Thursday, May 31, 2018

Broadly neutralizing antibodies take down bacteria, viruses, and yeast

Antibodies are an important player in the body's immune system. The job of an antibody is to recognize a very specific feature of a foreign protein, known as an epitope. Without high levels of epitope specificity, antibodies can often begin to bind to and attack self-proteins, leading to dangerous autoimmune reactions. By producing highly specific antibodies, the body can avoid these autoimmune disasters. However, this high level of specificity also means that antibodies typically only recognize one specific species or even sub-species of foreign invaders. Interestingly, a research group recently identified antibodies from healthy individuals that could recognize multiple subgroups of Klebsiella pneumoniae, as well as various other bacteria and even some yeasts and viruses. These “universal antibodies” have sparked a great deal of interest as a potential treatment option for patients suffering from infections.

K. pneumoniae is a species of bacteria that is found frequently in the environment and in people; it is estimated that over 1/3 of the world’s population is colonized by K. pneumoniae. In individuals with a healthy immune system, the level of bacteria is controlled, and illness does not occur. However, in immunocompromised and already-ill people, the bacteria can cause severe infections. Klebsiella are the third leading cause of hospital-acquired infections in the United States, with alarmingly high mortality rates: K. pneumoniae pneumonia can cause mortality in up to 50% of patients, and bloodstream infections can cause mortality in 20-30%. Equally concerning is the rising level of antibiotic resistance found in K. pneumoniae. This makes them increasingly difficult to treat.

K. pneumoniae (red).
CDC's Public Health Image Library.
Image # 18170; photo credit: NIAID.
The outer membrane of K. pneumoniae, and other bacteria, is covered in lipopolysaccharide (LPS) molecules. Because this molecule is exposed to the external environment, LPS serves as a good target for the immune system to produce antibodies against. LPS is made up of repeating sugar residues; in the case of the K. pneumoniae subgroups of interest in this research, that sugar is mannose connected by 1-2 or 1-3 linakages. Researchers identified a number of antibodies from the blood of healthy individuals that were highly efficient at neutralizing K. pneumoniae bacteria by binding to these mannose residues. Because mannose is a common surface sugar molecule and the mannose molecule arrangements used by K. pneumoniae are also used by other microbes, these antibodies had a very broad specificity. They bound not only K. pneumoniae, but also other intestinal microbes, HIV virions, and the yeast Saccharomyces cerevisiae

These antibodies open the possibility for their use as therapeutics. Giving pre-made antibodies to patients has already been established as an effective strategy to treat or prevent a number of infectious diseases, such as rabies, diptheria, tetanus, hepatitis B, and botulism. In the case of these infections, antibodies that are highly specific to the pathogen of interest have been made and used. However, the identification of these broadly neutralizing antibodies opens the door for a new opportunity. Giving a patient "universal" antibodies could help fight a variety of infections without even necessarily identifying the causative agent, which can be difficult and time-consuming in the face of a life-threatening infection. While it is a long process from antibody identification to the approved use of an antibody as a therapy in patients, this discovery provides researchers direction for the path ahead. Therapeutic advances that use alternative strategies to inhibit and kill pathogens are of the utmost importance in the current age of antibiotic resistance. Antibodies, instead of just antibiotics, that can fight disease will be one of the important tools in our arsenal against the ever-evolving microbes.