About

Jeffrey N. Weiser, M.D., is an Emeritus Professor of Microbiology in the Department of Microbiology at the University of Pennsylvania's Perelman School of Medicine. His research focuses on the molecular basis of infectious diseases, particularly host-pathogen interactions involving bacteria that reside in and infect the human respiratory tract. His laboratory investigates the pathogenesis of Streptococcus pneumoniae, a prominent cause of acute respiratory tract infections, along with other pathogens such as Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus, and influenza. His work emphasizes understanding bacterial colonization of the mucosal surface of the upper airway, which is the initial step in disease development. Dr. Weiser's research explores how colonizing microbes stimulate and evade immune clearance mechanisms, mechanisms facilitating interspecies competition within a host, and the effects of influenza co-infection on bacterial colonization. His studies utilize bacterial genetics and mouse models to examine microbial gene effects and host immune responses, including the role of bacterial surface constituents like phosphorylcholine in pathogenesis. His contributions include elucidating how bacteria evade immune responses, mechanisms of host-to-host transmission, and the interactions between bacteria and immune cells such as neutrophils and macrophages. His work has advanced understanding of bacterial immune evasion, colonization, and transmission, contributing significantly to the field of infectious disease microbiology.

Research topics

• Biology
• Microbiology
• Immunology
• Virology
• Medicine

Selected publications

• Pooled analysis of PCV13 efficacy from controlled human infection trials in Malawi and the UK

  npj Vaccines · 2026-02-26

  articleOpen access

  We conducted the first pooled analysis of two randomised controlled vaccine trials on experimental pneumococcal serotype 6B carriage, registered in Malawi (PACTR202008503507113) and the UK (ISRCTN45340436). This post-hoc exploratory study examined the sex-based differences in carriage, vaccine efficacy and vaccine-induced responses. PCV-13 reduced colonisation by 76% (p < 0.001) with non-significant interaction by sex (RR = 1.549, p = 0.413). Females showed a higher carriage rate than males (28% vs. 19%, p = 0.066). Baseline anti-6B Capsular Polysaccharide Immunoglobulin G (IgG) titres were higher in females, significantly in Malawi (2.62 µg/ml vs males 2.05 µg/ml, p = 0.015). Post-vaccination titres did not differ by sex. The pooled fold change in IgG pre-post vaccination, was higher in vaccinated females (5.47 vs 3.30, p = 0.053). This analysis demonstrates the utility and challenges of integrating CHIM data between diverse settings to evaluate vaccine efficacy, describe inter-setting differences, investigate biological and immunological factors influencing protection against pneumococcal carriage and ultimately inform future vaccine development strategies.

  PublisherOA PDFDOI

• Immune pathways that regulate neutrophil activation and replenishment prevent persistent pneumococcal colonization

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-15

  articleOpen accessSenior authorCorresponding

  Abstract Here, we examine immune signaling pathways affecting the duration of primary nasopharyngeal colonization by Streptococcus pneumoniae ( Spn ), the first step in its pathogenesis. Spn colonization which lasts days to weeks in WT mice was persistent ( &gt; 6 months) in the absence of IL-17RA-signaling. RNA-seq analysis confirmed the role of IL-17RA signaling in neutrophil-associated pathways. Rather than driving neutrophil specific chemokine expression, IL-17RA-signaling was required to replenish neutrophils in nasal tissue that were otherwise depleted during infection. Enhanced neutrophil trafficking correlated with IL-17RA-dependent expression of endothelial cell adhesion molecules that promote neutrophil trafficking from the circulation into nasal tissue. Persistent colonization was also observed in mice lacking IL-1R-signaling. Recognition of IL-1-family cytokines, however, was not necessary for the expression of IL-17A or neutrophil recruitment. Instead, IL-1R-signaling was associated with the activation of neutrophils in nasal tissue that displayed increased levels of the surface marker CD11b, an important receptor for the complement-opsonized phagocytosis of Spn . Our findings provide insight into the requirement for sustained neutrophil presence and activity to prevent persistent mucosal infection by a leading opportunistic mucosal pathogen. Author Summary Colonization of the upper airway by Streptococcus pneumoniae ( Spn ) is common and often asymptomatic, particularly in early life, yet prolonged colonization increases the risk of transmission and invasive disease. Despite its importance, the immune mechanisms that prevent long-term persistence of Spn in the upper airway are not fully understood. In this study, we investigated how two immune signaling pathways, the IL-17RA and IL-1R pathways, contribute to preventing persistent Spn colonization. Using a mouse model, we found that the IL-17RA pathway supports continued replenishment of neutrophils into nasal tissue by promoting expression of molecules that allow these cells to exit the bloodstream and enter the nasal tissue. In contrast, the IL-1R pathway activates neutrophils in a way that makes them more effective at clearing Spn . Loss of either pathway resulted in persistent Spn colonization, with an additive effect seen when both pathways were removed. Collectively, our results highlight how two distinct immune pathways cooperate to control pneumococcal colonization by sustaining neutrophil recruitment and function.

