Pacific Center for Emerging Infectious Diseases Research
John A. Burns School of Medicine, University of Hawai'i at Manoa
Director: Dr. Richard Yanagihara

RESEARCH PROJECTS

Consistent with the thematic research focus on emerging infectious diseases, as well as on a cross-disciplinary approach aimed at disease prevention and control, the COBRE Research Projects span the disciplines of epidemiology and public health, microbiology and immunology, biobehavioral health, and biostatistics and bioinformatics. The microbial diseases being targeted for initial study will build research capacity, and will enhance capability to adapt and respond to the ever-changing landscape of emerging and re-emerging microbial threats.

Brenda Y. Hernandez, Ph.D., M.P.H.
Molecular Epidemiology and Natural History of Human Papillomavirus Infection in Heterosexual Men.

Aims of project:

• Determine the prevalence and incidence genital HPV infection in heterosexual adult men.
• Determine the relative transience persistence of genital HPV infection in heterosexual men.
• Determine the viral and host factors associated with prevalent, incident, transient, and genital HPV infection in heterosexual adult men.

HPV is a frequent cause of sexually transmitted infections and is the causative agent of most cervical cancers worldwide. Among women, HPV infection typically occurs shortly after first sexual intercourse, and the risk of infection increases with each new sexual partner. While the natural history and molecular epidemiology of HPV infection in women have been well characterized during the past two decades, men have been largely ignored in population-based research on HPV, despite the presumption that men serve as the major “vector” of HPV. Transmission of HPV between men and women is presumed to occur via direct physical contact between the infected penis and cervix during sexual intercourse. This premise has been challenged by the recent detection of HPV in semen and recent reports of the transmission of HPV to genitalia via fomites or other nonsexual modes. Clearly, well-conducted, longitudinal studies are urgently needed to accurately assess the magnitude and natural history of HPV infection among heterosexual men and to identify specific host and viral factors which influence penile HPV infection and the transmission of HPV from heterosexual men to their partners.

The availability of a well-organized infrastructure developed for an NIH-funded longitudinal-cohort study of HPV infection among women in Hawai‘i provides an optimal setting from which to conduct a well-designed, longitudinal study on the natural history and incidence of genital HPV infection in a multi-ethnic cohort of heterosexual adult men. Exfoliated cells, collected from the genitalia over a two-year period, will be analyzed for HPV DNA by PCR; and information will be gathered via an interviewer-administered survey on socio-demographic characteristics, as well as sexual history and practices, contraceptive use, sexually transmitted diseases (STD), and tobacco and alcohol use. The focus on heterosexual men in the natural history of HPV infection is innovative and addresses a major gap in current knowledge. New findings from this study will lead to improved prevention of HPV infection in both genders and ultimately to reduction in cervical cancer.?

Allison Imrie, Ph.D.
Immunopathogenesis of Dengue Virus Infection

Aims of Project:

• Determine the specificity and duration of dengue virus serotype 1-specific T-cell responses following primary infection, and assess T-cell reactivity following stimulation with heterologous dengue virus antigens.
• Characterize the proinflammatory cytokine responses of dengue virus-specific T cells by flow cytometry.
• Characterize the relationship between viremia, immune-activation markers, and T-cell responses following primary dengue virus infection.

Dengue fever, the most important mosquito-borne viral diseases of humans, has appeared as explosive epidemics throughout the tropics in recent years. Millions of cases of dengue fever and thousands of cases of the more severe form, dengue hemorrhagic fever (DHF), occur worldwide annually, primarily in southeast Asia, the Caribbean basin and South America. The case-fatality rate of DHF in most countries is 5%, primarily among children and young adults. Although dengue fever epidemics affecting thousands of individuals have been recorded in Hawai‘i during the past 150 years, the abrupt “re-emergence” of this mosquito-borne febrile illness in September 2001, initially on Maui with subsequent cases on Kauai and Oahu, after an absence of nearly 60 years, was totally unanticipated. The economic consequences of this relatively mild outbreak, with only 119 documented cases (none requiring hospitalization), was not trivial. An already ailing recreational-travel industry in the State of Hawai‘i, linked to a prolonged recession in Japan and elsewhere in Asia, and the aftermath of the tragic events of September 11, 2001, was further crippled by the dengue fever outbreak. Conservative estimates place the loss of revenue resulting from reduced tourist travel (particularly on Maui) in the many tens of millions. Thus, despite the successful containment of the epidemic through rapid institution of aggressive and extensive mosquito-control measures on all islands, including spraying with residual adulticides, house-to-house source-reduction campaigns, and public education of local residents and visitors, the dengue fever outbreak of the year 2001 had a major economic impact. Whether or not the dengue outbreak of 2001-2002 may be the harbinger of future epidemic activity of this disease-causing flavivirus in Hawai‘i remains to be seen. In the meantime, capacity building in arbovirology is urgently needed to re-establish research excellence in mosquito-borne viral diseases in Hawai‘i, in part also because of the real and present danger that West Nile virus presents to human health and the future survival of exotic, endangered native bird species. The re-emergence of dengue fever in Hawai‘i provides a unique opportunity to investigate the robustness and duration of cell-mediated and humoral responses among individuals with clinical disease and subclinical infection.

