A Strategy to Overcome Group B Streptococcus Infections by Using a Vaccine that Mimics its Toxin
In our lab (@LabRajagopal), we study Group B Streptococcus (GBS), a Gram-positive bacterium that normally colonizes the female lower genital tract as a harmless member of the microbial community but can lead to severe infections during pregnancy, in newborns and in adults. Screening pregnant women for GBS and subsequent antibiotic therapy during birth has reduced the incidence of infection occuring within the first seven days of life, but these measures have little to no effect on preterm births, stillbirths or late-onset disease (disease occurring seven days after birth), and have no protective effect for infection occurring in adults. Notably, there is no FDA-approved vaccine to prevent GBS infections. A driving philosophy in our lab is that improved therapeutic strategies against GBS will arise from a greater understanding of the molecules this bacterium produces to cause disease.
GBS produces a range of molecules that allow these bacteria to deftly overcome a person’s immune response. One such molecule is the hemolytic pigment, also known as granadaene, which kills red blood cells and several other cells of the immune system. This toxin also helps GBS cross defensive barriers in the human body such as the placenta and blood-brain barrier. Compared to other bacterial toxins that act similarly, granadaene has an unusual structure. It is comprised of a long, unsaturated lipid flanked on one side with a rhamnose sugar and on the other side an ornithine amino acid (Fig. 1).
Due to granadaene’s instability and insolubility, structure-function studies have been limited, hindering our ability to completely understand how this toxin harms human cells and to devise therapeutic strategies against it. For the work presented in our recent paper in Nature Communications, we joined forces with an organic chemist, Dr. Juan Manuel Cuerva, and his group (@MOR_Fun_Group) at the University of Granada to come up with a solution for issues surrounding the insoluable grandaene. In collaboration with Dr. Cuerva’s group, we synthesized compounds similar to granadaene (hereafter called analogs) to understand which chemical components are important for its toxic activity. We found that compounds that had shorter polyene chains were less able to kill red blood cells, meaning the length of the polyene chain influences toxic activity of granadaene.
In addition to our structure-function studies, we were also curious to see if we could use the granadaene-inspired analogs to design a vaccine targeting granadaene. As granadaene is toxic to cells of the adaptive immune system ex vivo, this indicated that incorporating granadaene itself as a vaccine antigen may be unsafe and/or ineffective.
So, we turned to one of our non-hemolytic synthetic compounds, R-P4 (Fig. 2), with the idea that we may be able to elicit an immune response that could cross-protect against granadaene during GBS infection. After confirming that R-P4 was well tolerated by T cells and B cells, we put our idea to the test. We saw that mice vaccinated with R-P4 produced granadaene-binding antibodies with neutralizing properties and were protected against systemic infection with a GBS strain that over-produces the toxin.
Together, the work in this paper reveals the power of a collaborative, multidisciplinary approach in addressing key unanswered questions about GBS pathogenesis and anti-virulence factor vaccine strategies.
-- Lakshmi Rajagopal, PhD, Center for Global Infectious Disease Research