Pathogenicity and virulence of Rickettsia

Figures & data

Table 1. List of putative rickettsial virulence genes.

Gene	Protein	Putative functions	Predicted secretion pathways
sca0	Outer membrane protein A	Interacts with FGFR1 and α2β1 integrin and aids in the attachment and invasion to host cells	Sec-T5SS
sca1	Surface cell antigen 1	Involved in the attachment to host cells	Sec-T5SS
sca2	Surface cell antigen 1	Formin-like activity, nucleates actin and helps in the cell-to-cell spread at later stages of infection	Sec-T5SS
sca4	Surface cell antigen 1	Inhibits interaction of vinculin – α catenin at the focal adhesion sites and disturbs adherent junction complexes to aid in cell-to-cell spread	Sec-unknown
sca5	Outer membrane protein B	Interacts with Ku70 on the host cell surface and participates in the attachment and invasion to host cells. Blocks ubiquitination of OmpA and prevents autophagy	Sec-T5SS
tlyA	Haemolysin A	Assists rickettsial escape from vacuolar structures	Unknown
tlyC	Haemolysin C	Assists rickettsial escape from vacuolar structures	Unknown
pat1	Patatin-like phospholipase 1	Phospholipase activities involved in vacuole escape and avoidance of autophagy killing	Unknown
pat2	Patatin-like phospholipase 2	Phospholipase activities involved in vacuole escape	Unknown
pld	Phospholipase D	Phospholipase activities involved in vacuole escape	Unknown
rarp1	Rickettsial ankyrin repeat protein 1	Unknown	Sec-TolC
rarp2	Rickettsial ankyrin repeat protein 2	Cysteine protease activities involved in dispersing trans-Golgi network	T4SS
rickA	Arp2/3 complex-activating protein	Mimics WASP and activates Arp2/3 to form actin tails and mediate motility at the early stages of infection	Unknown
ralF	Guanine nucleotide exchange factor	Expressed early in infection activates Arf6 and mediates invasion	T4SS
risk1	Rickettsia intracellular secreted kinase-1	Phosphatidylinositol 3-kinase, which contributes to intracellular growth by directly engaging the Beclin-1 complex, facilitates internalization and escape into the host cytosol.	T4SS

Figure 1. Rickettsial intracellular lifecycle.

1. Rickettsia attaches to host cells via interaction of rickettsial surface proteins with host cell receptors; 2. Downstream signaling cascades lead to the internalization of Rickettsia; 3. Using several membranolytic factors, Rickettsia escapes the endocytic vacuoles; 4. Rickettsia resides within the host cytosol and replicates while taking nutrients from the host; 5. Some Rickettsia species exhibit actin-based motility; 6. Rickettsia undergoes cell-to-cell spread; 7. Rickettsia breaks double vacuolar membrane structures; 8. Rickettsia resides within the cytosolic compartment and reinitiates the infectious cycle.

Figure 2. Secretion systems in Rickettsia.

Rickettsia utilizes five secretion pathways: Sec-T5SS, Sec-TolC, Tat, T1SS, and T4SS. Most Sca proteins have three domains: the N-terminal secretion signal (black), passenger domain (blue), and C-terminal autotransporter domain (red). The black and purple boxes on RARP-1 denote the N-terminal secretion signal and C-terminal Ankyrin repeat domain. The C-terminal Ankyrin repeat domain of RARP-2 is colored in yellow. Question marks 1 and 2 indicate uncharacterized proteins that travel through the Tat and/or T1SS. Question mark 3 indicates divergent destinations of RARP-1 in Rickettsia. Lastly, question mark 4 indicates unresolved compositions of S-layer proteins and their interactions with the outer membrane components, such as O-Ag. IM-inner membrane; PP-periplasm; PG-peptidoglycan; OM-outer membrane; LPS-lipopolysaccharide; S-layer-surface layer.

Figure 3. Rickettsial determinants in host cell attachment and internalization.

A. Rickettsial entry into mammalian cells is mediated by interactions of its surface antigens- Sca0 with α2β1 integrin and FGFR1 receptor, Sca5 with Ku70, and Sca1 and Sca2 with unknown receptors on the cell surface; B. Ku70-Sca5 interaction leads to activation of E3 ubiquitin ligase c-Cbl causing ubiquitination of Ku70. This initiates several downstream host-signaling pathways leading to activation of the Arp2/3 complexes resulting in actin rearrangement; C. This induces bacterial internalization via actin, clathrin, and caveolin 2- mediated endocytosis.