About

Maria Gennaro, MSCI, MD, is a professor at Rutgers New Jersey Medical School Public Health Research Institute. She holds a Master of Science in Clinical Investigation from the London School of Hygiene & Tropical Medicine, obtained in 1981, and a Medical Degree from the University of Palermo, Italy, earned in 1977. Her areas of interest include immunology, tuberculosis, Th1 immunity, B-cell and T-cell epitopes, tuberculosis immunology in children, and infectious diseases. Her work focuses on understanding immune responses related to infectious diseases, particularly tuberculosis, and she contributes to advancing knowledge in these fields through her research and academic activities.

Research topics

• Medicine
• Immunology
• Virology
• Internal medicine
• Biology
• Pathology
• Computer Security
• Intensive care medicine
• Computer Science
• Computational biology
• Emergency medicine

Selected publications

• The role of co-infection in the pathogenesis of acute SARS-CoV-2 infection and development of post-acute sequelae: A perspective

  eLife · 2025-11-17

  articleOpen accessSenior author

  A major health challenge resulting from the COVID-19 pandemic is the manifestation of post-acute sequelae of SARS-CoV-2 (PASC). PASC (or long COVID) is a collective term used for clinical symptoms, various pathologies, and life-quality-changing functional impairment that persist for months to years after the initial SARS-CoV-2 infection. The mechanisms underlying PASC are not understood, although advances have been made in identifying factors that may contribute to long-term pathology. Recent data have emerged, showing an association between SARS-CoV-2 viral persistence and non-SARS-CoV-2 infections (pre-existing, viral reactivation, or new infections) in facilitating or mediating PASC. However, the heterogeneous nature and timing of co-infections have made it challenging to understand, interpret, and contextualize their contribution to PASC. Here, we summarize the impact of potential viral, bacterial, and fungal infections on SARS-CoV-2 pathogenesis, with a focus on their possible roles in the development of PASC. We also provide a framework to understand the mechanisms of PASC and inform basic, translational, and clinical research initiatives, including RECOVER, a large and ongoing research initiative to understand, treat, and prevent long COVID.

  PublisherDOI

• Cryptococcosis, tuberculosis, and a kidney cancer fail to fit the atherosclerosis paradigm for foam cell lipid content

  The Journal of Immunology · 2025-03-28 · 2 citations

  articleOpen accessSenior author

  Foam cells are dysfunctional, lipid-laden macrophages associated with chronic inflammation of diverse origin. The long-standing paradigm that foam cells are cholesterol-laden derives from atherosclerosis research. We previously showed that, in tuberculosis, foam cells surprisingly accumulate triglycerides. Here, we utilized bacterial (Mycobacterium tuberculosis), fungal (Cryptococcus neoformans), and human papillary renal cell carcinoma (pRCC) models to address the need for a new explanation of foam cell biogenesis. We applied mass spectrometry-based imaging to assess the spatial distribution of storage lipids relative to foam-cell-rich areas in lesional tissues, and we characterized lipid-laden macrophages generated under corresponding in vitro conditions. The in vivo data and the in vitro findings showed that cryptococcus-infected macrophages accumulate triglycerides, while macrophages exposed to pRCC-conditioned-medium accumulated both triglycerides and cholesterol. Moreover, Cryptococcus- and Mycobacterium-infected macrophages accumulated triglycerides in different ways. Collectively, the data show that the molecular events underlying foam cell formation are specific to disease and microenvironment. Since foam cells are potential therapeutic targets, recognizing that their formation is disease-specific opens new biomedical research directions.

  PublisherOA PDFDOI

• Accuracy of VIDASⓇ TB-IGRA in TB patients and individuals with different thresholds of exposure

  International Journal of Infectious Diseases · 2025-12-20 · 1 citations

  articleOpen access

  OBJECTIVES: TB-IGRA (bioMérieux) is a fully automated assay recently developed. We report here the results of a global, multicenter, cross-sectional, prospective study to evaluate the diagnostic accuracy of the assay. METHODS: -Plus, QIAGEN). RESULTS: ‑Plus. CONCLUSIONS: TB-IGRA was significantly more sensitive without a reduction in specificity, and it correlated better with an exposure gradient, suggesting that it is a valuable tool for TBI diagnosis.

