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Benjamin Janto

Benjamin Janto, PhD

Assistant Professor


Department: Microbiology & Immunology

Education

  • PhD - Drexel University College of Medicine (2012)

Dr. Janto is an assistant professor in the Department of Microbiology & Immunology at Drexel University College of Medicine.

Research

My laboratory works towards the goal of developing alternative targeted treatment strategies to combat chronic bacterial biofilm disease based on two underlying principles: 1) manipulation of bacterial behavior as opposed to eradication; and 2) the specific targeting of virulent strains and the sparing of commensal strains of the same species. Our normal bacterial flora plays a key role in our health in ways that we are only beginning to appreciate. Furthermore, our current antibiotic treatments are failing due to increasing resistance and a reduction in discovery and development. Therefore we seek to shift the clinical paradigm of treatment of chronic bacterial diseases away from traditional broad-spectrum antibiotics towards alternative strategies including behavioral manipulation and/or more targeted approaches at the subspecies or strain-level.

Much of our work is performed in the context of middle-ear diseases such as otorrhea, chronic otitis media with effusion (COME) and acute otitis media (AOM), which cause enormous morbidity, primarily in children. These chronic diseases place a substantial clinical and economic burden on families. The difficulty in treating these chronic diseases can primarily be attributed to the fact that the causative bacteria adopt the biofilm mode of growth, which renders them highly recalcitrant to both the body's defense mechanisms and to antibiotic therapy. As well as being largely ineffective at preventing recurrence and eradicating biofilm disease, antibiotic treatment also contributes to the emergence of antibiotic resistant bacterial populations and results in major disruptions to the hosts' normal microbiota leading to further acute and chronic conditions.

Non-typeable Haemophilus influenzae (NTHi) are ubiquitous colonizers of the human nasopharynx but are also major causes of COME and AOM, and are increasingly being found associated with invasive disease. The chronic nature of NTHi COME infections and resistance to immune clearance and antibiotic treatment is primarily due to their biofilm forming capabilities and ability to invade and survive within host cells. Because they lack a capsule or other common immunogenic features NTHi are not easily targeted by vaccination, thus identification of virulence-associated targets and alternatives to antibiotics provide attractive possibilities for interventions.

Several projects fall under the realm of NTHi pathogenesis in middle-ear disease:

  1. Characterization and disruption of strain-specific virulence factors in NTHi
  2. Characterization and manipulation of the NTHi Autoinducer-2 quorum sensing system
  3. Detection and production of novel biologicals

Characterization and disruption of strain-specific virulence factors in NTHi

We are studying a number of novel distributed (found in only a subset of strains) gene clusters, including the Sel1-like repeat (SLR) genes, some of which are strongly associated with invasive NTHi disease by both experimental, and statistical association studies. For example, disruption of an SLR gene, called msf, leads to: 1) dysregulation of the transcription of anaerobic respiration genes, 2) a decrease in phagocytosis and survival in macrophages, 3) a decrease in fitness compared to the WT in coinfections, and 4) loss of invasiveness in animal models. Because msf is statistically associated with disease-causing strains (as opposed to commensals from the normal flora) it suggests that we can use distributed virulence factors like msf to target subsets of strains within a host, specifically those with higher pathogenic potential while leaving less virulent commensal strains unaffected.

Our current projects focus on determining the mechanistic links among the different SLR subfamilies and their interactions with the anaerobic respiration regulon. Bioinformatic analysis of SLRs suggests they are involved in protein-protein interactions and are potentially phosphorylated or play a role in a phosphorylation cascade. An understanding of these molecular interactions will be key in determining how to control these systems in natural infections through development of novel targeted intervention strategies.

SLR Proteins contain 1-10 copies of this sequence motif.

Characterization and manipulation of the NTHi Autoinducer-2 quorum sensing system

Strains with an AI-2 importer (blue) are able to remove AI-2 from the media whereas strains that lack transporters (red) cannot.

The autoinducer-2 (AI-2) molecule is thought to be a signal in many bacterial species for population density that controls a population-based behavioral switch. Although many species produce this molecule, the response to the molecule (if any) appears to be highly species specific. In H. influenzae the only known active quorum sensing system is that of AI-2. Disruption of the AI-2 synthase gene has been shown to affect the biofilm phenotype both in vitro and in vivo, thus affecting the persistence and therefore virulence of the bacteria in animal models. Whether this phenotype is due to a classic quorum sensing signal cascade, or alternatively as a nutritional defect, is not currently known.

