June 01--Physicians have known for years that vaccines do not work as well in people who are suffering from a chronic infection such as malaria. Likewise, people with one kind of chronic infection tend to be more vulnerable to a second one.
A new study led by University of Pennsylvania researchers fingers a key culprit in these breakdowns of the immune system: chronic inflammation.
The research, published last month in the journal Immunity, reveals how long-term inflammation from one infection impairs the ability of infection-fighting T cells to form memories of any additional invaders -- thereby hampering the immune system's ability to recognize and attack those invaders on future occasions.
The findings suggest that treating inflammation could be one way to improve the effectiveness of vaccines, particularly in developing countries where the underlying infection resists treatment, said Penn's E. John Wherry, who oversaw the research. The study's lead author, Erietta Stelekati, is a postdoctoral fellow in Wherry's lab at Penn's Perelman School of Medicine.
Among other results, the authors showed how inflammation caused certain genes to be improperly "turned on" in memory-forming T cells. These findings got a thumbs-up from a prominent physician: Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.
"This is an advance because this tells you what the molecular mechanisms are," suggesting potential treatments, Fauci said by phone.
Treating people with anti-inflammatory drugs would have to be done carefully, Wherry said. While too much inflammation impairs the immune system's ability to form memories, a certain amount of inflammation is needed to initiate the immune system's response to infection, said Wherry, director of the Institute for Immunology at Penn.
"Inflammation is a double-edged sword," he said.
Treating the underlying infections would be even better where feasible, and indeed, trials are underway in developing countries to treat parasitic worm infections so that vaccines work better. But some of these chronic infections, such as malaria and tuberculosis, can be resistant to treatment.
Wherry said the research also could have implications for older people, for whom vaccines, notably the annual flu shot, do not work as well as they do in the young.
As they age, seniors exhibit a gradual increase in their baseline levels of inflammation. Wherry said it is possible this systemic inflammation is part of the reason vaccines are less helpful in older people, but he said this hypothesis needs testing.
Among the coauthors of the paper were scientists from Drexel and Harvard Universities.
The researchers studied mice that were infected with three kinds of chronic infections -- two parasites and a virus. In each case, the mice developed fewer memory T cells against subsequent pathogens, and those memory cells also were less "mature," Wherry said.
The researchers then studied humans with chronic hepatitis C who also were infected with a virus called CMV, and found that the pattern of genetic expression in their T cells echoed what was seen in the infected mice.
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