Dr. Barbara Sherry’s laboratory investigates the biology of chemokines and their receptors. Chemokines are a class of secreted proteins that regulate cell movement and serve as the “traffic cops” of the immune system.  They play a critical role in host defense and immune system homeostasis. Studies in Dr. Sherry’s laboratory are focused on elucidating the biological role of these molecules in the host response to bacterial and viral infections and neoplastic disease. Ultimately, these studies will reveal mechanisms for controlling innate immune responses during infection to improve clinical outcomes.

 
Dr. Sherry’s research team has recently discovered that chemokine-mediated cell trafficking is globally impaired in patients who suffer from systemic infections and sepsis. This defective trafficking may contribute to the increased susceptibility to secondary infections, impaired wound healing and poor survival observed in these patients. Dr. Sherry’s laboratory is working to define the molecular mechanisms that trigger this impairment. These studies will lead to the identification of new targets for immune regulation and therapeutic intervention in this high-risk group. Dr. Sherry’s laboratory is also exploring whether defective cell trafficking in response to chemokines contributes to other clinical syndromes that are associated with increased susceptibility to infection, including end-stage renal disease.
 
Dr. Sherry and her colleagues are also studying how the body’s immune system responds to HIV infection. One of the reasons that AIDS is such a devastating disease is that the virus is able to evade or subvert many of those natural defense mechanisms and Dr. Sherry’s laboratory is trying to understand how the virus is able to do this so effectively. They have recently identified a previously unrecognized mechanism by which HIV type 1 (HIV 1) subverts host chemokine responses - a discovery that opens the door to the development of new therapeutic strategies to improve immune function in HIV 1-infected individuals. They are now collaborating with physicians at North Shore University Hospital’s division of Infectious Disease to determine if a similar phenomenon occurs in people infected with HIV.

Research Activities of the Laboratory of Cytokine Biology

The innate immune system is the first line of defense against invasive trespassers, including bacteria, viruses, parasites, and tumors.  Our laboratory has had a long-standing interest in the mechanisms that coordinate the innate immune response.  Early work led to the discovery of a novel set of heparin-binding chemoattractant molecules produced by cells in response to bacterial challenge, and the identification that those proteins were in fact members of a larger family of proteins, the chemokine family, whose actions are critical for both host defense and immune system homeostasis.  As with other inflammatory cytokines, though, we now recognize that excessive production of these same chemokine proteins and/or dysregulation of chemokine receptor expression can be detrimental, contributing to disease-associated pathology. Our ongoing research goal is to gain a better understanding of the molecular mechanisms that regulate chemokine and chemokine receptor responses.   Our efforts are concentrated in the following areas:

Chemokine Receptor Regulation in Inflammation, Infection, and Sepsis

In the context of bacterial infection, our studies focus on aberrant chemokine and chemokine receptor expression that contribute to tissue and organ damage early in infection, and host immunosuppression late in infection.  One of the principal complications of sepsis syndrome, a potentially lethal illness triggered by systemic bacterial infection, is increased susceptibility to secondary lung infections.  Macrophages are known to play an essential role in the resolution phase of pulmonary infection, and they are recruited to the lung by chemokine/chemokine receptor interactions.  Our studies have shown that exposure of macrophages to LPS, a major constituent of gram-negative bacteria, downregulates two chemokine receptors (CCR1 and CCR5), thereby markedly impairing the ability of affected cells to migrate in response to chemokine signals.  We are currently using dominant negative mutant, siRNA, and pharmacologic inhibitor strategies to elucidate the mechanisms that contribute to LPS-triggered downregulation of chemokine receptors in macrophages, and to establish a link between chemokine receptor downregulation and increased susceptibility to secondary infection.  We are also exploring the hypothesis that chemokine receptor impairment, which leaves leukocytes unresponsive to migratory signals critical for host defense, places septic patients at increased risk for developing secondary infections.  We have recently begun an NIH funded collaborative study with Drs. Dana Lustbader, Marcia Epstein, and Erfan Hussain to assess whether chemokine receptor expression is suppressed in circulating leukocytes isolated from septic patients, and if so, to evaluate whether this defect correlates with increased susceptibility to secondary lung infection.  The results gained from this study will improve our understanding of chemokine/chemokine receptor interactions within the context of sepsis, provide valuable insight into why inflammatory responses are impaired in septic patients, and encourage the development of new therapeutic strategies to prevent and to control secondary lung infections in sepsis.