  PublisherOA PDFDOI

• Combining Mass Spectrometry with Machine Learning to Identify Novel Protein Signatures: The Example of Multisystem Inflammatory Syndrome in Children

  medRxiv · 2025-04-21

  preprintOpen accessSenior authorCorresponding

  Objectives: We demonstrate an approach that integrates biomarker analysis with machine learning to identify protein signatures, using the example of SARS-CoV-2-induced Multisystem Inflammatory Syndrome in Children (MIS-C). Methods: We used plasma samples collected from subjects diagnosed with MIS-C and compared them first to controls with asymptomatic/mild SARS-CoV-2 infection and then to controls with pneumonia or Kawasaki disease. We used mass spectrometry to identify proteins. Support vector machine (SVM) algorithm-based classification schemes were used to analyze protein pathways. We assessed diagnostic accuracy using internal and external cross-validation. Results: Proteomic analysis of a training dataset containing MIS-C (N=17), and asymptomatic/mild SARS-CoV-2 infected control samples (N=20) identified 643 proteins, of which 101 were differentially expressed. Plasma proteins associated with inflammation and coagulation increased and those associated with lipid metabolism decreased in MIS-C relative to controls. The SVM machine learning algorithm identified a three-protein model (ORM1, AZGP1, SERPINA3) that achieved 90.0% specificity, 88.2% sensitivity, and 93.5% area under the curve (AUC) distinguishing MIS-C from controls in the training set. Performance was retained in the validation dataset utilizing MIS-C (N=17) and asymptomatic/mild SARS-CoV-2 infected control samples (N=10) (90.0% specificity, 84.2% sensitivity, 87.4% AUC). We next replicated our approach to compare MIS-C with similarly presenting syndromes, such as pneumonia (N=17) and Kawasaki Disease (N=13) and found a distinct three-protein signature (VWF, SERPINA3, and FCGBP) that accurately distinguished MIS-C from the other conditions (97.5% specificity, 89.5% sensitivity, 95.6% AUC). We also developed a software tool that may be used to evaluate other protein pathway signatures using our data. Conclusions: We used MIS-C, a novel hyperinflammatory illness, to demonstrate that the use of mass spectrometry to identify candidate plasma proteins followed by machine learning, specifically SVM, is an efficient strategy for identifying and evaluating biomarker signatures for disease classification.

  PublisherOA PDFDOI

• Preliminary performance of the VIDAS TB-IGRA as an aid in the diagnosis of individuals infected with <i>Mycobacterium tuberculosis</i>

  Journal of Clinical Microbiology · 2025-05-14 · 7 citations

  articleOpen accessSenior author

  ABSTRACT This preliminary study compares VIDAS TB-IGRA (bioMérieux, Marcy-l'Etoile, France) with the established QuantiFERON-TB Gold Plus (QFT-Plus) (Qiagen, Hilden, Germany) to evaluate diagnostic performance for the diagnosis of individuals infected with Mycobacterium tuberculosis complex (latent infection and disease). The study was multi-center and performed between 2 October 2019 and 4 February 2020. Participants were divided into tuberculosis (TB) disease, high-risk, and low-risk populations. The confirmed TB disease population included 104 patients. The high-risk population included 162 individuals with flagged risk factors on a questionnaire but without objective clinical confirmation of TB. The low-risk population included 117 healthy blood donors from the French National Blood Bank. Positive and negative percent agreement (PPA and NPA) were determined between the VIDAS TB-IGRA and QFT-Plus. In the TB disease population, sensitivity was measured against bacterial culture and PCR. The VIDAS TB-IGRA produced fewer indeterminate results than the QFT-Plus (1/104 vs 23/104) in the TB disease population and exhibited a sensitivity of 95.0% against bacterial culture. Furthermore, a 98.2% PPA was obtained in comparison to QFT-Plus. In the low-risk population, the VIDAS TB-IGRA demonstrated high specificity (94.9%) and a strong NPA (98.2%) compared to QFT-Plus. In the high-risk population, the VIDAS TB-IGRA exhibited a strong PPA (94.4%) with the QFT-Plus. A lower NPA was observed (85.2%) compared to QFT-Plus, which may be due to a higher sensitivity demonstrated in the TB disease population. The fully automated VIDAS TB-IGRA is a promising aid in the diagnosis of individuals infected with Mycobacterium tuberculosis (latent infection and active disease). It exhibits higher sensitivity while maintaining specificity and produces fewer indeterminate interpretations than QFT-Plus. Its easy-to-use, single-patient format may lead to increased TB testing to aid in the adequate diagnosis and management of the disease. IMPORTANCE This study presents a comprehensive evaluation of the VIDAS TB-IGRA diagnostic test. This test is compared with the established QuantiFERON-TB Gold Plus to assess its effectiveness in diagnosing both latent and active tuberculosis (TB) infections. The study highlights the VIDAS TB-IGRA’s higher sensitivity, fewer indeterminate results, and robust performance across different patient populations, including those with confirmed TB disease, high-risk, and low-risk groups. The findings suggest that the VIDAS TB-IGRA could enhance TB diagnosis and management, offering a fully automated, easy-to-use solution that reduces human error and result variability.

