Bacterial Type IV secretion systems: versatile virulence machines

Abstract

Many bacterial pathogens employ multicomponent protein complexes to deliver macromolecules directly into their eukaryotic host cell to promote infection. Some Gram-negative pathogens use a versatile Type IV secretion system (T4SS) that can translocate DNA or proteins into host cells. T4SSs represent major bacterial virulence determinants and have recently been the focus of intense research efforts designed to better understand and combat infectious diseases. Interestingly, although the two major classes of T4SSs function in a similar manner to secrete proteins, the translocated 'effectors' vary substantially from one organism to another. In fact, differing effector repertoires likely contribute to organism-specific host cell interactions and disease outcomes. In this review, we discuss the current state of T4SS research, with an emphasis on intracellular bacterial pathogens of humans and the diverse array of translocated effectors used to manipulate host cells.

Figure 1. Genetic arrangement of T4SS-encoding genes

(A) The prototypical T4ASS structural proteins of Agrobacterium are encoded by virB1-11 in an operon and virD4. Rickettsial organisms and Anaplasma encode a T4ASS, but contain multiple copies of certain genes, such as virB6, virB8, and virB9. (B) The Dot/Icm T4BSS is typified by Legionella and is encoded by up to 27 genes. Dark gray arrows denote dot genes and light gray indicate icm genes. Coxiella encodes a homologous system with a few differences, including two copies of icmL, absence of icmR and lvgA, presence of the IcmR functional homolog CoxigA, and a disrupted icmF gene.

Figure 2. T4SS organization

T4SSs are multi-component machines that collectively serve to transport effector proteins from the bacterial cytoplasm to the eukaryotic cytosol, bypassing a periplasmic intermediate. This is accomplished by VirB/D4 proteins in the T4ASS and Dot/Icm proteins in the T4BSS. Each system forms a central channel through which effectors transit. In the bacterial cytoplasm, ATPases (VirB4, VirB11, VirD4, and DotB) provide the energy necessary for translocation, while chaperone proteins deliver effectors for entry into the central pore. DotV, DotE, DotJ, and IcmT (light gray) have not been localized experimentally but are predicted to be inner membrane proteins. The known or predicted function of individual T4SS components is described in the text.

Figure 3. Diversity of Legionella effector activities

Legionella produces over 300 Dot/Icm T4SS substrates that control numerous events during intracellular growth. Many effectors are involved in regulating formation and modification of the Legionella-containing vacuole, while others interact with host cell proteins involved in transcription and cell survival. Legionella provides an example of the potential versatility of a bacterial T4SS. Effectors are shown in boxed regions and are colored similar to the general process they regulate.