The Exhausted Immune Defence
Scientists from HZI unravel why immune cells tolerate bacteria during a chronic infection.
After an initial acute infection, Staphylococci can persist in our body for a long period of time leading to chronic disease. Scientists from the Helmholtz Centre for Infection Research (Helmholtz-Zentrum für Infektionsforschung, HZI) in Braunschweig, Germany, have revealed why the body's defense mechanisms fail to completely eliminate the bacteria during a chronic infection. The continuous confrontation with the pathogen makes a certain type of immune cell, the so-called T cells, from working properly – these cells become completely exhausted and can no longer recognize and fight the persistent bacterium. These results have been published in the latest issue of the scientific journal "EMBO Molecular Medicine".
Immunologists call this state of T cells fatigue "anergy" which means a lack of reaction to the infecting microbe. Generally, anergy is a protective mechanism for silencing autoreactive immune cells and prevents the immune defence from erroneously attacking our own body tissue, says Dr. Eva Medina, head of the HZI research group "Infection Immunology". Although it has been shown before that T cells can become anergic during chronic viral infections, it is a rather unusual event in the context of bacterial infections.
Staphylococci like the well-known strain Staphylococcus aureus are normal components of the bacterial flora harmlessly colonize our skin and body cavities such as the nose. This changes when S. aureus finds a way to invade and spread throughout our body, for example via a wound or skin cut, giving rise to severe complications including infections of the lungs, heart, bones and joints and other vital organs. In certain situations, these infections are refractory to antibiotic treatment producing chronic and recurrent infections.
Using a mouse model of S. aureus chronic infection that mimics the infection in humans, the researchers were able to show that during the early infection, the so-called acute phase, the immune defence functioned properly: “T cells recognized and combated the pathogen. But later on, the immune response became less and less energetic even though the bacteria are still present," says Christina Ziegler who investigated this theme in her PhD thesis. "The exhaustion of T cells and their incapacity to fight the pathogen marks the point when the infection starts to become chronic”.
The scientists have also tried to identify the molecular mechanisms responsible for the disability of the T cells to react during chronic infection. They found that a defect in the transmission of the cellular signals induced from the surface receptor after bacteria recognition impeded the activation response of the T cells. "We believe that during the chronic infection the continuous activation of T cells by the unremitting presence of bacteria provokes a disruption within the cell signalling circuits similar to an electrical short cut".
“If we know how to hamper the development of T cell anergy and keep them fully functional during staphylococcal chronic infection we will be able to develop new immunotherapies for the treatment of affected patients”.
Ziegler C, Goldmann O, Hobeika E, Geffers R, Peters G, Medina E. The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen-reactivity to in vivo anergy. EMBO Mol Med. 2011 Sep 2. doi: 10.1002/emmm.201100173. [Epub ahead of print]