  PublisherDOI

• A genetically modulated Toll-like receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome

  The Journal of Immunology · 2025-03-01 · 5 citations

  articleOpen accessSenior author

  Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To investigate innate immune functions, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in fully convalescent children months after MIS-C recovery. When we investigated the genetic background of patients in relation to TLR responsiveness, we found that cells from MIS-C children carrying rare heterozygous variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Moreover, these rare LYST variant heterozygous carriers tended to exhibit unfavorable clinical laboratory indicators of inflammation, including more profound lymphopenia. The results of our observational study have several implications. First, TLR hyporesponsiveness may be associated with hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands. Second, TLR hyporesponsiveness during MIS-C may be protective, since LYST variant heterozygous carriers exhibited reduced TLR hyporesponsiveness and unfavorable clinical laboratory indicators of inflammation. Thus, links may exist between genetic background, ability to establish a refractory immune state, and MIS-C clinical spectrum. Third, the possibility exists that prolonged TLR hyporesponsiveness is one of the mechanisms driving long coronavirus disease (COVID), which highlights the need to monitor long-term consequences of MIS-C.

  PublisherOA PDFDOI

• The phage shock protein (PSP) envelope stress response: discovery of novel partners and evolutionary history

  mSystems · 2024-05-29 · 25 citations

  articleOpen accessSenior author

  Bacterial phage shock protein (PSP) systems stabilize the bacterial cell membrane and protect against envelope stress. These systems have been associated with virulence, but despite their critical roles, PSP components are not well characterized outside proteobacteria. Using comparative genomics and protein sequence-structure-function analyses, we systematically identified and analyzed PSP homologs, phyletic patterns, domain architectures, and gene neighborhoods. This approach underscored the evolutionary significance of the system, revealing that its core protein PspA (Snf7 in ESCRT outside bacteria) was present in the last universal common ancestor and that this ancestral functionality has since diversified into multiple novel, distinct PSP systems across life. Several novel partners of the PSP system were identified: (i) the Toastrack domain, likely facilitating assembly of sub-membrane stress-sensing and signaling complexes, (ii) the newly defined HTH-associated α-helical signaling domain-PadR-like transcriptional regulator pair system, and (iii) multiple independent associations with ATPase, CesT/Tir-like chaperone, and Band-7 domains in proteins thought to mediate sub-membrane dynamics. Our work also uncovered links between the PSP components and other domains, such as novel variants of SHOCT-like domains, suggesting roles in assembling membrane-associated complexes of proteins with disparate biochemical functions. Results are available at our interactive web app, https://jravilab.org/psp.IMPORTANCEPhage shock proteins (PSP) are virulence-associated, cell membrane stress-protective systems. They have mostly been characterized in Proteobacteria and Firmicutes. We now show that a minimal PSP system was present in the last universal common ancestor that evolved and diversified into newly identified functional contexts. Recognizing the conservation and evolution of PSP systems across bacterial phyla contributes to our understanding of stress response mechanisms in prokaryotes. Moreover, the newly discovered PSP modularity will likely prompt new studies of lineage-specific cell envelope structures, lifestyles, and adaptation mechanisms. Finally, our results validate the use of domain architecture and genetic context for discovery in comparative genomics.

