Mechanism and Function of Type IV Secretion During Infection of the Human Host

Abstract

Bacterial pathogens employ type IV secretion systems (T4SSs) for various purposes to aid in survival and proliferation in eukaryotic host. One large T4SS subfamily, the conjugation systems, confers a selective advantage to the invading pathogen in clinical settings through dissemination of antibiotic resistance genes and virulence traits. Besides their intrinsic importance as principle contributors to the emergence of multiply drug-resistant ‘superbugs’, detailed studies of these highly tractable systems have generated important new insights into the mode of action and architectures of paradigmatic T4SSs as a foundation for future efforts aimed at suppressing T4SS machine function. Over the past decade, extensive work on the second large T4SS subfamily, the effector translocators, has identified a myriad of mechanisms employed by pathogens to subvert, subdue, or bypass cellular processes and signaling pathways of the host cell. An overarching theme in the evolution of many effectors is that of molecular mimicry. These effectors carry domains similar to those of eukaryotic proteins and exert their effects through stealthy interdigitation of cellular pathways, often with the outcome not of inducing irreversible cell damage but rather of reversibly modulating cellular functions. This chapter summarizes the major developments for the actively studied pathogens with an emphasis on the structural and functional diversity of the T4SSs and the emerging common themes surrounding effector function in the human host.

Stenotrophomonas maltophilia Encodes a VirB/VirD4 Type IV Secretion System That Modulates Apoptosis in Human Cells and Promotes Competition against Heterologous Bacteria, Including Pseudomonas aeruginosa

“…In regard to the proapoptotic effect that the K279a VirB/D4 T4SS has on macrophages, it is tempting to speculate that this function evolved as a result of S. maltophilia interacting with predatory protozoans (amoebae) in nature (113)(114)(115)(116)(117). Despite demonstrating the importance of the S. maltophilia T4SS in influ- encing the death of other cells, we do not believe that this is the only function of this VirB/D4 T4SS, given what is known about T4SS in general (35)(36)(37).…”

“…Thus, a recent bioinformatic study encompassing a very wide variety of organisms and their secretion systems suggested that S. maltophilia K279a encodes more than 25 putative T4SS effectors (125). Such a sized output is entirely compatible with the output of known T4SSs, which ranges from 1 (B. pertussis and H. pylori) to ϳ7 to 25 (Bartonella, Brucella, Anaplasma, and Ehrlichia) to Ͼ140 (Coxiella and Legionella) (35,45,46,49,126). Moreover, it could account for the multiple effects of the VirB/D4 system that we have defined in our study as well as other potential functions.…”

“…3C), showing that the effect was not an oddity of using A549 cells. Except for the secretion of pertussis toxin, the delivery of T4SS effectors typically requires contact between the T4SS apparatus and the target cell membrane (35,85). Thus, we inoculated the S. maltophilia strains and A549 cells on opposite sides of a transwell apparatus, such that the bacteria were prevented by a membrane filter from contacting the host cells.…”

Two pKM101‐encoded proteins, the pilus‐tip protein TraC and Pep, assemble on the Escherichia coli cell surface as adhesins required for efficient conjugative DNA transfer

“…Members of one large T4SS subfamily, designated as conjugation systems, mediate the propagation of mobile genetic elements (MGEs) and their collection of associated antibiotic resistance genes, virulence determinants and other fitness traits among bacterial populations (de la Cruz et al, 2010). Those of a second large subfamily evolved from ancestral conjugation systems for the specialized purpose of delivering effector proteins into eukaryotic target cells to aid in infection processes (Ben-Tekaya et al, 2013;Gonzalez-Rivera et al, 2016;Sherwood and Roy, 2016). The T4SSs translocate their macromolecular cargoes to bacterial or eukaryotic target cells by a mechanism generally requiring direct cell-to-cell contact.…”

Insights in a novel gram‐positive type IV secretion system

“…This T4SS subgroup is known to be one of the main mechanisms responsible of the spread of antibiotic resistance genes among pathogenic bacteria, the transference of genes encoding for toxins and the bacterial adaptation to environmental changes. Furthermore, they promote bacterial attachment to biotic and abiotic surfaces, interbacteria aggregation and development of biofilms in the human host (Gonzalez-Rivera et al, 2016).…”