The immune system, despite its immense complexity, really has only a few ways to kill bacteria.
Neutrophils and macrophages can capture and digest antibody-coated bacteria that live free in tissues and the bloodstream. Peptides—protein fragments—can punch holes in bacterial membranes or cross the membranes to disrupt bacterial processes. T cells can kill cells infected by bacteria.
Overall, T cells have been thought to focus mainly on viruses and play only a minor role in defending against bacteria, with neutrophils, macrophages, antibodies and antimicrobial peptides doing the lion’s share of antibacterial work.
“It’s one of the paradigms of immunology,” explained Judy Lieberman, professor of pediatrics at the HMS Immune Disease Institute and chair in cellular and molecular medicine at the Program in Cellular and Molecular Medicine at Boston Children’s Hospital, that “T cells protect against viruses, and other cells handle bacteria.”
When T cells do kill intracellular bacteria, it’s thought that they do it indirectly by eliminating the infected cells. Now, a paper by Lieberman reveals that T cells have a hitherto unnoticed way of killing intracellular bacteria directly. She found it because of HIV/AIDS.
Antimicrobial hole punch
Patients with HIV/AIDS, which knocks down T-cell counts, are highly susceptible to bacterial infections. That suggested to Lieberman that T cells must have an unknown method of killing bacteria.
To tease that method out, Lieberman and Michael Walch, now an assistant professor at the University of Fribourg, started with what was known about T cells’ response to intracellular bacteria.
When faced with an infected cell, T cells release cell-killing granules containing three kinds of proteins: perforins, which punch holes in cell membranes; granulysins, which open pores in the membranes of bacterial, fungal and parasite cells; and granzymes, which are enzymes that trigger the death of mammalian cells.
The granzymes get inside the cell and cut up proteins in mitochondria, interrupting cell metabolism. This causes mitochondria to produce toxic compounds called reactive oxygen species, which trigger the infected cell to kill itself through apoptosis, or programmed cell death.
Working with specially engineered mice, Lieberman and Walch found that there’s more to the story. As they reported in Cell, the pair discovered that granzymes attack and kill intracellular bacteria, such as Listeria monocytogenes, through a series of similar, but faster, steps.
First, perforin opens a path into the Listeria-infected cell. Then granulysin punches a hole into the membrane of the Listeria cell, enabling granzymes to get into the bacteria. Once inside, the granzymes do just what they do to cells’ mitochondria: They interrupt metabolism, triggering reactive oxygen species production and bacterial death.
Bacterial death starts within minutes and can take only half an hour. By comparison, it can take two hours for T cells to kill the infected cell. The timing of events seems to make sense; if an infected cell dies and the bacteria within it survive, they could be released and spread to other cells.
You can’t find what isn’t there
Why hasn’t this phenomenon of direct bacterial killing by T cells been noticed before? Lieberman cites the immunology field’s reliance on the mouse as an experimental model.
“Our immune system has evolved to fight our infections, not the ones that mice get,” she explained. “And mice don’t have granulysins.”
That means mouse granzymes normally have no way of getting into intracellular bacteria. So any experiments using mice with regular mouse immune systems would never reveal the enzymes’ direct effects. Lieberman and Walch had to rely on mice specially engineered to produce granulysin in order to tease out its effects.
Lieberman suspects there may be even more to the story. “We’ve only looked at one species of intracellular bacteria and haven’t really explored extracellular species,” she said. “There may be other T-cell antimicrobial peptides involved as well.”
She also thinks this mechanism could prove important for better understanding the immune system’s response to tuberculosis, a globally important intracellular bacterium that in many countries is closely associated with HIV/AIDS. It might also help provide new insights into how the body controls gut pathogens and highlight new targets for antibiotic development.
“This may be the beginning of a whole new field of study in immunology,” Lieberman said.
Adapted from an article in Vector, Boston Children’s Hospital’s science and clinical innovation blog.