Associate Professor, Biomedical Sciences
- Role of C-type lectin receptors in regulation of inflammation and myeloid cell function in bacterial pneumosepsis and chronic lung diseases
NIH COBRE P20
Pilot Postdoctoral Award (UND)
Funding (Recently Completed)
American Heart Association
AAI Careers in Immunology student fellowship
Dr. Anthony Steichen, PhD (Sept 2011-Oct 2015): Current Position: Technical Applications Specialist, BD Biosciences
Dr. Christopher Jondle, PhD (Sept 2012-Aug 2017): Current Position: Postdoctoral Fellow, Wisconsin Medical College
Dr. Atul Sharma (Assistant Professor Research)
Dr. Jitendra Tripathi (Postdoc)
Dr. Kuldeep Gupta (Postdoc)
Ms. Pooja Chauhan (Lab Manager)
Major focus of the lab research is Host-pathogen interaction, role of C-type lectin receptors and neutrophil function in regulation of inflammation in bacterial pneumonia, sepsis, CGD (Chronic Granulomatous Disease) and cigarette smoke exacerbation of COPD (Chronic Obstructive Pulmonary Disease). For our hypothesis driven research we work extensively with transgenic mouse strains as preclinical disease models as well as patient samples that we obtain through our collaborations with clinicians at the National Institutes of Health, Altru Clinic and the Department of Surgery at UND. The lab has various ongoing projects:
- Neutrophil extracellular Trap formation in pneumonia and Sepsis: Neutrophils are the first responders for combating pathological insults. A novel paradigm in neutrophil antimicrobial program is the formation of extracellular traps (Neutrophil Extracellular Traps, NETs), which are DNA fibrils expelled by these cells that can trap and kill extracellular microbes. We recently showed that Mincle, a C-type lectin receptor, regulates bacterial phagocytosis and Neutrophil Extracellular Trap (NET) formation during bacterial pneumonia. Based on these findings, we are currently engaged in identification and characterization of the molecular signaling pathways involved in Mincle-mediated neutrophil NET formation.
- Therapeutic modulation of NET formation: NETS play a protective antimicrobial function in a variety of infectious diseases. One the other hand, exuberant NET formation has been implicated in several inflammatory diseases including acute lunginflammation, myocardial infarction, vasculitis, rheumatoid arthritis, lupus, atherosclerosis, and Alzheimer’s. One of the projects in my lab deals with therapeutic modulation of NET formation, in order to harness their beneficial effects while avoiding their pathological consequences. In this regard, we have identified two compounds and a biomolecule that positively and negatively regulate NET formation. The goal of this project is to examine the therapeutic potential of these compounds and underlying mechanisms in treatment of infectious (pneumonic and neonatal sepsis) and sterile (chronic granulomatous diseases) inflammatory conditions.
- Pathogen induced modulation of neutrophil functions: Once the neutrophils complete their task of clearing the pathological insult, clearance of infiltrating immune cells and host cell debris is achieved by a process called efferocytosis which not only prevents the potential tissue damage caused by alarmins released from dead/dying cells but also promotes tissue repair. We showed for the first time that C-type lectin receptors (CLRs) play an important role in resolution of inflammation in Klebsiella infection induced pneumonic sepsis, possibly by facilitating neutrophil turnover via efferocytosis in lungs. We have also made novel observations of pathogen-mediated perturbations and modulation of these neutrophil functions eventuating in perpetuation of neutrophil-mediated inflammation and sepsis development. We are currently elucidating the molecular mechanisms of CLR-mediated efferocytosis as well as bacterial inhibition of efferocytosis in pneumonic sepsis.
- Mechanism of aberrant neutrophil function in COPD. Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of mortality worldwide. Accumulating evidence implicates increased influx and hyperactivation of neutrophil in sustained and damaging inflammatory response leading to obstructive airflow, emphysema and bronchitis in COPD. Cigarette smoke (CS) exposure is a major risk factor for development of neutrophilic inflammation and progression of COPD. The long-term objective of this project is to understand the mechanism of CS exposure-induced aberrant neutrophil function leading to chronic inflammation associated with COPD.
- Role of galectins as alarmins in Francisella-induced pneumonic sepsis. Another area of research in my lab is investigating the role of mammalian C-type lectins called galectins in induction of hyperinflammatory response during pulmonary Francisella infection. Francisella is the causative agent of life-threatening respiratory tularemia and has been listed by CDC as Category A select agent owing to the ease of its aerosolization and extreme virulence. Inhalation of as low as 10 bacteria can lead to a mortality rate of upto 60% in an untreated infection. Intriguingly, this pathogen is not known to produce any exotoxin, which can account for the lethality of this infection. We hypothesized that in the absence of any bacterial toxins, host endogenous molecules, called alarmins, released from dead or dying cells contribute to the inflammatory response culminating in sepsis development during respiratory infection with Francisella. Indeed, we recently showed that two β-galactoside binding lectins Galectin-3 and Galectin-9 play a pathogenic role as alarmins to exacerbate the inflammatory response during pulmonary infection with Francisella and contribute to sepsis development. We are currently exploring these galectins as potential target for treatment of inflammation during sepsis and other inflammatory conditions.
- Vaccination strategies for intracellular bacterial pathogens. Thus far there are no licensed immune therapies or vaccine strategies for prevention of Francisella infection. Studies in this direction in my lab are based on a novel approach of comparative analysis of immunodominant protein profile using sera from mice inoculated with attenuated but non-protective (AN) Francisella mutant strains versus attenuated and protective mutants (AP) of Francisella and test the protective potential of antigens recognized by AP but not AN sera. Using this approach we have identified several new vaccine candidate proteins. We are currently testing these proteins for their protective potential against this deadly infection.
Awards and honors and professional recognition
1. 2014: Early Career Faculty Travel Award, American Association of Immunologists
2. 2014: “Travel for Techniques” Award, American Association of Immunologists
3. 2016: Careers in Immunology Fellowship for graduate student, American Association of Immunologists
4. 2016: Co-Chair, Block Symposium “Bacterial and Parasitic Infection and Immunity 1”, AAI 2016, Seattle.
5. 2017: Co-Chair, Block Symposium: Tentative title “Innate Immune Signaling”, AAI 2017, May12-16, Washington D.C.
6. 2017-2021: Standing Member, NIH Study Section IHD
7. 2018: Plenary Speaker, Session IV: Bench to Bedside Translation of Therapeutucs-at the Crossroads of Immunity and Host Defense. 41st Annual Conference on Shock, Scottsdale, AZ