Neel K. Krishna, Ph.D.

 ‌

Associate Professor

Department of Microbiology and Molecular Cell Biology

Lewis Hall, Room 3184
700 W. Olney Road
Norfolk, Virginia 23508
Office: (757) 446- 5677
Lab: (757) 446- 5645
Email: krishnnk@evms.edu

Dr. Krishna’s profile on Google Scholar

LinkedIn

ORCiD

My Bibliography (NCBI)


Teaching:

Biomedical Graduate Students

  • Introduction to the Research Literature
  • Biomedical Sciences Seminar (Journal Club)
  • Concepts in Research Design
  • Research Techniques
  • Advanced Molecular and Cellular Techniques
  • Current Topics in Molecular Biology
  • Animal Virology
  • Advanced Cell Biology
  • Advanced Proteomics
  • Biomedical Sciences Program Track: Molecular Integrative Biosciences (MIB)

Medical Students

  • Medical Microbiology and Immunology, Course Director
  • Foundations in Immunology, Co-Course Director

Education

  • PhD, Pennsylvania State University School of Medicine, Hershey, PA
  • Postdoctoral Fellow, The Scripps Research Institute, La Jolla, CA

Professional Positions

2011 – Present

  • Associate Professor
    Eastern Virginia Medical School
    Department of Microbiology & Molecular Cell Biology
    Department of Pediatrics

2003 – 2011

  • Assistant Professor
    Eastern Virginia Medical School
    Department of Microbiology & Molecular Cell Biology
    Department of Pediatrics

Lab Members

Brittany Lassiter

   

Brittany Lassiter

Masters Student

Phone: (757) 446-5645

Email: lassitbp@evms.edu

 


Research Interests

Keywords:  astrovirus, capsid/coat protein, peptide, inhibitor, complement, classical pathway, lectin pathway, C1q, MBL, Peptide Inhibitor of Complement C1 (PIC1).

I. Mechanistic study of astrovirus peptide inhibition of the complement system

My laboratory has traditionally studied the human astroviruses (HAstVs), a family of non-enveloped, icosahedral RNA viruses that cause gastroenteritis, predominantly in infants. Eight HAstV serotypes have been identified with a worldwide distribution. While the HAstVs represent a significant public health concern, very little is known about the pathogenesis and host immune response to this virus. Our research group, along with the laboratory of our collaborator Dr. Kenji Cunnion in the Department of Pediatrics, has demonstrated that HAstV-1 virions, specifically the viral capsid protein, suppress the complement system, a fundamental component of the innate immune response against pathogens in vertebrates. This is achieved by the capsid protein binding to the first component of the complement pathway, C1q and the related molecule MBL. Binding of C1q/MBL by capsid protein inhibits complement activation and its downstream effects (e.g., inflammation, cell lysis, phagocytosis, etc.). Our laboratory has recently isolated a highly potent peptide of 15 amino acid residues derived from the astrovirus capsid protein that mediates this complement suppressing activity. This peptide is termed Peptide Inhibitor of Complement C1 (PIC1). We are interested in determining the precise mechanism whereby PIC1 inhibits complement activation. Our working hypothesis of PIC1 inhibition of C1/MBL is illustrated below. Additionally, we are analyzing the role PIC1 may play in blocking the interaction of C1q/MBL with its cell surface ligands cC1qR (calreticulin) and gC1qR and the functional consequence of this activity on immune cell signaling.

 

A working model of PIC1 inhibition of C1q/MBL activation. In serum, C1q/MBL are associated with their cognate serine proteases (C1r2C1s2/MASPs respectively, shown as yellow sphere). Under normal conditions, C1q/MBL binds to an activator (aggregated antibody or directly to certain pathogens) via the globular heads (blue spheres) activating the serine proteases which leads to downstream activation of the complement system. PIC1 binds tightly to C1q/MBL conformationally altering the interaction of C1q/MBL with its respective serine proteases, thus preventing their activation. 

