COTTER LAB

Bacterial control of inflammation in the respiratory tract

Using B. bronchiseptica and a mouse lung inflammation model, we discovered recently that filamentous hemagglutinin (FHA), a large protein virulence factor that is both surface associated and released into the extracellular environment, allows Bordetella to suppress the inflammatory response of its host. We have identified the domain within FHA that is responsible for this activity and are currently working to identify the host cell receptor(s) involved and to characterize the host signal transduction pathways that are affected in response to FHA binding. Using both genetic and biochemical approaches, we have also identified several additional Bordetella factors involved in controlling inflammation and are currently identifying their functional domains as well as their host cell receptors.

 

Mechanism of Two-Partner Secretion

Two-Partner Secretion (TPS) systems export large ‘exoproteins’ (TpsA family members) across the outer membranes of Gram-negative bacteria using channel-forming β-barrel proteins (TpsB family members). TPS systems are present in nearly all groups of Gram-negative bacteria and TpsB proteins belong to a large family of outer membrane protein-translocating porin-type proteins with members in the animal, plant and fungal kingdoms, making this general secretion mechanism the most widely distributed in nature. Filamentous hemagglutinin (FHA) is one of the prototypical members of the TPS family. Our studies with FHA revealed important aspects of the TPS mechanism, such as how the FHA protein is oriented topologically on the bacterial cell surface, and these results were critical in understanding FHA function during infection. Current projects are aimed at understanding how, biophysically, this very large protein is translocated across the bacterial outer membrane in the absence of an obvious energy source and how the large, C-terminal pro-domain controls the proper folding of the C-terminal domain of the mature protein.