This page has only limited features, please log in for full access.

Dr. Rajan Adhikari
Integrated Biotherapeutics, Rockville, MD 20878, USA

Basic Info

Basic Info is private.

Research Keywords & Expertise

0 Genetics
0 Antibody engineering
0 <em>Staphylococcus</em> spp., and other bacterial pathogens
0 Molecular pathogenicity
0 Vaccine and therapeutic development

Honors and Awards

The user has no records in this section


Career Timeline

The user has no records in this section.


Short Biography

The user biography is not available.
Following
Followers
Co Authors
The list of users this user is following is empty.
Following: 0 users

Feed

Editorial
Published: 18 May 2021 in Microorganisms
Reads 0
Downloads 0

In 1880, the Scottish surgeon Sir Alexander Ogston first described staphylococci in pus from a surgical abscess in a knee joint: “The masses looked like bunches of grapes”

ACS Style

Rajan Adhikari. Staphylococcal Infections: Host and Pathogenic Factors. Microorganisms 2021, 9, 1080 .

AMA Style

Rajan Adhikari. Staphylococcal Infections: Host and Pathogenic Factors. Microorganisms. 2021; 9 (5):1080.

Chicago/Turabian Style

Rajan Adhikari. 2021. "Staphylococcal Infections: Host and Pathogenic Factors." Microorganisms 9, no. 5: 1080.

Journal article
Published: 14 June 2019 in Toxins
Reads 0
Downloads 0

Staphylococcus aureus (SA) infections cause high mortality and morbidity in humans. Being central to its pathogenesis, S. aureus thwarts the host defense by secreting a myriad of virulence factors, including bicomponent, pore-forming leukotoxins. While all vaccine development efforts that aimed at achieving opsonophagocytic killing have failed, targeting virulence by toxoid vaccines represents a novel approach to preventing mortality and morbidity that are caused by SA. The recently discovered leukotoxin LukAB kills human phagocytes and monocytes and it is present in all known S. aureus clinical isolates. While using a structure-guided approach, we generated a library of mutations that targeted functional domains within the LukAB heterodimer to identify attenuated toxoids as potential vaccine candidates. The mutants were evaluated based on expression, solubility, yield, biophysical properties, cytotoxicity, and immunogenicity, and several fully attenuated LukAB toxoids that were capable of eliciting high neutralizing antibody titers were identified. Rabbit polyclonal antibodies against the lead toxoid candidate provided potent neutralization of LukAB. While the neutralization of LukAB alone was not sufficient to fully suppress leukotoxicity in supernatants of S. aureus USA300 isolates, a combination of antibodies against LukAB, α-toxin, and Panton-Valentine leukocidin completely neutralized the cytotoxicity of these strains. These data strongly support the inclusion of LukAB toxoids in a multivalent toxoid vaccine for the prevention of S. aureus disease.

ACS Style

Shweta Kailasan; Thomas Kort; Ipsita Mukherjee; Grant C. Liao; Tulasikumari Kanipakala; Nils Williston; Nader Ganjbaksh; Arundhathi Venkatasubramaniam; Frederick W. Holtsberg; Hatice Karauzum; Rajan P. Adhikari; M. Javad Aman. Rational Design of Toxoid Vaccine Candidates for Staphylococcus aureus Leukocidin AB (LukAB). Toxins 2019, 11, 339 .

AMA Style

Shweta Kailasan, Thomas Kort, Ipsita Mukherjee, Grant C. Liao, Tulasikumari Kanipakala, Nils Williston, Nader Ganjbaksh, Arundhathi Venkatasubramaniam, Frederick W. Holtsberg, Hatice Karauzum, Rajan P. Adhikari, M. Javad Aman. Rational Design of Toxoid Vaccine Candidates for Staphylococcus aureus Leukocidin AB (LukAB). Toxins. 2019; 11 (6):339.

Chicago/Turabian Style

Shweta Kailasan; Thomas Kort; Ipsita Mukherjee; Grant C. Liao; Tulasikumari Kanipakala; Nils Williston; Nader Ganjbaksh; Arundhathi Venkatasubramaniam; Frederick W. Holtsberg; Hatice Karauzum; Rajan P. Adhikari; M. Javad Aman. 2019. "Rational Design of Toxoid Vaccine Candidates for Staphylococcus aureus Leukocidin AB (LukAB)." Toxins 11, no. 6: 339.

