Impact

Ongoing Projects


Title: Active Dengue Surveillance and Predictors of Disease Severity in Maracay, Venezuela and Iquitos, Peru.


Collaborating Investigator: LCDR Tadeusz J. Kochel, Ph.D., Director Virology Program, NMRCD-Peru.


Significance

Dengue is one of the most important emerging tropical diseases whose resurgence is closely tied with population growth, urbanization and air travel. There are four closely related serotypes of dengue virus in the genus Flavivirus, family Flaviridae, and they cause more morbidity and mortality in humans than any other arboviral disease in the world today. All 4 serotypes cause disease in humans, and frequently co-circulate (hyperendemicity). Worldwide, estimates indicate that 50 to 100 million people are infected with dengue each year and between 250,000 and 500,000 dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) cases occur each year, with case fatality rates between 1 and 5%.


Alarmingly, the incidence, distribution and severity of dengue in the Americas have dramatically increased in the last 25 years. In 1981, a major outbreak of dengue-2 virus in Cuba resulted in over ten thousand cases and 158 deaths due to DHF/DSS. A prolonged outbreak of DHF/DSS occurred in Venezuela from October 1989 until April 1990 leading to over six thousand DHF cases and 73 deaths. From 1990 to 1995 more than 26,000 cases of DHF were documented in the Americas.


Humans are infected with dengue viruses by the bite of an infective mosquito, with Aedes aegypti being the principal vector. After infection, the virus undergoes an incubation period of ~4-7 days, after which the person may present acute onset of fever accompanied by a variety of nonspecific signs and symptoms. During this acute febrile period, which may be as short as 2 days and as long as 10 days, dengue viruses may circulate in the peripheral blood. Important risk factors influencing the disease severity include the strain and serotype of the infecting virus and the immune status, age, and genetic background of the human host.


Goals and Objectives

The study goal is to identify plasma protein patterns associated with the development of DHF. From these proteins, we will generate robust predictors of disease severity based on initial plasma protein measurements.




Title: Biomarkers of Helicobacter pylori associated peptic ulcer disease


Collaborating Investigator: David Y. Graham, M.D., Professor of Medicine, Baylor College of Medicine.


Significance

Helicobacter pylori (Hp) is an emerging bacterial pathogen that colonizes the human gastroduodenal mucosa in more than half of the world's population. This Gram-negative bacterium is etiologically linked to gastritis and peptic ulcer disease (PUD). PUD results in a significant burden in morbidity, mortality and health care costs. Annually in the US, PUD affects 5 million people resulting in 1 million hospitalizations and 6,500 fatalities. More than 85% of cases of PUD are due to infection with Hp. According to the CDC, the annual health care costs associated with PUD in the US are estimated at $6 billion. In most cases Hp infections remain latent with only about 20% ever developing clinical disease such as PUD. Approximately 25% of those with PUD suffer a serious complication such as major bleeding. The availability of reliable biomarkers of disease that may be easily accessible would facilitate early intervention which would in turn result in significant reductions in morbidity and mortality associated with PUD.


Goals and Objectives

The study goal is to identify candidate biomarkers or biomarker panels present in the sera of Hp-infected individuals that could be used for early diagnosis and treatment of PUD. These findings can be used clinically to indicate the presence of PUD without invasive testing or assessing treatment response.




Title: Prognostic Plasma Markers of Progression to Severe Disease in Dengue Virus Infection


Collaborating Investigator: Nikos Vasilakis, PhD, Galveston National Laboratory, Dept of Pathology, UTMB, Galveston, Ernesto Marques Jr, MD, PhD, Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, Fundação Oswaldo Cruz, Centro de Pesquisas Aggeu Magalhães, Cidade Universitaria, Recife, PE - Brasil.


Significance

The goal of our research is to better understand the mechanisms that allow progression to severe disease during infection with dengue virus (DENV). One of the proposed mechanisms of DENV virulence, antibody-dependent enhancement (ADE), is based on epidemiological and experimental observations where secondary infection with a heterotypic DENV is often associated with increased risk in developing severe disease due to existence of non-neutralizing heterologous antibodies. However, epidemiologic and genetic studies have indicated that intrinsic viral factors (i.e. specific genotypes and/or serotypes, viral structures, etc) may also be important indicators of DENV virulence.
Understanding the inherent host- and virus-related factors and the underlying mechanisms responsible for progression to severe disease during DENV infection has major public health implications. Although severe dengue disease may be primarily prevalent in pediatric populations, recent epidemiologic evidence suggests that adult populations are at equal risk. Although the economic burden of severe disease may be different among the affected populations, the overall cost and disability-adjusted life years (DALYs) lost are significant. Therefore identification and characterization of host predictive biological markers for dengue virulence will allow us to develop successful countermeasures - such as vaccines, therapeutics, diagnostics - and significantly reduce the overall burden of disease in hyperendemic countries. The aim of this proposal is therefore to identify and characterize host predictive biological markers that are essential in assessing the risk of progression to severe dengue disease.


Goals and Objectives

We propose to prospectively investigate the nature and breadth of host predictive biologic markers (biomarkers) responsible for progression to severe dengue disease. Our research will initially focus on human sera obtained from a well-characterized dengue patient cohort from Recife, Brazil. The projected outcome of this proposal will broaden the breadth of our understanding of the underlying mechanisms responsible for progression to severe disease during DENV infection. Most profoundly, our results will improve predictions of the risk of severe dengue disease following DENV infection in susceptible human populations in hyperendemic countries.




Title: AsTeC Pre-proposal to Identify Biomarkers of Invasive Aspergillosis


Collaborating Investigator: John R. Wingard, M.D.,University of Florida Shands Cancer Center, Barbara D. Alexander, M.D., M.H.S., Duke University Medical Center, Durham, NC 27710.


Significance

Candida and Aspergillus are the two most common invasive fungal pathogens in hospitalized patients in the United States (U.S.). They cause considerable morbidity and case fatality rates are high in immunocompromised patients. For Candida, effective therapeutics have quelled the threat to life for many, but for Aspergillus, mortality rates continue to rise. For Invasive Aspergillosis (IA), diagnosis is difficult. effective control occurs in only half of infected patients, and control rates are even worse in certain highly immunocompromised patient groups. Deaths due to IA in U.S. hospitalized patients have mounted10 and costs to the U.S. health care system are enormous with incremental costs per IA case estimated to range between $30,000 - $100,000, depending on the underlying disease condition. Aspergillus accounts for the most deaths due to mold pathogens and is among the top 3 fungal killers in the world.
The lack of accurate diagnostics for Aspergillus is the most important unmet need in clinical mycology. IA is most commonly initiated by inhalation of ubiquitous, airborne fungal spores that establish a primary pulmonary disease and which can relatively quickly disseminate via the blood to involve multiple organ systems. Despite hematogenous dissemination, fungal blood cultures are rarely positive and the form of the pathogen that circulates in the blood in disseminated infection is not known. It is hoped that new diagnostic assays will offer a more accurate and earlier diagnosis resulting in earlier therapy and improved outcomes.


Goals and Objectives

The principal goal of this project is to determine if pathogen and/or host response proteins can be identified in clinical samples which can be used as specific biomarkers of IA in future diagnostic tests. Secondary goals are to determine how early in the course of IA these biomarkers can be found, whether protein signatures can be identified as markers of treatment response, and whether different protein signatures are characteristic of different IA infection sites.








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