Pathogenicity determinant protein E is a Francisella type VI secretion system effector protein that modulates host death

Francisella tularensis is a highly pathogenic Gram-negative intracellular bacterial pathogen and the etiologic agent of tularemia, a fatal zoonotic disease that poses a threat to global public health. F. tularensis virulence is mediated by genes on the Francisella pathogenicity island (FPI), which encodes a unique contractile secretion apparatus with functional and structural similarity to bacterial type VI secretion systems (T6SSs). T6SSs can inject effector proteins into host cells to facilitate invasion, intracellular proliferation, and pathogenesis; however, the identity and function of Francisella effectors are still unclear. In this study, we measured T6SS activity in a series of FPI deletion mutants to identify genes that are required for core apparatus activity. We found that Pathogenicity Determinant Protein E (PdpE) is not required for secretion of T6SS substrates or intramacrophage growth. Instead, PdpE forms a complex with another T6SS-secreted effector, PdpC, and limits death of infected host cells by attenuating the macrophage type I interferon response. Importantly, a Δ pdpE mutant more rapidly induces death in an established invertebrate in vivo model for Francisella infection. These data define the role of a previously uncharacterized substrate of the Francisella T6SS and provide new insights into host- Francisella interaction.