Journal article
Published: 18 September 2018 in Toxins
Reads 0
Downloads 0

Cytolytic pore-forming toxins including alpha hemolysin (Hla) and bicomponent leukotoxins play an important role in the pathogenesis of Staphylococcus aureus. These toxins kill the polymorphonuclear phagocytes (PMNs), disrupt epithelial and endothelial barriers, and lyse erythrocytes to provide iron for bacterial growth. The expression of these toxins is regulated by the two-component sensing systems Sae and Agr. Here, we report that a point mutation (L18P) in SaeS, the histidine kinase sensor of the Sae system, renders the S. aureus Newman hemolytic activity fully independent of Hla and drastically increases the PMN lytic activity. Furthermore, this Hla-independent activity, unlike Hla itself, can lyse human erythrocytes. The Hla-independent activity towards human erythrocytes was also evident in USA300, however, under strict agr control. Gene knockout studies revealed that this Hla-independent Sae-regulated activity was entirely dependent on gamma hemolysin A subunit (HlgA). In contrast, hemolytic activity of Newman towards human erythrocytes from HlgAB resistant donors was completely dependent on agr. The culture supernatant from Newman S. aureus could be neutralized by antisera against two vaccine candidates based on LukS and LukF subunits of Panton-Valentine leukocidin but not by an anti-Hla neutralizing antibody. These findings display the complex involvement of Sae and Agr systems in regulating the virulence of S. aureus and have important implications for vaccine and immunotherapeutics development for S. aureus disease in humans.

ACS Style

Arundhathi Venkatasubramaniam; Tulasikumari Kanipakala; Nader Ganjbaksh; Rana Mehr; Ipsita Mukherjee; Subramaniam Krishnan; Taeok Bae; M. Javad Aman; Rajan P. Adhikari. A Critical Role for HlgA in Staphylococcus aureus Pathogenesis Revealed by A Switch in the SaeRS Two-Component Regulatory System. Toxins 2018, 10, 377 .

AMA Style

Arundhathi Venkatasubramaniam, Tulasikumari Kanipakala, Nader Ganjbaksh, Rana Mehr, Ipsita Mukherjee, Subramaniam Krishnan, Taeok Bae, M. Javad Aman, Rajan P. Adhikari. A Critical Role for HlgA in Staphylococcus aureus Pathogenesis Revealed by A Switch in the SaeRS Two-Component Regulatory System. Toxins. 2018; 10 (9):377.

Chicago/Turabian Style

Arundhathi Venkatasubramaniam; Tulasikumari Kanipakala; Nader Ganjbaksh; Rana Mehr; Ipsita Mukherjee; Subramaniam Krishnan; Taeok Bae; M. Javad Aman; Rajan P. Adhikari. 2018. "A Critical Role for HlgA in Staphylococcus aureus Pathogenesis Revealed by A Switch in the SaeRS Two-Component Regulatory System." Toxins 10, no. 9: 377.

Journal article
Published: 01 March 2016 in Journal of Immunological Methods
Reads 0
Downloads 0

An electrochemiluminescent (ECL)-based multiplex immunoassay using Meso-Scale Discovery (MSD) technology was developed for detecting antibody response toward 10 Staphylococcus aureus (S. aureus) exotoxins. These 10 antigens included three different groups of toxins: 1) single component pore-forming toxins such as alpha- and delta-hemolysins, 2) the bicomponent pore-forming toxin Panton–Valentine leukocidin (PVL), comprised of LukS-PV and LukF-PV subunits, and 3) enterotoxin/superantigens — Staphylococcal enterotoxins A (SEA), B (SEB), C1 (SEC1), D (SED), K (SEK) and Toxic shock syndrome toxin-1 (TSST-1). Assay development included optimization steps with a conventional SEB ELISA-based serological assay and then optimized parameters were transferred and re-optimized in a singleplex ECL format. Finally, two pentaplex solid-phase ECL formats were developed. As proof of concept, one set of pentaplex ECL data was compared with conventional ELISA results. During the assay development controls were screened and developed for both the singleplex and multiplex assays. ECL-based multiplex assays were more sensitive with a wide dynamic range and proved more time-efficient than conventional ELISAs. Using the newly developed ECL method we showed, for the first time, that delta-hemolysin toxin can induce an immune response as antibody titers could be detected.

ACS Style

Rajan P. Adhikari; Christian Haudenschild; Patricia M. Sterba; Sara Sahandi; Sven Enterlein; Frederick W. Holtsberg; M. Javad Aman. Development of a novel multiplex electrochemiluminescent-based immunoassay for quantification of human serum IgG against 10 Staphylococcus aureus toxins. Journal of Immunological Methods 2016, 430, 33 -42.