  PublisherOA PDFDOI

• Bacterial and host factors affecting acquisition of <i>Streptococcus pneumoniae</i> in a murine model

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-13

  articleOpen accessSenior authorCorresponding

  Abstract Initial acquisition is a critical step in the establishment of colonization that in turn enables transmission to new hosts and potentially leads to invasive disease. Here, we studied host and bacterial factors affecting acquisition, as distinct from those affecting colonization density, using Streptococcus pneumoniae (Spn) in a mouse model. Acquisition was quantified using nasal inocula of limiting size to determine the proportion of hosts infected, as well as the median infectious dose. Infant mice (&lt;7 days of age) were highly susceptible to acquisition (ID 50 &lt;30 CFU) compared with adults (&gt;6 weeks of age), with rates declining with increasing host age. Prior influenza A infection greatly increased acquisition in adults. Expression of Spn capsule was also an important factor influencing acquisition in adults, with less of a role for the highly susceptible infants. Prior Spn colonization with a heterologous or homologous strain effectively blocked acquisition in infants by completely occupying the upper respiratory tract niche. Immunity due to prior colonization and nasal microbiota were not found to be factors limiting acquisition. Together, our findings show how high carriage rates of encapsulated Spn during early life and in the setting of recent viral infection could be explained by effects on acquisition. Our study describes an approach for studying factors that specifically affect the step of acquisition.

  PublisherDOI

• 2023 - Zhu and Abruzzo et al - Raw Data

  Figshare · 2026-03-06

  datasetOpen access

  The dataset contains the raw files to the pulished data in the article "Effects of Capsular Polysaccharide amount on Pneumococcal-Host interactions". The research presents that capsular polysaccharide amount directly interferes witht he host-pathogen interaction and immunoblots were used to measure polysaccharide production. An infant-mouse model of infection was used to determine the <i>in vivo</i> effects of the capsule production. Numerical data from these experiments is deposited in a GraphPad Prism file.

  PublisherDOI

• Immune pathways that regulate neutrophil activation and replenishment prevent persistent pneumococcal colonization

  PLoS Pathogens · 2026-05-05

  articleOpen accessSenior author

  Here, we examine immune signaling pathways affecting the duration of primary nasopharyngeal colonization by Streptococcus pneumoniae (Spn), the first step in its pathogenesis. Spn colonization which lasts days to weeks in WT mice was persistent (> 6 months) in the absence of IL-17RA-signaling. RNA-seq analysis confirmed the role of IL-17RA signaling in neutrophil-associated pathways. The onset of clearance required neutrophils, but there was no detectable increase in their numbers. IL-17RA-signaling was required to replenish neutrophils in nasal tissue that were otherwise depleted during infection. Enhanced neutrophil trafficking correlated with IL-17RA-dependent expression of endothelial cell adhesion molecules that promote neutrophil trafficking from the circulation into nasal tissue. Persistent colonization was also observed in mice lacking IL-1R-signaling. Recognition of IL-1-family cytokines, however, was not necessary for the expression of IL-17A or neutrophil recruitment. Instead, IL-1R-signaling was associated with the activation of neutrophils in nasal tissue that displayed increased levels of the surface marker CD11b, an important receptor for the complement-opsonized phagocytosis of Spn. Colonization of dual-knockout mice showed the contributions of IL-1 and IL-17 signaling pathways were non-redundant. Expression of the chemokine Cxcl5 was impaired in the absence of either IL-1R or IL-17RA signaling, suggesting a role in both activation and maintenance of the neutrophil population during infection. Our findings provide insight into the requirement for sustained neutrophil presence and activity to prevent persistent mucosal infection by a leading opportunistic mucosal pathogen.

  PublisherDOI

• Bacterial and host factors affecting acquisition of <i>Streptococcus pneumoniae</i> in a murine model

  Infection and Immunity · 2026-04-30

  articleOpen accessSenior author

  ABSTRACT Initial acquisition is a critical step in the establishment of colonization that in turn enables transmission to new hosts and potentially leads to invasive disease. Here, we studied host and bacterial factors affecting acquisition, as distinct from those affecting colonization density, using Streptococcus pneumoniae (Spn) in a mouse model. Acquisition was quantified using nasal inocula of limiting size to determine the proportion of hosts infected, as well as the median infectious dose. Infant mice (&lt;7 days of age) were highly susceptible to acquisition (ID 50 &lt; 30 CFU) compared with adults (&gt;6 weeks of age), with rates declining with increasing host age. Prior influenza A infection greatly increased acquisition in adults. Expression of Spn capsule was also an important factor influencing acquisition in adults, with less of a role for the highly susceptible infants. Prior Spn colonization with a heterologous or homologous strain effectively blocked acquisition in infants by completely occupying the upper respiratory tract niche. Nasal microbiota and immunity due to prior colonization were not found to be factors limiting acquisition. Together, our findings show how high carriage rates of encapsulated Spn during early life and in the setting of recent viral infection could be explained by effects on acquisition. Our study describes an approach for studying factors that specifically affect the step of acquisition.