The more severe clinical manifestations of dengue virus infection are more common among individuals with prior immunity to a particular dengue virus serotype, who are subsequently infected with a different serotype. That is, secondary infection with a heterologous dengue virus serotype appears to enhance the cell-mediated immune response, thereby increasing the risk of developing DHF. To clarify the immunopathogenesis of dengue fever and DHF, Dr. Imrie will analyze the differential proinflammatory cytokine responses in peripheral blood mononuclear cells from patients with naturally acquired, primary dengue virus infection. In addition, she will examine the specificity and duration of dengue virus serotype 1-specific T-cell responses following primary infection, and characterize the relationship between viremia, immune activation, and T-cell responses. Dr. Imrie will focus initially on T-cell responses to dengue virus serotype 1, which was responsible for the recent outbreak of dengue fever in Hawai‘i. Subsequent studies will examine the role of serotype cross-reactive T lymphocytes in the immunopathogenesis of severe dengue virus infection elsewhere in the Pacific.

Guliz Erdem, M.D.
Molecular Epidemiology and Adhesion Properties of Group A Streptococci in Relation to High-Incidence Acute Rheumatic Fever in Hawai‘i

Aims of Project:

• Characterize the group A streptococci (GAS) in Hawai‘i and evaluate the epidemiologic factors that correlate with the high incidence of acute rheumatic fever (ARF) in native Hawaiians and other Polynesian ethnic groups.
• Assess the GAS pharyngeal carrier status in different ethnic groups, as well as the adhesion properties of GAS in carriers and patients with ARF and invasive GAS disease in Hawai‘i.

Infections caused by group A streptococci (GAS) result in a wide spectrum of diseases, ranging from relatively benign conditions (such as impetigo) to more severe invasive diseases and serious nonsuppurative sequelae (such as acute poststreptococcal glomerulonephritis and acute rheumatic fever or ARF). Approximately 25 to 35 million cases of GAS infections occur each year in the United States, with the most common manifestation being acute streptococcal pharyngitis in school-aged children. Up to 5% of these pharyngitis cases, if left untreated or if inadequately treated, can lead to ARF. While the incidence of ARF has declined dramatically in industrialized countries during the past several decades, ARF still remains the leading cause of acquired heart disease among children in developing countries. For unclear reasons, the overall annual incidence rate of ARF in Hawai‘i has remained approximately 40-fold higher than that on the continental United States, with Hawaiians and other Polynesian groups being over-represented.

Recent studies in geographic regions with very high incidence rates of ARF (such as among aboriginals in the Northern Territory of Australia) indicate that GAS belonging to the established rheumatogenic M serotypes are almost never encountered, suggesting that putative rheumatogenic factors may not be limited to the so-called rheumatogenic strains. Dr. Erdem’s preliminary data indicate similar findings in GAS isolates among ARF patients in Hawai‘i. That is, skin-associated and unusual M types of GAS have been identified in local patients with ARF and other invasive and non-invasive GAS diseases. She will take full advantage of this unique opportunity to identify the M serotypes which are prevalent among native Hawaiians and other Polynesian groups in Hawai‘i and identify those serotypes which are associated with ARF and other streptococcal diseases and their sequelae. Dr. Erdem will also determine the prevalence of GAS pharyngeal carriage in susceptible populations, and compare the adhesion properties of GAS from Polynesian groups with those from other communities. Collectively, newfound knowledge from this research will provide the basis for developing vaccines aimed specifically at preventing infections by the unique M types in Hawaii and the Pacific, leading to an overall reduction in the devastating health and economic consequences of ARF and other streptococcal diseases.