AMA Style

Rajan P. Adhikari, Christian Haudenschild, Patricia M. Sterba, Sara Sahandi, Sven Enterlein, Frederick W. Holtsberg, M. Javad Aman. Development of a novel multiplex electrochemiluminescent-based immunoassay for quantification of human serum IgG against 10 Staphylococcus aureus toxins. Journal of Immunological Methods. 2016; 430 ():33-42.

Chicago/Turabian Style

Rajan P. Adhikari; Christian Haudenschild; Patricia M. Sterba; Sara Sahandi; Sven Enterlein; Frederick W. Holtsberg; M. Javad Aman. 2016. "Development of a novel multiplex electrochemiluminescent-based immunoassay for quantification of human serum IgG against 10 Staphylococcus aureus toxins." Journal of Immunological Methods 430, no. : 33-42.

Research article
Published: 14 September 2015 in PLOS ONE
Reads 0
Downloads 0

S. aureus vaccine development has proven particularly difficult. The conventional approach to achieve sterile immunity through opsonophagocytic killing has been largely unsuccessful. S. aureus is highly toxigenic and a great body of evidence suggests that a successful future vaccine for this organism should target extracellular toxins which are responsible for host tissue destruction and immunosuppression. Major staphylococcal toxins are alpha toxin (a single subunit hemolysin) along with a group of bicomponent pore-forming toxins (BCPFT), namely Panton-Valentine leukocidin (PVL), gamma hemolysins (HlgCB and AB), LukAB and LukED. In our previous report, an attenuated mutant of LukS-PV (PVL- S subunit) named as “LukS-mut9” elicited high immunogenic response as well as provided a significant protection in a mouse sepsis model. Recent discovery of PVL receptors shows that mice lack receptors for this toxin, thus the reported protection of mice with the PVL vaccine may relate to cross protective responses against other homologous toxins. This manuscript addresses this issue by demonstrating that polyclonal antibody generated by LukS-mut9 can neutralize other canonical and non-canonical leukotoxin pairs. In this report, we also demonstrated that several potent toxins can be created by non-canonical pairing of subunits. Out of 5 pairs of canonical and 8 pairs of non-canonical toxins tested, anti-LukS-mut9 polyclonal antibodies neutralized all except for LukAB. We also studied the potential hemolytic activities of canonical and noncanonical pairs among biocomponent toxins and discovered that a novel non-canonical pair consisting of HlgA and LukD is a highly toxic combination. This pair can lyse RBC from different species including human blood far better than alpha hemolysin. Moreover, to follow-up our last report, we explored the correlation between the levels of pre-existing antibodies to new sets of leukotoxins subunits and clinical outcomes in adult patients with S. aureus bacteremia. We found that there is an inversed correlation between the antibody titer to sepsis for leukotoxins LukS-mut9, LukF-PV, HlgC, LukE and LukAB, suggesting the risk of sepsis was significantly lower in the patients with higher antibody titer against those toxins.

ACS Style

Rajan P. Adhikari; Thomas Kort; Sergey Shulenin; Tulasikumari Kanipakala; Nader Ganjbaksh; Mary-Claire Roghmann; Frederick W. Holtsberg; M. Javad Aman. Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs. PLOS ONE 2015, 10, e0137874 .

AMA Style

Rajan P. Adhikari, Thomas Kort, Sergey Shulenin, Tulasikumari Kanipakala, Nader Ganjbaksh, Mary-Claire Roghmann, Frederick W. Holtsberg, M. Javad Aman. Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs. PLOS ONE. 2015; 10 (9):e0137874.

Chicago/Turabian Style

Rajan P. Adhikari; Thomas Kort; Sergey Shulenin; Tulasikumari Kanipakala; Nader Ganjbaksh; Mary-Claire Roghmann; Frederick W. Holtsberg; M. Javad Aman. 2015. "Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs." PLOS ONE 10, no. 9: e0137874.

