Journal Publication

Human Genetics and Emerging Infectious Diseases: Issues and Prevention Opportunities

by Janet M. McNicholl and James M. Hughes

Dr. McNicholl is a medical scientist in the Immunology Branch, Division of AIDS, STD, and TB Laboratory Research, NCID, CDC and an Assistant Professor of Medicine (Rheumatology) and Pathology at Emory University. Her interests include immunogenetics and T cell antigen recognition in infectious and autoimmune diseases. She also serves as the NCID coordinator for CDC human genetics activities and participated in the development of the CDC genetics strategic plan.

For many years, it has been known that host genes influence the differential susceptibility of individuals or populations to infectious diseases. Conversely, pathogens influence the genetic composition of human populations, often by selecting for persons resistant to the pathogens. Identifying the genes responsible for infectious disease susceptibility or severity of illness and how they interact with other risk factors may offer new opportunities for disease prevention. For example, the identification of the molecular basis of many of the rare single gene disorders that increase infectious disease susceptibility (e.g., primary immunodeficiencies such as adenosine deaminase deficiency) has led to new therapies such as gene therapy or bone marrow transplantation. However, advances in human genetics are also identifying genetic variants that do not result in genetic disorders, but do modify the infectious disease risk of individuals or populations, often through interactions with other risk factors.

The mapping of the 80-100,000 genes that constitute the human genome, as part of the human genome and related projects, is proceeding rapidly. Concurrently, the role of these genes in human biology and in determining disease risk is being defined. New laboratory tools, ever faster and more efficient computer-based technologies, and new epidemiologic approaches to studying complex human diseases are elucidating the relationship of these genes to disease. With each new discovery come new opportunities to prevent or treat disease.

This increasing knowledge and the emerging opportunities for prevention led CDC to develop a strategic plan for the agency to translate advances in human genetics into public health action. This plan emphasizes surveillance and applied research, genetic testing, program development and evaluation, and dissemination of information about genetics to the community. In relation to infectious diseases, these four areas of emphasis overlap with CDC's plan for Emerging Infectious Diseases, which emphasizes surveillance, research, prevention, and infrastructure strengthening. Translating knowledge about host genes and their relationship to emerging or reemerging infectious diseases into public health action will require increasing interaction between members of the public health community involved in host genetics and infectious diseases. One of the complexities of identifying risk factors for infectious diseases relates to the composite nature of affected or at risk populations. Genetic tools have the ability to stratify individuals or populations based on genotype, allowing more precise assessment of risk.

What is the state of our current knowledge about the relationship of human genes to infectious diseases? Many genes or loci have been identified that modify the risk or severity of many viral, bacterial, fungal and parasitic diseases. For example, certain chemokine receptor genotypes (e.g., the delta 32 CCR5 gene) provide protection against acquisition of HIV infection when present in the homozygous state, while delta 32 CCR5 heterozygotes, and persons with certain HLA (histocompatibility) types, once HIV infected, have a delayed progression to AIDS. HLA genes also influence the host's ability to clear hepatitis B infection, the severity of hantavirus illness, and the ability of human papilloma virus to induce cervical carcinoma. Persons with blood group 0 have a predisposition to very severe infection with Vibrio cholerae, while Vibrio vulnificus can cause a fatal septicemia in persons with iron overload due to hereditary hemochromatosis. HLA, macrophage phagolysosome (NRAMP1), and vitamin D receptor genes influence the susceptibility of persons to TB and other mycobacterial diseases.

Malaria provides a classic example of the ability of host genes to influence infectious disease susceptibility and severity. Malaria infection may be considered polygenic, in that genes of the chemokine receptor, HLA, and tumor necrosis factor families influence parasite entry into red blood cells or the severity of malaria infection, while disorders of red blood cell components (e.g., sickle cell trait, alpha-thalassemia or glucose-6 phosphate dehydrogenase deficiency) provide protection against the disease. Malaria and cholera have both influenced the genetic composition of peoples in regions where these pathogens are prevalent, as is the case with the high prevalence of some Duffy chemokine receptor, sickle cell or blood group genotypes in parts of Africa or Southeast Asia, respectively. Host genotype (e.g., certain blood group antigens of the Lewis family) also influences susceptibility to fungal infections such as recurrent candidiasis.