We are tackling this issue by focusing on the AI-2 import systems and investigating transcriptional and phenotypic profiles. In this way we are working towards determining if it is possible to control the expression of biofilm and virulence factors and ultimately the virulence phenotype, by manipulating the QS system as an alternative to treating with broad-spectrum antibiotics.

Center for Advanced Microbial Processing: Detection and production of novel biologicals

Novel ET-743 biosynthesis gene cluster and proposed sythesis pathway identified from hologenomic sequencing.

Antibiotic pipelines in industry are drying up, and more and more pathogens are emerging with resistance to our current treatments. Our goal at the Center for Advanced Microbial Processing (CAMP) is to tackle this problem by using microbes as both a source and a tool for the discovery and production of therapeutic agents including but not limited to antibiotics. With access to a state of the art next-generation sequencing facility at CAMP, my lab will play a role in the sequencing and analysis of microbial genomes, metagenomes and hologenomes that we identify as producers of target molecules.

We intend to identify and isolate the genetic components responsible for the generation of the target molecules and to engineer them for insertion into model bacterial hosts with the ultimate goal being the efficient and cost-effective production of the target molecule. We demonstrated a portion of this pipeline in a project to identify the organism and genes responsible for production of an anti-tumorigenic compound called ET-743, which currently can only feasibly be produced by a laborious semi-synthetic chemical synthesis with high associated cost.

The molecule was first identified in a marine invertebrate sample; however, structural analysis suggested it was actually produced by an associated prokaryote. We sequenced the host genome and all of the associated microbial communities, AKA the hologenome, as a single mixture and were able to piece together a large part of the ET-743 synthesis pathway and confirm the functions of several of the predicted protein products in vitro. This study forms the basis for the CAMP pipeline and future projects.

Publications

"Development and Validation of an Haemophilus influenzae Supragenome Hybridization (SGH) Array for Transcriptomic Analyses"
Janto B, Hiller NL, Eutsey R, Dahlgren ME, Earl J, Powell E, Ahmed A, Hu FZ, and GD Ehrlich
PloS One, 9(10): e105493, 2014

"Design and validation of a supragenome array for determination of the genomic content of Haemophilus influenzae isolates"
Eutsey R, Hiller NL, Earl J, Janto B, Dahlgren ME, Ahmed A, Powell E, Schultz M, Gilsdorf J, Zhang L, Smith A, Murphy TF, Sethi S, Shen K, Post JC, Hu FZ, and GD Ehrlich
BMC Genomics, 14: 484, 2013

"Comparative genomic analyses of seventeen clinical isolates of Gardnerella vaginalis provides evidence of multiple genetically isolated clades consistent with sub-speciation into genovars"
Ahmed A, Earl J, Retchless A, Hillier SL, Rabe LK, Cherpes TL, Powell E, Janto B, Eutsey R, Hiller NL, Boissy R, Dahlgren ME, Hall BG, Costerton JW, Post JC, Hu FZ, and GD Ehrlich
J Bacteriol, 194(15): 3922-3937, 2012

"In vivo capsular switch in Streptococcus pneumoniae - analysis by whole genome sequencing"
Hu FZ, Eutsey R, Ahmed A, Frazao N, Powell E, Hiller NL, Hillman T, Buchinsky FJ, Boissy R, Janto B, Kress-Bennett J, Longwell M, Ezzo S, Post JC, Nesin M, Tomasz A, and GD Ehrlich
PloS One, 7(11):e47983, 2012

"Genome of alkaliphilic Bacillus pseudofirmus OF4 reveals adaptations that support the ability to grow in an external pH range from 7.5 to 11.4"
Janto B, Ahmed A, Ito M, Lui J, Hicks DB, Pagni S, Fackelmayer OJ, Smith TA, Earl J, Elbourne LDH, Hassan K, Paulsen IT, Kolsto AB, Tourasse N, Ehrlich GD, Boissy R, Ivey DM, Li G, Xue Y, Ma Y, Hu FZ, and TA Krulwich
Env. Micro, 13(12): 3289-3309, 2011

"Comparative Supragenomic Analyses among the Pathogens Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae Using a Modification of the Finite Supragenome Model"
Boissy R, Ahmed A, Janto B, Earl J, Hall BG, Hogg J, Pusch G, Hiller NL, Powell E, Hayes J, Yu S, Kathju S, Stoodley P, Post JC, Ehrlich GD, and FZ Hu
BMC Genomics, 12: 187, 2011

"Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743"
Rath C*, Janto B*, Earl J, Ahmed A, Hu FZ, Hiller NL, Dahlgren M, Kreft R, Yu F, Wolff JJ, Kweon HK, Chrstiansen MA, Hakansson K, Williams RM, Ehrlich GD, and DH Sherman
ACS Chem. Bio, 18;6(11): 1244-1256, 2011

"Differences in genotype and virulence among four multidrug-resistant Streptococcus pneumoniae isolates belonging to the PMEN1 clone"
Hiller NL, Eutsey RA, Powell E, Earl JP, Janto B, Martin DP, Dawid S, Ahmed, A, Longwell MJ, Dahlgren ME, Ezzo S, Tettelin H, Daugherty SC, Mitchell TJ, Hillman TA, Buchinsky FJ, Tomasz A, de Lencastre H, Sa-Leao R, Post JC, Hu FZ, and GD  Ehrlich
PloS One, 6(12): e28850, 2011

"Generation of genic diversity among Streptococcus pneumoniae strains via horizontal gene transfer during a chronic polyclonal pediatric infection"
Hiller NL, Ahmed A, Powell E, Eutsey R, Earl J, Martin D, Janto B, Boissy R, Hogg J, Barbadora K, Sampath R, Lonergan S, Post JC, Hu FZ, and GD Ehrlich
PLoS Pathogens, 16;6(9): e1001108, 2010

"Cellulosilyticum ruminicola, a newly described rumen bacterium that possesses redundant fibrolytic-protein-encoding genes and degrades lignocellulose with multiple carbohydrate-borne fibrolytic enzymes"
Cai S, Li J, Hu FZ, Zhang K, Luo Y, Janto B, Boissy R, Ehrlich G, and X Dong
Appl Environ Microbiol, 76(12): 3818-3824, 2010

"Insights into the Genome of Large Sulfur Bacteria Revealed by Analysis of Single Filaments"
Mussmann M, Hu FZ, Richter M, de Beer D, Preisler A, Jørgensen BB, Huntemann M, Glöckner FO, Amann R, Koopman WJ, Lasken RS, Janto B, Hogg J, Stoodley P, Boissy R, and GD Ehrlich
PLoS Biol, 5(9): e230, 2007

"Comparative genomic analyses of seventeen Streptococcus pneumoniae strains:  Insights into the pneumococcal supragenome"
Hiller NL°, Janto B°, Hogg JS, Boissy R, Yu S, Powell E, Keefe R, Ehrlich NE, Shen K, Hayes J, Barbadora K, Klimke W, Dernovoy D, Tatusova T, Parkhill J, Bentley SD, Post JC, Ehrlich GD, and FZ Hu
J Bacteriol, 189(22): 8186-8195, 2007

"Characterization and modeling of the Haemophilus influenzae core- and supra-genomes based on the complete genomic sequences of Rd and 12 clinical nontypeable strains"
Hogg JS, Hu FZ, Janto B, Boissy R, Hayes J, Keefe R, Post JC, and GD Ehrlich
Genome Biol, 8(6): R103, 2007

"Characterization, Distribution and Expression of Novel Genes Among Eight Clinical Isolates of Streptococcus pneumoniae"
Shen K, Gladitz J, Antalis P, Dice B, Janto B, Keefe R, Hayes J, Ahmed A, Dopico R, Ehrlich N, Jocz J, Kropp L, Yu S, Nistico L, Greenberg DP, Barbadora K, Preston RA, Post JC, Ehrlich GD, and FZ Hu
Infect Immun, 74(1): 321-330, 2006

"Identification, distribution and expression of novel genes in 10 clinical isolates of nontypeable Haemophilus influenzae"
Shen K, Antalis P, Gladitz J, Sayeed S, Ahmed A, Yu S, Hayes J, Johnson S, Dice B, Dopico R, Keefe R, Janto B, Chong W, Goodwin J, Wadowsky RM, Erdos G, Post JC, Ehrlich GD, and FZ Hu
Infect Immun, 73(6): 3479-3491, 2005


Contact Information


Research Office

Department of Microbiology & Immunology
245 N. 15th Street
14th Floor, Room 14305
Philadelphia, PA 19102
Phone: 215.762.1903
Fax: 215.762.1003