Research Feature

Microbes Versus Mankind

As humans and medicine evolve, so do the diseases we battle

by Amanda Leigh Mascarelli

Man in a mask

Suppose you lived in the mid-1800s in Cleveland, population 17,000. You likely wouldn't have ventured beyond the surrounding countryside, perhaps 10 to 20 miles at most, during your lifetime. Fast-forward to Cleveland today, population about 400,000. Air travel makes it possible to zigzag across continents and oceans in days, putting you—and the microbes you carry—in contact with tens of thousands of people at every stop. The impact this has on disease evolution is profound.

"I could get on the plane Monday, be halfway around the world in a day, become colonized or infected with a drug-resistant bacteria because I got exposed through food or a handshake, then bring it back to the United States and put it in an environment where it has no competition," says Robert A. Bonomo, MD, professor of medicine, pharmacology, molecular biology and microbiology at Case Western Reserve University School of Medicine and chief of medical service at the Louis Stokes Cleveland VA Medical Center.

Such globe-trotting is one of the many ways in which human behavior is radically changing the nature of the diseases we face. Bonomo and a handful of other researchers at Case Western Reserve are investigating how diseases are rapidly evolving as a result of globalization, modernization and the spread of Westernized medicine throughout the world.

Antibiotics and resistance: making "superbugs"

One of the most pressing problems facing medicine today is antibiotic resistance. Antimicrobial drugs have led to some of the greatest medical advances in history, making it possible to care for and save many sick patients. Yet bacteria's adaptability has proven great. "It's a struggle between us and the bacterial world; sometimes the bacteria win and sometimes we win," says Bonomo.

Antibiotics are commonly used to treat infections and to prevent certain types of complications of pregnancy. But Bonomo and others warn that antimicrobial agents are being over-prescribed and used when they are not beneficial, such as for treatment of viral infections and for situations when prophylaxis is not indicated. And when patients don't complete the entire course of antibiotics, harmful, resistant bacteria proliferate.

A particularly troublesome pathogen is Acinetobacter baumannii, notorious for its prevalence among troops wounded in Iraq and Afghanistan. A. baumannii, which originates in water and soil, evolved long before humans, but the unique conditions of wartime and excess antibiotic use have given it a foothold. Soldiers wounded in battle are evacuated to military facilities, where they sometimes contract the stubbornly resistant bug through open wounds and medical equipment. Soldiers then stop over at hospitals out of the country and in the United States on their return home, further disseminating the pathogen. Most strains of A. baumannii are 'multidrug resistant,' meaning they have acquired resistance to numerous types of antibiotics. "Acinetobacter is cunning: this pathogen keeps changing its face, acquiring resistance genes and finding new ones from the environment at a pace that's unbelievable," Bonomo says.

Another formidable pathogen is Staphylococcus aureus, a life-threatening microbe that has traditionally been a hospital-acquired infection. Now, dangerous antibiotic-resistant strains of the bacterium, methicillin-resistant Staphylococcus aureus (MRSA), are commonly contracted in community settings.

Bonomo and others at Case Western Reserve are working with collaborators in academia and the pharmaceutical industry to evaluate and develop new drugs, including beta-lactamase inhibitors, novel beta-lactams and new aminoglycosides--some of which are now in advanced clinical trials. Bonomo is also collaborating on making current anti-microbial drugs and drug combinations more effective. "Antimicrobial resistance to our current drugs is at a critical point," says Bonomo. "We have a few drugs that are in the pipeline. But it's a contentious race."

Additionally, Bonomo is working to implement tools that will make it possible to diagnose serious infections more rapidly. In one application, he is comparing the use of a microarray to conventional bacteria identification. In another, he has tested a novel method that uses polymerase chain reaction and mass spectrometry.

Research shows that excessive use of antibiotics also has the unfortunate effect of killing not only harmful germs, but also beneficial microbes that keep us healthy. This, in turn, allows unwanted invaders to move in and proliferate. Beneficial microbes not only keep harmful bacteria at bay, but they also help maintain healthy digestion, regulate metabolism and synthesize vital nutrients such as vitamin K, among other functions.

