Dartmouth Medical School Professors of Microbiology and Immunology William Wade and George O’Toole recently proposed that Gram-negative bacteria can recognize antibodies and immune effectors in their hosts, allowing the bacteria to modulate their phenotypes and virulence accordingly. The researchers offer criteria for assessing phenotypic regulation in a new approach to protect against bacterial diseases. Their work was recently published in Trends in Microbiology.
Traditional immunology models have emphasized only the host’s response to bacterial infections. Pathogens are recognized by host receptors that bind to bacterial molecules and activate the immune system by mobilizing immune effectors (IE), which in turn, recruit immune cells and antibodies to the site of inflammation.
However, it is becoming more apparent now that just like the host’s immune system can recognize pathogens, bacteria can similarly sense the presence of antibodies and IE, alerting them to a hostile environment and allowing them to alter their pathogenic ability in response.
For example, bacterial membranes contain receptors with a high affinity for certain cytokines, signaling molecules secreted by the host’s immune cells to fight the infection, which allow for enhanced bacterial virulence. The researchers cited studies showing that patients who suffer from acute respiratory distress syndrome (ARDS) have high levels of bacteria and cytokines. Moreover, clinical samples displayed improved bacterial growth in the presence of high cytokine concentrations.
The article laid down a set of five criteria to establish the significance of antibodies and IE in regulating bacterial phenotype. These include the presence of specific receptors to bind the antibodies or IE; a signal transduction pathway that links binding with a bacterial response; induction of this bacterial response upon binding, such as altered transcription; regulation of the pathogenic potential or virulence of the bacteria; and the possibility of developing novel therapies to target antibodies or IE to decrease the ability of microbes to maintain a robust pathogenic phenotype.
“This new concept may represent a means to reduce disease and start to turn pathogens into commensals,” said Wade in an email to DUJS.
The article suggests that since cytokines cannot be targeted due to the vital role they play in the host’s defense system, outer membrane (OM) structures on bacteria are more practical targets for therapy. Antibodies derived from recombinant libraries can target the OM structures, resulting in phenotypes that lead to slower reproduction rates for bacteria and lower virulence. These antibodies may be delivered alone to the host or in conjunction with other antibiotics.
Future investigation may include finding all the probes that bind the OM structures of pathogens and mapping the signaling pathway networks in order to better manipulate bacterial cells. The researchers are also in the midst of developing another method that uses fluorescent proteins along with probes to better identify which antibodies are effective in changing cell phenotypes. Thus, this new paradigm conveying the ability of bacteria to alter its phenotype in accordance with their hosts’ immune response may present a powerful approach to counteracting diseases.