Less is known about the influence of host genes on responses to, efficacy of, or adverse events related to antibiotics or vaccines. However, host genotype (e.g., HLA or blood group genes) influence responses to hepatitis B, measles, cholera and Mycobacterium leprae vaccines, while HLA genes also determine the efficacy of a-interferon therapy for hepatitis C. Rare mutations of the receptor for gamma-interferon predispose to severe disseminated infection with bacille Calmette-Guerin following vaccination, as well as to recurrent infections with mycobacteria that are normally non-pathogenic. The rate at which individuals metabolize drugs such as isoniazid influences drug levels and is genetically determined by genes of the N-acetyl transferase system, which are associated with slow or rapid acetylator genotypes.

What is the current and what may be the future role of public health agencies in determining how host genes influence risk factors for emerging or reemerging infectious diseases? One role is to continue to identify other genes associated with risk of infectious diseases. The attributable fraction of each genotype and the interaction with other risk factors must then be determined. These goals can be accomplished through surveillance and applied research. Second, important aspects of genetic testing of persons or populations need to be resolved. These include ethical, legal, and social issues and the quality of genetic testing. Through education and dissemination of information about genes and infectious diseases, persons with genes that increase the risk of certain infections may be encouraged to alter behaviors that increase their risk of infection.

Public health agencies already play important roles in many aspects of the interaction between genetics and emerging infectious diseases. For example, through surveillance, public health agencies monitor the safety of blood products (e.g., immunoglobulins or plasma derived products) used in treatment of persons with heritable immunodeficiencies. By providing guidelines about vaccines and antibiotic use and through surveillance of antibiotic resistance, appropriate treatment and prevention strategies in persons with heritable disorders such as sickle cell disease or cystic fibrosis (who are more susceptible to certain bacterial infections) can be provided. Many groups worldwide are assessing the role of human genes in infectious diseases. At NCID, several emerging infectious diseases including HIV, malaria, acute liver disease, coccidiodomycosis, and hantavirus infections are the focus of host gene studies. Many of these studies involve collaborations with the Ministries of Health of other countries, CDC field stations in Africa (KEMRI at Kisumu in Kenya) and Thailand (HAC in Bangkok), academic centers in the US and overseas, state health departments, and managed care organizations.

Recently, NCID has sponsored sessions on the implications of advances in host gene and infectious disease research on public health at meetings including the International Molecular Epidemiology and International Emerging Infectious Diseases conferences and in a series of articles on host genes and infectious diseases in the Emerging Infectious Disease Journal (available at http://www.cdc.gov). These forums for information exchange encourage the translation of knowledge into public health action. CDC public information sources can be used to disseminate information about host genes and infectious diseases. For example, a fact sheet about HIV and the CCR5 genes was prepared in response to queries to the CDC AIDS hotline about the new findings; the fact sheet recommended that testing for the CCR5 gene not be done to determine a persons's risk of HIV infection or the course of their HIV disease, as some persons with the protective genotype can become HIV infected. NCID is also training public health professionals in aspects of genetics and infectious diseases through a new CDC career development awardee (CDA) program (information available at http://www.cdc.gov), in collaboration with the Association of Teachers of Preventive Medicine.

Model programs that involve interventions for persons with genotypes that predispose to infectious diseases are already in existence: the best example is sickle cell disease. At the other extreme, biological therapies such as cytokines or chemokines, or agents targeted to their receptors, are mainly in the developmental stage. They hold great promise and may become standard parts of the treatment armamentarium, as is already the case with a-interferon and hepatitis C. Gene therapy (e.g., for immunodeficiencies) is becoming more common as technologies advance. New vaccines that may be safer or more effective are being developed because of increased knowledge of the molecular structure of HLA and other molecules that influence host responses to pathogens. On the other hand, simple interventions such as reduction of iron-overload in persons with hereditary hemochromatosis or education of such persons about their increased risk of severe consequences of Vibrio vulnificus acquired through food, occupational, or recreational exposure, could have a great impact in reducing the burden of this and other infectious diseases. Future prevention opportunities will require the dissemination of genetic information to the public to ensure the translation of genetic knowledge into effective public health programs.