Role of the Adenylate Cyclase cyaB and the Cyclic AMP Signaling Pathway at the Borrelia burgdorferi Host-Pathogen Interface
Abstract
Borrelia burgdorferi, a bacteria, is the cause of the most common tick-borne illness in the United States, Lyme disease. Lyme disease affects over 300,000 people each year, with the number of cases steadily rising. This is a multiple stage disease that causes severe inflammation in a variety of tissues resulting in patients experiencing a poor quality of life. Symptoms of localized Lyme disease are general flu-like illness and a painless bullseye rash, called an erythema migrans, at the site of the tick bite. The bacteria disseminate from the tick bite through the blood and lymphatic system to colonize specific tissues, like the joints, heart, and central nervous system, resulting in debilitating arthritis and cardiac and neurologic complications, respectively. Antibiotic treatment is highly effective when the B. burgdorferi is localized to the site of the tick bite but during later disease stages, chronic symptoms are not resolved. These severe chronic symptoms can persist for decades posing a sizable burden on Chronic Lyme sufferers. Currently, there is not a human vaccine for disease prevention or effective treatment for Chronic Lyme available. Individuals who spend extended time outdoors in rural areas, such as military personnel, who are exposed to deer ticks are at risk of contracting Lyme disease and for significant physical impairment. Bacteria use signaling molecules to communicate with each other, with the outside environment, and within themselves. Through these signaling molecules the bacteria can rapidly respond to internal and external changes and alter their behavior. B. burgdorferi is highly responsive to the environmental changes that occur when it travels between ticks and mammals, such as humans and small rodents. The pathogen is also able to sense and adapt to environmental changes in different mammalian tissues. It has been shown B. burgdorferi uses another signaling molecule, c-di-GMP, when located in the tick. We hypothesize that the small signaling molecule cAMP is important for B. burgdorferi during mammalian infection. cAMP is used by several microbes to regulate pathogenesis through manipulation of host cells, regulation of virulence factors, and environmental sensing. cAMP is produced by the enzyme adenylate cyclase often in response to environmental signals. In previous studies, we have found that B. burgdorferi cyaB, the sole adenylate cyclase, influences the production of proteins that are important for establishing mammalian localized infection and colonization of secondary tissues. The cyaB gene is specifically induced when exposed to mammalian cells in culture. This is an important observation because cell culture expression patterns are expected to be similar to what is occurring in the mouse model. The deletion of cyaB from the borrelial genome resulted in a reduction of infectivity in the experimental mouse model. Together, this data indicates the adenylate cyclase in B. burgdorferi is important for the development and progression of Lyme disease. An ongoing independently funded study will identify all borrelial genes and proteins regulated by cyaB through high-throughput transcriptomic and proteomic approaches. The regulation of cAMP production by the adenylate cyclase, the downstream effects of changing cAMP concentrations, and the mechanism of cAMP regulation is not known. The goal of this proposal is to examine the roles of cyaB and cAMP in regulating B. burgdorferi pathogenesis. This will be addressed by the following aims: (1) Characterize the role of B. burgdorferi cyaB in host-pathogen interactions; (2) Assess production of B. burgdorferi cAMP during host-pathogen interactions; (3) Elucidate the role of B. burgdorferi cyaB during murine infection. The results from these studies will be impactful by characterizing the effect of interactions between B. burgdorferi and the mammalian host that contributes to the development of inflammatory infection. The significance of this propose
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110845
Entities
People
- Vanessa Ante
Organizations
- Texas A&M Health Science Center
- United States Army