"We're much more bacteria than we are human, in terms of the amount of DNA in us," says Jonathan Stamler, MD, director of the Institute for Transformative Molecular Medicine and the Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor in Cardiovascular Innovation at the Case Western Reserve University Cardiovascular Center and University Hospitals (UH) Case Medical Center. "They have a function, a purpose--we've evolved to benefit one another. One way we benefit is that when good bugs are there, other bugs can't take up residence. It's better to have bugs that don't hurt us than bugs that do." But studies suggest that when resident microbes are replaced by harmful, resistant germs as a result of antibiotic use, the 'good' bugs don't always recover.

Stamler is investigating how a natural molecule could be harnessed to help patients counter drug resistance to a common, hospital-acquired pathogen, Clostridium difficile. The bug, which causes diarrhea and can lead to serious illness and death, secretes a toxin, which it uses to make its host--humans--very sick. Stamler and his colleagues discovered a "souped-up derivative of nitric oxide," S-nitrosoglutathione, that has evolved to trap and inactivate these toxins and that could soon be used as a therapeutic treatment for C. diff. infections.

Poverty and overcrowding: Proliferating TB

Antibiotic resistance is also a growing problem for the treatment of tuberculosis (TB), an often-lethal respiratory infection that is transmitted from person to person, particularly where people live in crowded quarters. Illness from TB is rare in the United States, but experts estimate that a third of the world's population is infected with TB (though only a fraction of people who are infected get sick).

TB has a high cure rate if antibiotics are taken properly for the entire course of treatment, which usually consists of four antibiotics taken over six months. But patients often begin feeling better within weeks of starting treatment and then discontinue use of the antibiotics, says W. Henry Boom, MD, a professor of medicine and director of the Tuberculosis Research Unit at the medical school and UH Case Medical Center. Another challenge is that in some developing countries, patients often do not have access to all of the required drugs. "There's still a huge problem in many parts of the world where TB is just not being treated because of poverty and poor access to care, and the countries are not doing well enough at delivering the drugs," says Boom. "This results in the emergence of highly resistant, so-called MDR and XDR, strains of TB."

Tuberculosis Research Unit investigators are working to develop novel drug therapies, better diagnostics and improved vaccines for TB by combining new technologies in molecular and systems biology with carefully designed clinical trials and observational studies in TB-endemic countries such as Uganda, South Africa, the Philippines, Brazil and Morocco. But, Boom laments, "the dirty secret is that TB is part of the vicious cycle of poverty and crowding, and poverty and crowding are not going away any time soon in our world."

Close to nature: jumping across species

Since the dawn of humanity, we have been altering the path of infectious diseases that make their way from animals to humans over evolutionary time. "Most infectious agents that we deal with are ultimately of animal origin," says James Kazura, MD, professor of international health and medicine and director of the Center for Global Health and Diseases. HIV, Ebola virus, West Nile virus and SARS (Severe Acute Respiratory Syndrome) all travel through animals. As the world population grows and people live in increasingly crowded communities and continue to infringe on remote areas with large wildlife populations, we will continue to face new infectious diseases, says Kazura.

Kazura studies Rift Valley Fever virus, which is transmitted to livestock by mosquitoes, then passed to humans when they come into contact with infected animal tissues. An epidemic in Kenya in 2006-2007 sickened hundreds and resulted in more than 100 deaths. Kazura, along with assistant professor Amy Hise, MD, and other colleagues, is working to understand human genetic susceptibility to the virus and why it kills some people, results in blindness in others, and leaves those more fortunate with only mild illness.

Their studies in biologic models have shown that early inflammatory responses seem to play an important role in disease severity. Furthermore, there appears to be individual differences in ability to generate those inflammatory responses, which help to fight off the virus and limit clinical outcomes. The research team has collected about 1,000 blood samples from the affected population to examine the association between exposure, variance of antibody response and clinical outcome. They hope to determine if there is a genetic component to that variation.

Though the challenges of emerging infections are daunting, Kazura says that bioinformatics and new genomic approaches are transforming researchers' abilities to study animal viruses and predict the potential life cycles of others that haven't yet made the leap from animals to humans. In the case of Rift Valley Fever virus, Kazura's team is using methods such as quantitative trait loci, or QTL, to help better detect patterns of genetic polymorphisms and phenotype variances in regards to infection severity. As many human characteristics are influenced by more than one gene, this research approach is a recent advancement for immunology. "It really increases our ability to make a precise diagnosis and gain insight as to what this might be like in terms of controlling it or treating it," says Kazura.