  PublisherDOI

• 2023 - Zhu and Abruzzo et al - Raw Data

  Open MIND · 2026-03-06

  dataset

  The dataset contains the raw files to the pulished data in the article "Effects of Capsular Polysaccharide amount on Pneumococcal-Host interactions". The research presents that capsular polysaccharide amount directly interferes witht he host-pathogen interaction and immunoblots were used to measure polysaccharide production. An infant-mouse model of infection was used to determine the <i>in vivo</i> effects of the capsule production. Numerical data from these experiments is deposited in a GraphPad Prism file.

  DOI

• Inhibitory effect of capsule on natural transformation of <i>Streptococcus pneumoniae</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-10 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT The capsule of Streptococcus pneumoniae ( Spn ) is highly heterogeneous based on expression of distinct polysaccharides. Spn transformation, controlled by the Com regulon, has been predominantly focused on unencapsulated laboratory strains. However, genomic studies revealed different rates of recombination events in clinical isolates of different serotypes. As these isolates were genetically distinct beyond capsule-encoding genes, the exact relationship between transformation and capsule remains unclear. Herein, we compared the transformability of a collection of isogenic capsule-switch strains. Strains with different capsule types and amounts significantly differed in their transformation frequency, with the unencapsulated strain having a higher frequency compared to encapsulated strains. A GFP-reporter of each strain monitoring the expression of a Com regulon-controlled gene showed similar kinetics, indicating differences in transformability were due to processes downstream of competence activation. The Com pilus, induced by competence, binds and takes in the donor DNA, and is the central component of the transformation apparatus. The surface exposure of Com pilus significantly differed among serotypes with highly transformable strains having more cells binding ComGC antibody. Further, electron microscopy demonstrated that transformability correlated with the proportion of cells bearing a Com pilus, which was affected by both the presence of capsule and serotype. Additionally, the unencapsulated strain displayed longer pili than encapsulated strains. Examination of capsule porosity revealed that serotypes with higher transformation frequencies had more porous capsules. Together, these results indicate that the capsule interferes with the assembly of Com pilus, thereby inhibiting the natural transformation of Spn . IMPORTANCE The capsule is a major virulence factor of Streptococcus pneumoniae ( Spn ), providing a physical shield and exhibiting extensive diversity across at least 100 serotypes. Although natural transformation of Spn has predominantly been characterized in unencapsulated laboratory strains, clinical encapsulated isolates also exhibit transformability and demonstrate varied recombination rates during host carriage. We utilized otherwise genetically identical capsule-switch strains to isolate the effect of capsule on transformation. We demonstrate serotype- and quantity-dependent inhibition of transformation by the capsule, mediated through hindrance with the transformation pilus assembly and function. This study challenges the paradigm that unencapsulated laboratory strains fully recapitulate natural transformation dynamics. By redefining capsule as a multifunctional modulator of Spn biology, balancing virulence and adaptability, our findings advance our understanding of pneumococcal evolution.

  PublisherOA PDFDOI

• Inhibitory effect of capsule on natural transformation of <i>Streptococcus pneumoniae</i>