Review
Published: 04 March 2014 in Toxins
Reads 0
Downloads 0

Staphylococccus aureus represents one of the most challenging human pathogens as well as a common colonizer of human skin and mucosal surfaces. S. aureus causes a wide range of diseases from skin and soft tissue infection (SSTI) to debilitating and life-threatening conditions such as osteomyelitis, endocarditis, and necrotizing pneumonia. The range of diseases reflects the remarkable diversity of the virulence factors produced by this pathogen, including surface antigens involved in the establishment of infection and a large number of toxins that mediate a vast array of cellular responses. The staphylococcal toxins are generally believed to have evolved to disarm the innate immune system, the first line of defense against this pathogen. This review focuses on recent advances on elucidating the biological functions of S. aureus bicomponent pore-forming toxins (BCPFTs) and their utility as targets for preventive and therapeutic intervention. These toxins are cytolytic to a variety of immune cells, primarily neutrophils, as well as cells with a critical barrier function. The lytic activity of BCPFTs towards immune cells implies a critical role in immune evasion, and a number of epidemiological studies and animal experiments relate these toxins to clinical disease, particularly SSTI and necrotizing pneumonia. Antibody-mediated neutralization of this lytic activity may provide a strategy for development of toxoid-based vaccines or immunotherapeutics for prevention or mitigation of clinical diseases. However, certain BCPFTs have been proposed to act as danger signals that may alert the immune system through an inflammatory response. The utility of a neutralizing vaccination strategy must be weighed against such immune-activating potential.

ACS Style

M. Javad Aman; Rajan P. Adhikari. Staphylococcal Bicomponent Pore-Forming Toxins: Targets for Prophylaxis and Immunotherapy. Toxins 2014, 6, 950 -972.

AMA Style

M. Javad Aman, Rajan P. Adhikari. Staphylococcal Bicomponent Pore-Forming Toxins: Targets for Prophylaxis and Immunotherapy. Toxins. 2014; 6 (3):950-972.

Chicago/Turabian Style

M. Javad Aman; Rajan P. Adhikari. 2014. "Staphylococcal Bicomponent Pore-Forming Toxins: Targets for Prophylaxis and Immunotherapy." Toxins 6, no. 3: 950-972.

Journal article
Published: 17 July 2012 in The Journal of Infectious Diseases
Reads 0
Downloads 0

Background. Staphylococcus aureus has numerous virulence factors, including exotoxins that may increase the severity of infection. This study was aimed at assessing whether preexisting antibodies to S. aureus toxins are associated with a lower risk of sepsis in adults with S. aureus infection complicated by bacteremia. Methods. We prospectively identified adults with S. aureus infection from 4 hospitals in Baltimore, MD, in 2009–2011. We obtained serum samples from prior to or at presentation of S. aureus bacteremia to measure total immunoglobulin G (IgG) and IgG antibody levels to 11 S. aureus exotoxins. Bacterial isolates were tested for the genes encoding S. aureus exotoxins using polymerase chain reaction (PCR). Results. One hundred eligible subjects were included and 27 of them developed sepsis. When adjusted for total IgG levels and stratified for the presence of toxin in the infecting isolate as appropriate, the risk of sepsis was significantly lower in those patients with higher levels of IgG against α-hemolysin (Hla), δ-hemolysin (Hld), Panton Valentine leukocidin (PVL), staphylococcal enterotoxin C-1 (SEC-1), and phenol-soluble modulin α3 (PSM-α3). Conclusions. Our results suggest that higher antibody levels against Hla, Hld, PVL, SEC-1, and PSM-α3 may protect against sepsis in patients with invasive S. aureus infections.

ACS Style

Rajan P. Adhikari; Adebola O. Ajao; M. Javad Aman; Hatice Karauzum; Jawad Sarwar; Alison D. Lydecker; J. Kristie Johnson; Chinh Nguyen; Wilbur H. Chen; Mary-Claire Roghmann. Lower Antibody Levels to Staphylococcus aureus Exotoxins Are Associated With Sepsis in Hospitalized Adults With Invasive S. aureus Infections. The Journal of Infectious Diseases 2012, 206, 915 -923.

AMA Style

Rajan P. Adhikari, Adebola O. Ajao, M. Javad Aman, Hatice Karauzum, Jawad Sarwar, Alison D. Lydecker, J. Kristie Johnson, Chinh Nguyen, Wilbur H. Chen, Mary-Claire Roghmann. Lower Antibody Levels to Staphylococcus aureus Exotoxins Are Associated With Sepsis in Hospitalized Adults With Invasive S. aureus Infections. The Journal of Infectious Diseases. 2012; 206 (6):915-923.

Chicago/Turabian Style

Rajan P. Adhikari; Adebola O. Ajao; M. Javad Aman; Hatice Karauzum; Jawad Sarwar; Alison D. Lydecker; J. Kristie Johnson; Chinh Nguyen; Wilbur H. Chen; Mary-Claire Roghmann. 2012. "Lower Antibody Levels to Staphylococcus aureus Exotoxins Are Associated With Sepsis in Hospitalized Adults With Invasive S. aureus Infections." The Journal of Infectious Diseases 206, no. 6: 915-923.