  PublisherDOI

• Pharmacological inhibition of macrophage triglyceride biosynthesis pathways does not improve <i>Mycobacterium tuberculosis</i> control in infected mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-11

  preprintOpen access

  Abstract Triglyceride rich macrophages (foam cells) are a hallmark of necrotic granulomas in tuberculosis, and multiple antimicrobial functions are down-regulated in these cells. In this study, we assessed the ability of two different compounds to reduce triglyceride content and intracellular burden in Mycobacterium tuberculosis (Mtb)-infected macrophages: A-922500 (DGATi), an inhibitor of diacylglycerol acyltransferase 1, an enzyme involved in triglyceride synthesis; and LY2584702 (p70S6Ki), an inhibitor of p70 S6 kinase, a serine/threonine kinase involved in mTORC-1dependent lipid biogenesis. Additionally, we evaluated the adjunctive activity of these inhibitors as host-directed therapies against chronic Mtb infection in C3HeB/FeJ mice. DGATi and p70S6Ki significantly reduced the lipid content and bacillary burden in Mtb-infected human monocyte-derived macrophages. In Mtb-infected mice, each inhibitor reduced the triglyceride content (P≤ 0.0001) in cells from bronchoalveolar lavage samples. Adjunctive treatment of DGATi with isoniazid and p70S6Ki monotherapy reduced the lipid droplet content (P≤ 0.05) within lung macrophages of Mtb-infected mice. However, neither inhibitor reduced the lung bacterial burden in Mtb-infected mice alone or in combination with isoniazid, and they did not alter lung inflammation. These findings provide further insights into the role of foam cells in tuberculosis pathogenesis and the utility of interventions targeting these cell populations as adjunctive host-directed therapies.

  PublisherOA PDFDOI

• Pharmacologic Inhibition of Macrophage Triglyceride Biosynthesis Pathways Does Not Improve <i>Mycobacterium tuberculosis</i> Control in Infected Mice

  The Journal of Infectious Diseases · 2024-11-19 · 1 citations

  articleOpen access

  Tuberculosis necrotic granulomas contain triglyceride-rich macrophages (foam cells) with reduced antimicrobial functions. We assessed the ability of 2 compounds to reduce the triglyceride content and Mycobacterium tuberculosis (Mtb) burden in infected human monocyte-derived macrophages and in the lungs of Mtb-infected C3HeB/FeJ mice: A-922500 (DGATi), an inhibitor of diacylglycerol O-acyltransferase 1, and LY2584702 (p70S6Ki), an inhibitor of p70 S6 kinase. DGATi and p70S6Ki significantly reduced the lipid content and bacillary burden in Mtb-infected macrophages. Each inhibitor reduced the cellular triglyceride content in bronchoalveolar lavage samples of Mtb-infected mice. After 6 weeks of treatment, p70S6Ki alone reduced the lung bacterial burden in Mtb-infected mice. However, DGATi alone and DGATi or p70S6Ki in combination with isoniazid did not reduce lung bacterial burden or alter lung inflammation. These findings provide further insight into the role of foam cells in tuberculosis pathogenesis and the utility of interventions targeting these cell populations as adjunctive host-directed therapies.

  PublisherOA PDFDOI

• A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome

  medRxiv · 2024-02-04 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after SARS-CoV-2 exposure. To investigate innate immune functions in MIS-C, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in children enrolled months after MIS-C recovery. Moreover, cells from MIS-C children carrying rare genetic variants of lysosomal trafficking regulator ( LYST ) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Our results strongly suggest that MIS-C hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands drive immune cells to a lasting refractory state. TLR hyporesponsiveness is likely beneficial, as suggested by excess lymphopenia among rare LYST variant carriers. Our findings point to cellular mechanisms underlying TLR hyporesponsiveness; identify genetic determinants that may explain the MIS-C clinical spectrum; suggest potential associations between innate refractory states and long COVID; and highlight the need to monitor long-term consequences of MIS-C.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01HL106788

  NIH · $3.1M · 2015

• Foam cells as drug targets in tuberculosis

  NIH · $3.2M · 2019–2025

• Rapid Analysis of Single T Cell Immunity Signatures in Tuberculosis

  NIH · $3.8M · 2012–2019

• Foam cells as drug targets in tuberculosis

  NIH · $754k · 2019–2022

• NIH Grant R21AI095924

  NIH · $426k · 2014

Frequent coauthors

• Sindhu Mohandas

  45 shared

• Valentina Guerrini

  Rutgers, The State University of New Jersey

  42 shared

• Natalie Bruiners

  42 shared

• Rahul Ukey

  Rutgers, The State University of New Jersey

  41 shared

• Stuart D. Katz

  New York University

  39 shared

• Daniel B. Horton

  Rutgers, The State University of New Jersey

  35 shared

• Andrea S. Foulkes

  34 shared

• Sunanda Gaur

  33 shared

Education

• M.D.

  University of Palermo

  1977

• Other

  London School of Hygiene & Tropical Medicine

  1981