Rickettsia-host interaction: strategies of intracytosolic host colonization

Abstract

Bacterial infection is a highly complex biological process involving a dynamic interaction between the invading microorganism and the host. Specifically, intracellular pathogens seize control over the host cellular processes including membrane dynamics, actin cytoskeleton, phosphoinositide metabolism, intracellular trafficking and immune defense mechanisms to promote their host colonization. To accomplish such challenging tasks, virulent bacteria deploy unique species-specific secreted effectors to evade and/or subvert cellular defense surveillance mechanisms to establish a replication niche. However, despite superficially similar infection strategies, diverse Rickettsia species utilize different effector repertoires to promote host colonization. This review will discuss our current understandings on how different Rickettsia species deploy their effector arsenal to manipulate host cellular processes to promote their intracytosolic life within the mammalian host.

Keywords: Rickettsia-host interaction; bacterial adherence and engulfment; bacterial effector molecules; host defenses; intracellular trafficking; phagosomal escape; phosphoinositide metabolism; spotted fever group; transition group; typhus group.

Figure 1. Rickettsia species-specific pathogenicity and disease development in humans. Natural transmission of rickettsiae to humans is accomplished by various arthropod vectors (ticks, fleas, lice, or mites) resulting in rickettsiosis with various degrees ranging from highly severe [e.g. Rocky Mountain Spotted Fever (RMSF)], to moderate (like cat-flea typhus), or ultimately asymptomatic (Hackstadt ; Hackstadt ; Azad and Beard ; Sahni et al. ; Clark et al. ; Curto et al. 2016). SFG: Spotted Fever Group; TRG: Transition Group; TG: Typhus Group; R. rickettsii [Sheila Smith, (SS)], R. rickettsii [Iowa, (IA)].

Figure 2.

Life cycle of ticks and fleas and their natural transmission of rickettsiae. Black arrow lines emphasis key events of ticks natural cycle: (1) oviposition by engorged female ticks; (2) eggs hatched into larvae; (3) larvae feeding on rodents; (4) larvae molting to nymphs; (5) feeding of nymphs on larger animals; and (6) molting of nymphs into adult ticks that can feed on larger animals or infect humans (diagram was modified from (Eremeeva and Dasch 2015)). Broken black lines highlights transovarial (7) and transstadial transmission (8) of rickettsiae, while broken red lines show transmission of rickettsiae to humans through a direct bite of nymphs (9, 10) or adult ticks (11). Blue arrow lines emphasis key events of fleas natural cycle: (12) female fleas shed eggs into the environment (13) eggs hatched into larvae; (14) larvae form pupae; (15) pupae hatch to adult fleas; while transmission of rickettsiae to animals (16) or humans (broken red line, 17) occurs through inoculation of bacteria-laden flea feces onto flea bite wounds or mucous membranes (Azad et al. ; Anstead 2020).

Figure 3.

Effector section systems and distribution across divergent Rickettsia species. (A)Rickettsia spp utilize two distinct secretory pathways (adopted and updated from our previous reporting (Gillespie et al. 2015)). The T5SS and Sec-TolC pathway are two Sec-dependent pathways. The T5SS system is considered to be involved in the secretion of the surface cell antigen (Sca) family. Currently, Rickettsia ankyrin repeat protein 1 (RARP-1) is the only effector secreted by the Sec-TolC system and involves its N-Terminal secretion signal (Sec SS), C-Terminal ankyrin (ANK) domain, and the TolC protein. The highly conserved sec-independent secretory pathways included the twin-arginine translocation (Tat), T1SS and T4SS systems. The Tat system is composed three components (TatA, TatB and TatC) and involved in the translocation of folded substrates across the inner membrane (IM). The TolC protein combined with additional IM proteins (AprE and AprD) form the functional T1SS system. The Rickettsiales vir homolog (rvh) T4SS, is highly similar to the vir structure of Agrobacterium tumefaciens, however with some difference including the duplication of several scaffold molecules and the lack of a pilus. CP: cytoplasm; PP: periplasm; OM: outer membrane; LPS: lipopolysaccharide; ?: unknown effectors or mechanism remains to be determined. (B) Phylogeny and effector molecules distribution across transitional group (TRG), spotted fever group (SFG) and typhus group (TG) Rickettsia spp (Rahman et al. ; Sears et al. ; Kaur et al. ; Rahman et al. ; Gillespie et al. ; Rennoll-Bankert et al. ; Gillespie et al. ; Lehman et al. ; Voss et al. 2020). Full length protein; Truncated with active site; D denotes divergent passenger domain fused to Sca2 β-domain; Fragmented; n denotes ankyrin repeat number within full length protein; X not detected.

Figure 4.

Repurposing of host phosphoinositides (PI) metabolism by intracellular bacterial effectors. The repurposing of host cell phosphoinositides (PI) is highly effective process of various intracellular pathogens to hijack intracellular trafficking and subvert host defense mechanisms to establish an intracellular niche (Pizarro-Cerdá et al. ; Walpole et al. ; Allen and Martinez 2020). Host enzymes for PI metabolism are shown in grey. Bacterial effectors that modulate host PI metabolism directly or indirectly are depicted in the corresponding colors (Niebuhr et al. ; Hernandez et al. ; Vergne et al. ; Pendaries et al. ; Beresford et al. ; Hsu et al. ; Toulabi et al. ; Rennoll-Bankert et al. ; Dong et al. ; Ledvina et al. ; Voss et al. 2020).

Figure 5.

Model for host cell colonization mediated by effectors of the virulent R. typhi spp. Stage 1, RalF activates Arf6, which in turn recruits PIP5K to generate PI(4,5)P₂ and to promote actin remodeling for pseudopodia formation (Rennoll-Bankert et al. ; Rennoll-Bankert et al. 2016); Stage 2, Risk1 promotes phagocytic uptake into host cells through the conversion of PI(4,5)P₂ to PI(3,4,5)P₃; Stage 3, Risk1 facilitates the generation of vacuolar PI(3)P to delay/subvert phagosomal maturation and allows rickettsial phospholipase effectors Pat1 and Pat2 (Pat1/2) to mediate bacterial escape into host cytosol; Stage 4, after phagosomal escape Rickettsia/Rickettsia-associated membrane remnants becomes ubiquitinated, resulting in the initiation of autophagy; Stage 5, Risk1 binds with Beclin-1, and facilitates generation of vacuolar PI(3)P, that (Stage 6) leads to delay/subvert autophagosomal maturation and likely the inhibition of inflammasome activation; Stage 7, the delay in autophagosomal maturation, allows Pat1 and Pat2 to mediate bacterial escape into host cytosol to establish replication niche (Rahman et al. ; Voss et al. 2020).