Mechanisms contributing to impaired innate immune responses in end stage renal disease

Patients with end stage renal disease (ESRD), especially those on dialysis, are at increased risk for serious bacterial infections.  The early inflammatory response is decreased in dialysis patients and abnormalities in macrophage and neutrophil function contribute to their increased susceptibility to infection.  The cellular and molecular basis for the immune dysfunction observed in patients with ESRD is not fully understood.  Chemokine receptors are critical regulators of macrophage and neutrophil trafficking and activation state, and we are currently studying whether chemokine receptor expression and/or function is dysregulated in patients with ESRD, contributing to leukocyte dysfunction.  In collaborative studies with Dr. Howard Trachtman at Schneider Children’s Hospital, we have shown that ESRD is associated with reduced expression of the chemokine receptors CXCR1 and CCR2 on circulating neutrophils and monocytes, respectively.  Chemokine receptor impairment is most dramatic in a subpopulation of patients that have had three or more infections in the preceding twelve months.  We have further shown that reduced chemokine receptor expression on peripheral blood leukocytes results in failure of these cells to respond to chemokine-mediated trafficking signals.  These data provide a better understanding of the immune dysfunction involved in the pathogenesis of catheter-related infections in children with ESRD on dialysis, and may help identify a subset of patients at increased risk of developing serious bacterial infections.  We are now carrying out studies to determine the mechanisms that contribute to chemokine receptor dysregulation in ESRD.

Regulation of host antiviral β-chemokine responses in HIV-infected individuals

Paradoxically, chemokine receptors, critical for the transduction of intracellular signals that promote innate immune responses, are sometimes used by intracellular pathogens to facilitate their entry into cells and/or their transmission.  Seminal studies by others revealed that a subset of chemokine receptors function as co-receptors for HIV 1, and that chemokines (the natural ligands for one of the HIV-1 co-receptor CCR5) exert potent anti-viral effects in T cells, presumably through their ability to interfere with viral co-receptor usage.  Several recent reports indicate that chemokine responses are defective in HIV-infected individuals, although the molecular basis for this defect is not fully understood.  Our focus is on identifying mechanisms whereby HIV-1 manipulates host anti-viral β-chemokine responses to its own benefit and assessing whether dysregulated chemokine responses may underlie abnormal cellular trafficking in patients with AIDS. We have recently identified a previously unrecognized mechanism by which HIV type 1 (HIV-1) subverts the innate immune response- a discovery that opens the door to the development of new therapeutic strategies to improve immune function in HIV-1-infected individuals.  On another front, we are identifying potential mechanisms that negatively regulate β-chemokine receptor (CCR5) expression and inhibit HIV-1 infection.  In differentiated macrophages, an important cellular reservoir for the virus in vivo, we have shown that LPS activation markedly downregulates CCR5 receptor expression making these cells effectively resistant to HIV-1 infection.  This LPS-mediated down-regulation is independent of de novo protein synthesis and differs from the rapid turnover of CCR5 in response to its natural ligands. Our current work focuses on defining the underlying mechanisms (transcriptional blockade, post-translational modification, altered recycling, enhanced degradation), which lead to sustained downregulation of β-chemokine receptors in macrophages exposed to LPS, and characterizing the ramifications of this process for macrophage susceptibility to HIV infection.

Role of Chemokines in B Cell Chronic Lymphocytic Leukemia

B Cell Chronic Lymphocytic Leukemia (B-CLL) is a B-cell malignancy that is characterized by the accumulation of monoclonal CD5+ B cells in the blood and tissues.  Signals provided by the microenvironment are known to greatly influence the growth and survival of CLL cells.  Some of these conditioning signals are provided by chemokines, a family of chemotactic proteins that play a role in both host defense and immune system homeostasis   We are currently collaborating with Dr. Nicholas Chiorazzi and members of the CLL Research and Treatment Program at The Feinstein to better understand the role of chemokine mediated trafficking and survival signals in the growth and survival of CLL cells, and the factors that regulate the expression of chemokines within the leukemic microenvironment.

Ovarian Cancer Discovery Program

We are currently developing a collaborative discovery program to identify potential risk factors and early diagnostic markers for ovarian cancer.  In conjunction with the Tissue Donation Program, we are collaborating with Christine Metz, PhD, Peter Gregersen, MD, John Lovecchio, MD, and the members of the Department of Gynecology Oncology to collect important biological samples for this program.