARDS (n = 18) compared to either hypoinflammatory ARDS (n = 6) or non-ARDS controls (n = 6). Dimensionality reduction using t-distributed Stochastic Neighbor Embedding (tSNE) separated hypo- and hyperinflammatory ARDS. Leukocytes were the dominant source of cfDNA in both ARDS and non-ARDS, and hyperinflammatory ARDS was also characterized by higher levels of hepatocyte cfDNA. Conclusions: Pediatric ARDS, especially the hyperinflammatory subphenotype, is characterized by elevated levels of plasma cfDNA originating primarily from leukocyte turnover. Hepatocyte death may also contribute to inflammation by impairing clearance of cfDNAs and other DAMPs in sicker subjects. Plasma cfDNA methylomics is a novel approach to quantify and characterize tissue injury in critical illness syndromes.

  PublisherDOI

• Acute Respiratory Distress Syndrome in Trauma 2007–2019: Comprehensive Patient and Center-Level Retrospective Cohort Analysis

  Critical Care Medicine · 2025-11-12 · 1 citations

  article

  OBJECTIVES: Acute respiratory distress syndrome (ARDS) represents a significant complication in trauma patients. Yet the epidemiology of ARDS in trauma remains incompletely characterized. We sought to define trends in ARDS frequency and the effect of temporal, patient, and center-level factors on outcomes with the hypothesis that ARDS independently predicts mortality. DESIGN: Retrospective cohort study. SETTING: Hospitals submitting data to the American College of Surgeons National Trauma Data Bank. PATIENTS: Injured patients 18 years old or older from 2007 to 2019 on mechanical ventilation (MV) for greater than or equal to 2 days were included, and patients with ARDS were compared with those without ARDS. A subgroup with transfusion data was also identified. Multivariable logistic regression models by year adjusted for patient demographics, center characteristics, and blood products identified factors independently associated with ARDS diagnosis and 30-day hospital mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 384,032 injured patients on MV, ARDS was documented in 29,359 (8 per 100 MV patients) with a significant decrease over the study period (22 in 2007 vs. 3 in 2019, p < 0.001). Patient-level risk factors independently associated with ARDS were blunt injury (odds ratio [OR] 1.25; 95% CI, 1.20-1.30), severe sepsis (OR 2.16; 95% CI, 2.06-2.27), ventilator-associated pneumonia (OR 2.91; 95% CI, 2.82-3.00), and acute kidney injury (AKI, OR 2.98; 95% CI, 2.85 to 3.12). In the transfusion subset, 24-hour plasma (OR 1.02; 95% CI, 1.01-1.04) and platelets (OR 1.03; 95% CI, 1.02-1.05) were independently associated with ARDS. Crude ARDS mortality increased over the study period (2007, 15.1% vs. 2019, 29.7%, p < 0.001), and after adjusting for significant differences, ARDS was independently associated with 30-day hospital mortality (OR 1.32; 95% CI, 1.27-1.37). Independent risk factors for 30-day mortality in patients with ARDS included head injury (OR 1.54; 95% CI, 1.43-1.66), severe sepsis (OR 1.48; 95% CI, 1.34-1.63), and AKI (OR 2.72; 95% CI, 2.50-2.96). Patients with ARDS managed in Prevention and Early Treatment of Acute Lung Injury and the Extracorporeal Life Support Organization centers were less likely to die (OR 0.78; 95% CI, 0.72-0.84). CONCLUSIONS: From 2007 to 2019, ARDS decreased significantly in trauma patients. Over the same time, mortality increased to nearly 30%, and after adjusting for other risks factors, ARDS was strongly associated with 30-day mortality. Future studies should examine modifiable patient and center-level factors to improve mortality in these high-risk patients.

  PublisherDOI

• Human red blood cells express the RNA sensor TLR7

  Scientific Reports · 2024-07-09 · 8 citations

  articleOpen accessSenior author

  Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs.

  PublisherOA PDFDOI

Recent grants

• NIH Grant F32HL091644

  NIH · $103k · 2010

• Role of RAGE and Necroptosis in Transfusion Mediated Lung Inflammation

  NIH · $2.0M · 2015–2021

• NIH Grant K08HL098362

  NIH · $658k · 2016

Frequent coauthors

• Nuala J. Meyer

  University of Pennsylvania

  47 shared

• Michael G. S. Shashaty

  University of Pennsylvania

  28 shared

• John P. Reilly

  26 shared

• E. John Wherry

  University of Pennsylvania

  24 shared

• Jason D. Christie

  University of Pennsylvania

  23 shared

• C.A.G. Ittner

  University of Pennsylvania

  19 shared

• Janet Lee

  Washington University in St. Louis

  18 shared

• Steven Μ. Albelda

  15 shared

Labs

• Nilam S. Mangalmurti LabPI