  mBio · 2025-08-28 · 3 citations

  articleOpen accessSenior author

  ABSTRACT The capsule of Streptococcus pneumoniae ( Spn ) is highly heterogeneous based on the expression of distinct polysaccharides. Spn transformation, controlled by the Com regulon, has been predominantly studied using unencapsulated laboratory strains. However, genomic studies revealed different rates of recombination events in clinical isolates of different serotypes. As these isolates were genetically distinct beyond capsule-encoding genes, the exact relationship between transformation and capsule remains unclear. Herein, we compared the transformability of a collection of isogenic capsule-switch strains. Strains with different capsule types and amounts significantly differed in their transformation frequency, with the unencapsulated strain having a higher frequency compared to encapsulated strains. A GFP-reporter of each strain monitoring the expression of a Com regulon-controlled gene showed similar kinetics, indicating differences in transformability were due to processes downstream of competence activation. The Com pilus, induced by competence, binds and takes in the donor DNA and is the central component of the transformation apparatus. The surface exposure of Com pilus significantly differed among serotypes with highly transformable strains having more cells binding ComGC antibody. Furthermore, electron microscopy demonstrated that transformability correlated with the proportion of cells bearing a Com pilus, which was affected by both the presence of capsule and serotype. Additionally, the unencapsulated strain displayed longer pili than encapsulated strains. Examination of capsule porosity revealed that serotypes with higher transformation frequencies had more porous capsules. Together, these results indicate that the capsule interferes with the assembly of Com pilus, thereby inhibiting the natural transformation of Spn . IMPORTANCE The capsule is a major virulence factor of Streptococcus pneumoniae ( Spn ), providing a physical shield and exhibiting extensive diversity across at least 100 serotypes. Although natural transformation of Spn has predominantly been characterized in unencapsulated laboratory strains, clinical encapsulated isolates also exhibit transformability and demonstrate varied recombination rates during host carriage. We utilized otherwise genetically identical capsule-switch strains to isolate the effect of capsule on transformation. We demonstrate serotype- and quantity-dependent inhibition of transformation by the capsule, mediated through hindrance with the transformation pilus assembly and function. This study challenges the paradigm that unencapsulated laboratory strains fully recapitulate natural transformation dynamics. By redefining the capsule as a multifunctional modulator of Spn biology, balancing virulence and adaptability, our findings advance our understanding of pneumococcal evolution.

  PublisherDOI

• Increased Late Time Point Lung Inflammation in Mice Given a Streptococcus Pneumoniae Challenge Following Several Weeks of E-Cigarette Whole Body Aerosol Exposure

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

  article

  Abstract RATIONALE: Tobacco smoking habits in America have changed drastically with the belief that the new nicotine delivery devices (e.g. e-cigarettes (e-cigs) are safer. Despite limited data available on toxicity, about 11 million Americans, including high school students and dual (cigarette/e-cig) are currently consuming nicotine-based e-cigs. Our previous studies identified immune cells as potential targets of e-cig toxicity. The current study's goal was to understand if there would be in vivo consequences for an acute bacterial lung challenge that engages neutrophil defenses. We chose Streptococcus (S.) pneumoniae type III because it causes significant morbidity and mortality in both elderly adults and young children with incomplete protection by current vaccines. METHODS: Four groups of male and female C57BL/6 mice were exposed for a total of 5 weeks (3 hours/day, 5 days/week) via whole body inhalation to: 1) filtered room air; 2) propylene glycol and vegetable glycerin (50:50 PG/VG); 3) PG/VG and 36 mg/mL nicotine; or 4) PG/VG and nicotine and 5 mg/ml menthol. Three weeks following e-cig cessation, the animals were inoculated with S. pneumoniae type III by intranasal instillation. The animals were euthanized 24-72 hours post inoculation and bronchoalveolar lavage (BAL), blood and lungs harvested. RESULTS: Irrespective of exposure status or gender, the highest bacterial counts in the BAL were measured at the 24- and 48-hour time points. Blood bacterial counts were most frequently detected at the 48- and 72-hour time points. The exposure groups (e-cig) were not different from the filtered air group in bacterial counts. However, there was a trend to increased frequency of female mice with septicemia (blood counts) in the nicotine/nicotine-menthol groups compared with the air group. At the 72-hour time point, higher inflammation scores were detected in the nicotine/nicotine-menthol groups compared to the air and Pg/VG control groups in the lungs. This was confirmed by morphometry using QuPath software, as the cell counts in the inflammation area / cell counts in the whole lung were significantly higher in the nicotine exposure group vs no-nicotine exposure group; Mann Whitney U test p&amp;lt;0.01. Currently, further analysis is aimed at quantification of the area of inflammation, and location of the inflammation originating from the pleura. CONCLUSIONS: While e-cig exposure did not significantly affect the intensity of pneumococcal infection (bacterial counts), there was increased inflammation in the lungs due to pneumococcal infection at the 72-hour time point.

  PublisherDOI

Recent grants

• Early Events in Pneumococcal Colonization

  NIH · $2.1M · 2015–2019

• NIH Grant R01AI078538

  NIH · $1.9M · 2013

• NIH Grant R01AI044231

  NIH · $2.9M · 2011

• Infectious Disease and Basic Microbiological Mechanisms.

  NIH · $12.7M · 1979–2023

• NIH Grant R21AI054647

  NIH · $462k · 2006

Frequent coauthors

• S. E. Lysenko

  Kurchatov Institute

  28 shared

• Stephen B. Gordon

  Malawi-Liverpool-Wellcome Trust Clinical Research Programme

  21 shared

• Aoife M. Roche

  University of Pennsylvania

  20 shared

• Mikhail Shchepetov

  University of Pennsylvania

  20 shared

• Adam J. Ratner

  New York University

  20 shared

• Nina Pan

  University of Pennsylvania

  19 shared

• Adèle Martin

  18 shared

• John A. Lees

  18 shared

Labs

• Weiser LabPI