Karsten R. O. Hazlett

Albany Medical Center Hospital

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Justin D. Radolf

UConn Health

Edmund J. Gosselin

Albany Medical Center Hospital

Timothy J. Sellati

Southern Research Institute

Sarah J. Rosa

Albany Medical Center Hospital

Sudeep Kumar

Albany Medical Center Hospital

Eileen M. Barry

University of Maryland, Baltimore

Prachi Namjoshi

Knoxville College

Douglas S. Reed

University of Pittsburgh

Raju Sunagar

Dr. Reddy's Foundation

Jeffrey A. Banas

University of Iowa

Cooperative Institutions

Albany Medical Center Hospital

UConn Health

University of Pittsburgh

The University of Texas Southwestern Medical Center

National Institutes of Health

Harvard University

New York State Department of Health

University of Connecticut

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Centers for Disease Control and Prevention

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Mucosal immunity elicited by a human-Fcγ receptor-I targeted intranasal vaccine platform enhances resistance against nasopharyngeal colonization of Streptococcus pneumoniae and induces broadly protective immunity against respiratory pathogens

Vaccine (2025)

Sudeep Kumar Karsten R. O. Hazlett Guangchun Bai

Mucosal Immunity

Pneumococcal infections

10.1016/j.vaccine.2025.126729

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Citations (0)

PCR-Based Identification of Bacteria Associated with Endodontic Infections

Journal of Clinical Microbiology (2002)

Ashraf Fouad Jody Barry Melissa J. Caimano Michael L. Clawson Qiang Zhu

PCR primers that target the bacterial 16S rRNA genes (or the tuf gene for the genus Enterococcus) were used to identify 10 putative bacterial pathogens in root canals with necrotic pulp. In addition, the associations of these microorganisms with symptoms and a history of diabetes mellitus were investigated. Microbial samples from the root canals of 24 teeth with necrotic pulp were included in the study. PCR with universal bacterial primers identified bacterial DNA in 22 specimens; the remaining 2 specimens were from intact teeth that had been traumatized 6 months prior to treatment. PCR with specific primers showed that preoperative symptoms were significantly associated with the presence of Streptococcus spp. (P < 0.001 by chi-square analysis). There was also a nonsignificant trend for symptoms to be associated with Fusobacterium nucleatum and Porphyromonas gingivalis (odds ratio, >2) and for diabetes mellitus to be associated with P. gingivalis and Porphyromonas endodontalis (odds ratio, >2). Cloning and sequencing of the universal PCR product in one specimen revealed the presence of an organism related to the genus Olsenella, which has not previously been described in endodontic infections.

Fusobacterium nucleatum

Bacteroidaceae

Primer (cosmetics)

Fusobacterium

10.1128/jcm.40.9.3223-3231.2002

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Citations (264)

The coenzyme A disulphide reductase of Borrelia burgdorferi is important for rapid growth throughout the enzootic cycle and essential for infection of the mammalian host

Molecular Microbiology (2011)

Christian H. Eggers Melissa J. Caimano Robert A. Malizia Toru Kariu Brian Cusack

Summary In a microarray analysis of the RpoS regulon in mammalian host‐adapted Borrelia burgdorferi, bb0728 ( cdr ) was found to be dually transcribed by the sigma factors σ 70 and RpoS. The cdr gene encodes a coenzyme A disulphide reductase (CoADR) that reduces CoA‐disulphides to CoA in an NADH‐dependent manner. Based on the abundance of CoA in B. burgdorferi and the biochemistry of the enzyme, CoADR has been proposed to play a role in the spirochaete's response to reactive oxygen species. To better understand the physiologic function(s) of Bb CoADR, we generated a B. burgdorferi mutant in which the cdr gene was disrupted. RT‐PCR and 5′‐RACE analysis revealed that cdr and bb0729 are co‐transcribed from a single transcriptional start site upstream of the bb0729 coding sequence; a shuttle vector containing the bb0729‐cdr operon and upstream promoter element was used to complement the cdr mutant. Although the mutant was no more sensitive to hydrogen peroxide than its parent, it did exhibit increased sensitivity to high concentrations of t ‐butyl‐hydroperoxide, an oxidizing compound that damages spirochetal membranes. Characterization of the mutant during standard (15% oxygen, 6% CO 2 ) and anaerobic (< 1% O 2 , 9–13% CO 2 ) cultivation at 37°C revealed a growth defect under both conditions that was particularly striking during anaerobiosis. The mutant was avirulent by needle inoculation and showed decreased survival in feeding nymphs, but displayed no survival defect in unfed flat nymphs. Based on these results, we propose that Bb CoADR is necessary to maintain optimal redox ratios for CoA/CoA‐disulphide and NAD + /NADH during periods of rapid replication throughout the enzootic cycle, to support thiol‐disulphide homeostasis, and to indirectly protect the spirochaete against peroxide‐mediated membrane damage; one or more of these functions are essential for infection of the mammalian host by B. burgdorferi .

rpoS

10.1111/j.1365-2958.2011.07845.x

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Citations (39)

