Research Profile: Charles Cook, MD

Charles Cook, MD

Associate Professor of Surgery, Harvard Medical School

Chief of Acute Care Surgery, Trauma, and Surgical Critical Care, BIDMC

Research Group

Thomas Marandu, PhD

Research Focus

Most people are infected with multiple herpes family viruses. Unlike many viral infections, these viruses are not eradicated from the host, but become dormant in the host’s tissues for their lifetime. During periods of immune compromise or stress, these viruses can reactivate. It is understood that herpes family viral reactivation is pathologic in immunocompromised people, such as transplant recipients or AIDS patients. My laboratory has been focused on defining the impact that these persistent viral infections have on immune competent hosts.

During the past 20 years, we and others have confirmed that these viruses can reactivate during critical illness. Of the family, cytomegalovirus (CMV) reactivation has been associated with worsened outcomes. My laboratory spent our early years of funding defining mechanisms by which CMV reactivation might be triggered using murine models to test our hypotheses. This transitioned to understanding the consequences of such reactivations; specifically how CMV reactivation might harm an immune competent host.

We identified the lungs as a potential target for CMV reactivation, and showed that reactivation is associated with lung injury during bacterial sepsis, something that we named CMV-ALI (cytomegalovirus associated acute lung injury). Clinical outcomes support this hypothesis, with roughly doubled durations of mechanical ventilation required for patients with CMV reactivation. Perhaps most importantly, our work showed that such reactivation events (and their attendant lung injury) can be prevented by antiviral prophylaxis. These results have been foundational to several clinical trials (two completed, one ongoing) that are beginning to corroborate these experimental observations.

Our current focus is to try to understand the mechanism of CMV-ALI. CMV infection/latency makes a lasting imprint in the immunity of its host, leaving CMV-latent hosts with exaggerated immune potential in their lungs. This means that when they encounter bacterial infections (like pneumonia or sepsis) they are more prone to inflammation and lung injury. We are currently evaluating different immune cell populations to understand their individual contributions to CMV-ALI. Our most recent work, done in collaboration with Drs. Carl Hauser, Michael Yaffe, Leo Otterbein, and the HALO group at BIDMC, suggests that neutrophils may play a pivotal role in these exaggerated immune responses.
 
Because we have a robust understanding of CMV biology, and have an animal model, we have been fortunate to develop numerous collaborations with colleagues in overlapping fields. We are currently supported for work with Dr. Antonio Chiocca’s group at Brigham and Women’s Hospital, studying the interactions between CMV and glioblastoma. Our current results have confirmed a contributory role of CMV to progression of this deadly brain tumor. More importantly, we are defining mechanistic pathways that should lead to novel therapies. We have also begun early collaborations with Dr. Richard Cummings at BIDMC to understand how CMV infection impacts cellular protein glycosylation.

Accomplishments 2016-17

Named Chair of Strategic Planning Committee for Surgical Infection Society

Invited Lectures:

  • Cost and Consequences of Surgical Infections; 36th Annual Meeting Surgical Infection Society, May 18, 2016
  • Impact of Latent Herpes viruses on Host Immunity; 14th Annual Advances in Inflammation Research, Alpert Medical School of Brown University, Providence RI, October 6, 2016
  • Catheter associated blood stream infections: The quest for zero; American College of Surgeons Clinical Congress, San Diego CA, October 24, 2017
  • Geriatric Injuries: Are rib fractures lethal in the elderly? Harvard Medical School Trauma and Critical Care Symposium, Boston, MA, November 21, 2017
  • Surgical Infections: We need to start thinking differently; Department of Surgery Grand Rounds, VA Medical Center, Boston, MA, December 15, 2017

New Memberships:

  • Boston Surgical Society
  • New England Surgical Society

Teaching, Training, and Education

Marion Griessl and Michael Gutknecht successfully completed their post-doctoral training in my laboratory in 2016 and 2017 and have returned to Germany. Thomas Marandu joined my laboratory from Tanzania to begin his postdoctoral studies in 2017.

Selected Research Support

NIH RO1 CA195532, Investigating the cytomegalovirus link to glioblastoma using a novel mouse model; NIH, 2015-2020; Co-Investigator (10% effort)

Selected Publications

Mansfield S, Dwivedi V, Byrd S, Trgovcich T, Griessl M, Gutknecht M, Cook CH. Bronchoalveolar lavage to detect cytomegalovirus infection, latency, and reactivation in immune competent hosts. J Med Virol 2016;88(8):1408-16.

Trgovcich T, Kincaid M, Thomas A, Griessl M, Zimmerman PD, Dwivedi V, Bergdall V, Klenerman P, Cook CH. Cytomegalovirus reinfections stimulate CD8 T-memory inflation. PLOS One 2016;11(11):e0167097
Griessl M, Gutknecht M, Cook CH. Determination of suitable reference genes for RT-qPCR analysis of murine Cytomegalovirus in vivo and in vitro. J Virol Methods 2017;248:100-106.

Celestin AT, Odom SR, Angelidou K, Evans S, Coimbra R, Guidry CA, Cuschieri J, Banton KL, O'Neill PJ, Askari R, Namias N, Duane T, Dellinger EP, Sawyer R, Cook CH. Novel method suggests global superiority of short duration antibiotics for intra-abdominal infections. Clin Infect Dis 2017;65(9):1577-1579.