II. Therapeutic development of PIC1

Inhibition of the Complement System. A second area of interest for our laboratory is the development PIC1 as a therapeutic for complement-mediated disease. Whilst the human complement system represents a front-line defense against pathogens such as bacteria and viruses, its uncontrolled activation can lead to severe pathology in many different inflammatory and autoimmune disorders with an immune component such as systemic lupus erythematosis, rheumatoid arthritis, inflammatory bowel disease, ischemia-reperfusion injury (myocardial infarct, stroke), glomerulonephritis, adult respiratory distress syndrome, transplant rejection, graft versus host disease and burn injuries.

Complement is an extremely powerful immunological amplification cascade (avalanche) for killing infectious microbes. However, disregulated complement activity can also severely damage the host and is responsible for many inflammatory and autoimmune diseases in humans. PIC1 is a synthesized peptide designed to stop complement activation at the first step in the cascade.

Currently there are only two complement inhibitors on the market. Given the very potent inhibition of the astrovirus derived peptides on the complement system, we are currently interested in developing PIC1 into a therapeutic compound as a method for regulating aberrant complement activity. Recently published data from the Cunnion and Krishna labs demonstrates that this peptide can block ABO incompatibility in vitro (a classical pathway mediated disease) and inhibit complement activation in vivo. We are currently evaluating the efficacy of PIC1 in pre-clinical models of complement-mediated disease such as acute intravascular hemolytic transfusion reaction (ABO incompatibility) as a proof of concept for eventual therapeutic development for conditions such as hemolytic anemia of the newborn (fetal hydrops, newborn jaundice), sickle cell crisis, and generalized acute intravascular transfusion reactions.


PIC1 inhibits human red blood cell (RBC) lysis in vitro. In this example, human RBCs expressing A antigen have been exposed to incompatible recipient serum containing anti-A IgM. The bound IgM molecule is then recognized by serum complement C1 complex (C1q + C1r2C1s2). Upon binding IgM, C1 activates the classical pathway resulting in complement deposition on the donor cell and eventual clearance or lysis of host RBCs by the membrane attack complex (MAC). For clarity, only C1 binding and MAC formation are illustrated here. Data from our laboratory demonstrates that PIC1 inhibits classical pathway mediated destruction of the target RBCs added to human AB erythrocytes. Mauriello et al., 2013.

Antimicrobial Activity. In collaboration with Dr. Cunnion’s research team, we have recently determined that PIC1 possesses potent anti-microbial activity that appears to be independent of its complement inhibitory activity. We are currently pursuing the mechanism by which this novel ‘antibiotic’ exerts its effects.

Collaborators:

Kenji Cunnion, MD, MPH
Associate Professor, Department of Pediatrics, EVMS, CSG, CHKD, Norfolk, VA USA 

Frank Lattanzio, PhD
Associate Professor, Department of Physiological Sciences, EVMS, Norfolk, VA USA 

Tushar Shah, MD
Assistant Professor, Department of Pediatrics, EVMS, CSG, CHKD, Norfolk, VA USA

Jerry Nadler, MD, FAHA, MACP
Full Professor and Chair, Department of Internal Medicine, EVMS, Norfolk, VA USA

Nicole Thielens, PhD
Head of the Group “Immune response to pathogens and altered-self” and of the Team “Innate Immune proteins at the host-pathogen interface” at the Institute for Structural Biology (IBS), Grenoble, France

Lanne Maes, MD
Medical Director, American Red Cross, Norfolk, VA USA

Funding and Partnerships:

 

 

Patent Applications

Provisional application filed 27 June, 2015. Title: “Peptide inhibitors of complement with antimicrobial and complement inhibitory activity.” Inventors: Krishna NK and Cunnion KM.


Patents Granted

United States Patent 8,906,845. Issued: 9 December, 2014. Title: “Peptide compounds to regulate the complement system.” Inventors:  Krishna NK and Cunnion KM.

United States Patent 8,241,843. Issued: 14 August, 2012. Title: “Methods for regulating complement cascade proteins using astrovirus coat protein and derivatives thereof.” Inventors: Krishna NK and Cunnion KM.

United states Patent US 20080286294. Issued: 20 November, 2008. Title: “Nodavirus-VLPs Immunization Composition.” Inventors: Thiery R, Baud M, Cabon J, Cozien J, Lamour F, Lin CS, Krishna NK, Johnson JE and Schneemann A.