An improved vaccine for prevention of respiratory tularemia caused by Francisella tularensis SchuS4 strain

Vaccine (2008)

Chandra Shekhar Bakshi Meenakshi Malik Manish Mahawar Girish S. Kirimanjeswara Karsten R. O. Hazlett

Tularemia

Attenuated vaccine

Francisella

10.1016/j.vaccine.2008.07.051

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Citations (71)

Development, Characterization, and Standardization of a Nose-Only Inhalation Exposure System for Exposure of Rabbits to Small-Particle Aerosols Containing Francisella tularensis

Infection and Immunity (2019)

Katherine J. O’Malley Jennifer D. Bowling Eileen M. Barry Karsten R. O. Hazlett Douglas S. Reed

Inhalation of Francisella tularensis causes pneumonic tularemia in humans, a severe disease with a 30 to 60% mortality rate. The reproducible delivery of aerosolized virulent bacteria in relevant animal models is essential for evaluating medical countermeasures. Here we developed optimized protocols for infecting New Zealand White (NZW) rabbits with aerosols containing F. tularensis We evaluated the relative humidity, aerosol exposure technique, and bacterial culture conditions to optimize the spray factor (SF), a central metric of aerosolization. This optimization reduced both inter- and intraday variability and was applicable to multiple isolates of F. tularensis Further improvements in the accuracy and precision of the inhaled pathogen dose were achieved through enhanced correlation of the bacterial culture optical density and the number of CFU. Plethysmograph data collected during exposures found that respiratory function varied considerably between rabbits, was not a function of weight, and did not improve with acclimation to the system. Live vaccine strain (LVS)-vaccinated rabbits were challenged via aerosol with human-virulent F. tularensis SCHU S4 that had been cultivated in either Mueller-Hinton broth (MHB) or brain heart infusion (BHI) broth. LVS-vaccinated animals challenged with SCHU S4 that had been cultivated in MHB experienced short febrile periods (median, 3.2 days), limited weight loss (<5%), and longer median survival times (∼18 days) that were significantly different from those for unvaccinated controls. In contrast, LVS-vaccinated rabbits challenged with SCHU S4 that had been cultivated in BHI experienced longer febrile periods (median, 5.5 days) and greater weight loss (>10%) than the unvaccinated controls and median survival times that were not significantly different from those for the unvaccinated controls. These studies highlight the importance of careful characterization and optimization of protocols for aerosol challenge with pathogenic agents.

Aerosolization

Tularemia

Brain heart infusion

10.1128/iai.00198-19

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Citations (8)

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

Frontiers in Immunology (2017)

Sudeep Kumar Raju Sunagar Giang Pham Brian J. Franz Sarah J. Rosa

Francisella tularensis (Ft) is a Category A biothreat agent for which there is no FDA-approved vaccine. Ft can survive in a variety of habitats with a remarkable ability to adapt to changing environmental conditions. Furthermore, Ft expresses distinct sets of antigens (Ags) when inside of macrophages (its in vivo host) as compared to those grown in vitro with Mueller Hinton Broth medium (MHB). However, in contrast to MHB-grown Ft, Ft grown in Brain Heart Infusion medium (BHI) more closely mimics the antigenic profile of macrophage-grown Ft. Thus, we anticipated that when used as a vaccine, BHI-grown Ft would provide better protection compared to MHB-grown Ft, due primarily to its greater antigenic similarity to Ft circulating inside the host (macrophages) during natural infection. Our investigation however revealed that inactivated Ft (iFt) grown in MHB (iFt-MHB) exhibited superior protective activity when used as a vaccine, as compared to iFt grown in BHI (iFt-BHI). The superior protection afforded by iFt-MHB compared to that of iFt-BHI was associated with significantly lower bacterial burden and inflammation in the lungs and spleens of vaccinated mice. Moreover, iFt-MHB also induced increased levels of Ft-specific IgG. Further evaluation of early immunological cues also revealed that iFt-MHB exhibits increased engagement of Ag presenting cells (APCs) including: increased iFt binding to dendritic cells (DCs), increased expression of costimulatory markers, and increased secretion of pro-inflammatory cytokines. Importantly, these studies directly demonstrate that Ft growth conditions strongly impact Ft vaccine efficacy and that the growth medium used to produce whole cell vaccines to Ft must be a key consideration in the development of a tularemia vaccine.

