Tracking infectious diseases

Oct. 1, 2010

I nfectious diseases continue to be a major concern for public health globally. MLO asked Jeffery K. Taubenberger, MD, PhD, chief of the Viral Pathogenesis and Evolution Section in the Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) in Bethesda, MD, to provide an update and also discuss what he is working on here in the United States.

It has been estimated that at least one-quarter of annual deaths globally can be related directly to infectious diseases. While this burden is greater in the developing world, infectious diseases are still major causes of illness and death in the United States.

There are many prevalent infectious-disease problems that remain unsolved including, but not limited to, HIV/AIDS, tuberculosis (TB), acute gastrointestinal infections (e.g., noroviruses and rotaviruses) and acute respiratory infections (e.g., influenza and respiratory syncytial virus).

Also important is the rise in infectious agents that have developed resistance to one or more antimicrobial drugs. Examples include influenza viruses with resistance to both adamantane- and neuraminidase-inhibitor classes of antiviral drugs, and the increasing prevalence of antibiotic resistance in pathogenic bacteria (e.g., methicillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant Enterococcus [VRE]). Rapidly evolving resistance affects both individual care and outbreak control both within hospitalized patients and community-acquired infections.

Examining infectious diseases in new ways
Tremendous advances in microbiology, particularly virology, have occurred in the past decade including enhanced surveillance and full genomic sequencing of large numbers of viral isolates, initially with HIV but also now with influenza and other viruses.

Advances in sequencing technology have also been critical to the full genomic sequencing of a number of important bacterial and parasitic pathogens. Using these genetic sequences, new tools in computational biology and bioinformatics have made possible large-scale analyses of pathogen gene evolution.

Another key advance in virology has been the ability to produce infectious viruses entirely from cloned genes; this method is often referred to as reverse genetics. Using this technology, vaccine strains can be rapidly produced; and, experimentally, viruses can be produced to allow examination of the molecular basis of virulence, transmissibility, or antimicrobial resistance.

Advances in understanding innate and adaptive immune responses, including the reagents to examine the host response by gene expression arrays, proteomics, and many functional assays, have played key roles in helping to dissect how the immune response helps provide protection from a vaccine, help the infected person or animal recover from acute infection, or — paradoxically — how the immune response may actually contribute to disease development in some circumstances.

The next big disease threat
Influenza viruses pose a continual but ever-changing threat. It remains unclear whether the new pandemic H1N1 will cause the pre-existing seasonal influenza viruses (H3N2 and H1N1) to become extinct, whether it will co-circulate with them, or even possibly become extinct itself. “I remain confident, however, that influenza viruses will continue to pose a threat to both humans and animals,” Taubenberger maintains. The significance of seasonal influenza infections in humans is often underappreciated. On average, more than 36,000 people die annually after influenza infection in the United States.

Jeffery K.
Taubenberger, MD, PhD

The threat posed by highly pathogenic avian influenza H5N1 viruses remains. “While much attention was — rightly — placed on the novel swine-origin H1N1 pandemic in 2009, H5N1 viruses continue to cause high mortality in domestic poultry populations in several countries, and we continue to see human infections,” Taubenberger states.

While there have been only approximately 500 documented infections since 2003, about 300 of these avian influenza cases were fatal. Thus, a virus with a current 60% case fatality rate must continue to be considered a serious threat. “We remain at risk that this virus could adapt to humans with stable transmission. Of course, we also remain at risk from other novel, animal-adapted influenza viruses from other sources, as the swine-origin 2009 pandemic taught us.”

Since the recognition of HIV/AIDS approximately 30 years ago, it is clear that newly emerging or re-emerging infectious diseases continue to pose a significant threat to the global population. Novel pandemic influenza viruses and the SARS virus are examples of newly emerging infectious disease, while long-recognized re-emerging infections such as malaria and tuberculosis remain extremely important public-health threats globally.

Research studies underway
Taubenberger and his section's group at NIH are currently exclusively studying influenza viruses. This includes work on pandemic influenza virus strains, including the 1918 influenza, the 1957, 1968, and the 2009 influenza viruses, human seasonal influenza viruses, and influenza viruses from birds (avian influenza), swine, and horses. The group is engaged in a variety of research projects including

  • archaevirology (characterizing “fossil” influenza viruses from archival autopsy material);
  • studying the evolutionary dynamics of influenza viruses in different hosts and in host-switch events;
  • characterizing how influenza viruses adapt to new hosts;
  • mapping virulence factors in different influenza viruses and studying how host responses contribute to disease progression;
  • experimental therapeutics studies for treating severe influenza infection;
  • translational and clinical research involving influenza infections in humans in clinical trials; and
  • the development of molecular diagnostics assays for influenza virus detection and characterization.

Taubenberger is particularly fascinated by influenza A viruses. These viruses constitute a huge population of extremely diverse viruses, both genetically and antigenically, that are able to productively infect a wide variety of animal hosts, both avian and mammalian. “Influenza A viruses have a huge natural reservoir in wild birds. The role played by the different host species, their migration, and ecological patterns in the spread and persistence of influenza viruses is itself fascinating,” he says. “Even more so, however, is the incredible ability of influenza A viruses to infect novel species of birds and mammals, and adapt to stable transmission in these new hosts.”

It has been estimated that at least one-quarter of annual deaths
globally can be related directly to infectious diseases.

Influenza viruses are major pathogens of a number of agriculturally and economically important animal species, including chickens, turkeys, swine, horses, and dogs. While it is important to focus efforts on combating the occasional appearance in humans of a novel influenza virus derived from an animal source that can lead to a pandemic, it is also crucial not to neglect the importance of seasonal influenza virus infections that lead to more than 200,000 hospitalizations and more than 36,000 deaths each year in the United States alone.

Influenza viruses evolve at an incredible rate in response to different environmental pressures — switching animal hosts, responding to immunologic (antigenic) pressures and to antiviral drugs, and developing resistance mutations. Human-adapted influenza viruses cause annual outbreaks of seasonal influenza predominantly in the winter months, and circulating viruses evolve very rapidly to escape population immunity. “This is why the annual vaccine for influenza must be reformulated on an annual basis,” Taubenberger says. Issues relating to the immune response to influenza, and why prior infection does not give long-term cross-reactive antibody-mediated protection are another big problem.

Antiviral drug-resistance mutations are also rapidly developing in both seasonal and 2009 pandemic influenza virus strains. The mechanisms of drug-resistance development are of significant research interest but, on a broader level, point out the great need for novel strategies to treat influenza.

Final thoughts
Influenza A viruses can infect hundreds of species of wild and domestic animals as well as humans, and evolve in rapid and unpredictable ways. New strains continually emerge via a variety of genetic mechanisms. Developing strategies to combat influenza infection in humans and animals will take a concerted long-term strategy to enhance surveillance and advancements in basic and translational research to improve vaccine design and therapeutics strategies.



Karen Lynn is a freelance medical writer and editor.