Brain heart infusion

10.3389/fimmu.2016.00677

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Citations (6)

Autotransporter-Mediated Display of Complement Receptor Ligands by Gram-Negative Bacteria Increases Antibody Responses and Limits Disease Severity

Pathogens (2020)

Kristen M Holland-Tummillo Lauren E. Shoudy Donald Steiner Sudeep Kumar Sarah J. Rosa

The targeting of immunogens/vaccines to specific immune cells is a promising approach for amplifying immune responses in the absence of exogenous adjuvants. However, the targeting approaches reported thus far require novel, labor-intensive reagents for each vaccine and have primarily been shown as proof-of-concept with isolated proteins and/or inactivated bacteria. We have engineered a plasmid-based, complement receptor-targeting platform that is readily applicable to live forms of multiple gram-negative bacteria, including, but not limited to, Escherichia coli, Klebsiella pneumoniae, and Francisella tularensis. Using F. tularensis as a model, we find that targeted bacteria show increased binding and uptake by macrophages, which coincides with increased p38 and p65 phosphorylation. Mice vaccinated with targeted bacteria produce higher titers of specific antibody that recognizes a greater diversity of bacterial antigens. Following challenge with homologous or heterologous isolates, these mice exhibited less weight loss and/or accelerated weight recovery as compared to counterparts vaccinated with non-targeted immunogens. Collectively, these findings provide proof-of-concept for plasmid-based, complement receptor-targeting of live gram-negative bacteria.

Heterologous

Gram-Negative Bacteria

10.3390/pathogens9050375

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Citations (4)

Role of antibody in vaccine-mediated protection against pneumonic tularemia in the rabbit model

The Journal of Immunology (2020)

Douglas S. Reed Emily Olsen Jennifer Bowling Katherine Willett Karsten R. O. Hazlett

Abstract Francisella tularensis, a gram negative coccobacillus, is the causative agent of tularemia, a severe zoonotic infection. When inhaled, as few as 15 cfu is sufficient to cause disease. There is concern that tularemia could be used as a biological weapon so vaccines are urgently needed. We have previously shown that the New Zealand White (NZW) rabbit is a good model of human disease; after exposure to small particle aerosols containing virulent F. tularensis at doses as low as 66 cfu, naive NZW rabbits develop fever within 3 days and succumb within 4–7 days. Disease pathology in the NZW rabbit strongly resembles what has been reported in humans. Recombinant derivatives of a virulent strain of F. tularensis are highly attenuated in NZW rabbits and protect against aerosol challenge with virulent F. tularensis. The level of protection is dependent on the strain used, the route of vaccination, and the number of vaccinations. Using a prime-boost small particle aerosol vaccination regimen, 73% percent of rabbits survived a robust (100 LD50) challenge when vaccinated with a strain that is deficient in the aromatic amino acid synthase pathway. Pre-challenge, post-vaccination plasma IgG and IgM titers against heat-killed F. tularensis correlate with protection. A single inoculation of plasma from hyper-immune rabbits extended the survival of naïve rabbits by one day. We will report our efforts to evaluate the role of antibody in protection of NZW rabbits against tularemia, including passive immunization of mice using purified immunoglobulin from hyper-immune rabbits and in vitro assays of antibody function.

Tularemia

Attenuated vaccine

10.4049/jimmunol.204.supp.168.12

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Citations (0)

[30] An in vitro model for studying the contributions of the streptococcus mutans glucan-binding protein A to biofilm structure

Methods in enzymology on CD-ROM/Methods in enzymology (2001)

Jeffrey A. Banas Karsten R. O. Hazlett Joseph E. Mazurkiewicz

Crystal violet

Dental plaque

10.1016/s0076-6879(01)37031-3

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Citations (23)

Inactivation of the gbpA Gene of Streptococcus mutans Alters Structural and Functional Aspects of Plaque Biofilm Which Are Compensated by Recombination of the gtfB and gtfC Genes

Infection and Immunity (1999)

Karsten R. O. Hazlett Joseph E. Mazurkiewicz Jeffrey A. Banas

Inactivation of the gbpA gene of Streptococcus mutans increases virulence in a gnotobiotic rat model and also promotes in vivo accumulation of organisms in which gtfB and gtfC have recombined to reduce virulence (K. R. O. Hazlett, S. M. Michalek, and J. A. Banas, Infect. Immun. 66:2180-2185, 1998). These changes in virulence were hypothesized to result from changes in plaque structure. We have utilized an in vitro plaque model to test the hypothesis that the absence of GbpA alters S. mutans plaque structure and that the presence of gtfBC recombinant organisms within a gbpA background restores a wild-type (wt)-like plaque structure. When grown in the presence of sucrose within hydroxyapatite-coated wells, the wt S. mutans plaque consisted primarily of large aggregates which did not completely coat the hydroxyapatite surface, whereas the gbpA mutant plaque consisted of a uniform layer of smaller aggregates which almost entirely coated the hydroxyapatite. If 25% of the gbpA mutants used as inoculum were also gtfBC recombinants (gbpA/25%gtfBC), a wt-like plaque was formed. These changes in plaque structure correlated with differences in susceptibility to ampicillin; gbpA plaque organisms were more susceptible than organisms in either the wt or gbpA/25%gtfBC plaques. These data allow the conclusion that GbpA contributes to S. mutans plaque biofilm development. Since the changes in plaque structure detailed in this report correlate well with previously observed changes in virulence, it seems likely that S. mutans biofilm structure influences virulence. A potential model for this influence, which can account for the gtfBC recombination compensating gbpA inactivation, is that the ratio of glucan to glucan-binding protein is a critical factor in plaque development.

Dental plaque

10.1128/iai.67.8.3909-3914.1999

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Citations (57)