Recent Molecular Insights into Rickettsial Pathogenesis and Immunity

Sahni, Sanjeev K.; Narra, Hema P.; Sahni, Abha; Walker, David H.

doi:10.2217/fmb.13.102

Cited by 98 publications

(92 citation statements)

References 180 publications

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“…typhi (Sears et al ., 2012) and R . heilongjiangensis (Qi et al ., 2013) , suggesting that surface exposed proteins may undergo methylation of Lys residues, a process that would help neutralize the highly acidic rickettsial proteins exposed to the host cytoplasm, such as Sca5 (Sahni et al ., 2013) . It is tempting to speculate that extracellular chaperones, such as PrsA, may primarily function in folding other secretory proteins, but also may themselves undergo post-translational modification to provide rickettsiae with additional surface variability and/or ligands for mediating interactions with host receptors.…”

Section: Secretory Proteins At the Host Interfacementioning

confidence: 99%

Secretome of obligate intracellularRickettsia

et al. 2014

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The genus Rickettsia (Alphaproteobacteria; Rickettsiales; Rickettsiaceae) is comprised of obligate intracellular parasites, with virulent species of interest both as causes of emerging infectious diseases and for their potential deployment as bioterrorism agents. Currently there are no effective commercially available vaccines, with treatment limited primarily to tetracycline antibiotics, though others (e.g., josamycin, ciprofloxacin, chloramphenicol and azithromycin) are also effective. Much of the recent research geared towards understanding mechanisms underlying rickettsial pathogenicity has centered on characterization of secreted proteins that directly engage eukaryotic cells. Herein, we review all aspects of the Rickettsia secretome, including six secretion systems, 19 characterized secretory proteins, and potential moonlighting proteins identified on surfaces of multiple Rickettsia species. Employing bioinformatics and phylogenomics, we present novel structural and functional insight on each secretion system. Unexpectedly, our investigation revealed that the majority of characterized secretory proteins have not been assigned to their cognate secretion pathways. Furthermore, for most secretion pathways, the requisite signal sequences mediating translocation are poorly understood. As a blueprint for all known routes of protein translocation into host cells, this resource will assist research aimed at uniting characterized secreted proteins with their apposite secretion pathways. Furthermore, our work will help in the identification of novel secreted proteins involved in rickettsial “life on the inside”.

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Section: Secretory Proteins At the Host Interfacementioning

confidence: 99%

Secretome of obligate intracellularRickettsia

et al. 2014

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“…In addition, there were more advanced lesions and more bacteria when supportive therapy was given as opposed to untreated infections. Considering that endothelial cells are recognized as key immunoreactive cells involved in host defense and inflammation (Sahni et al, 2013), some of the alterations observed in the various organs may be the result of a strong immune response.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, stimulation through the intracellular route that activates T cells and induces cytokines like IFN-␥, TNF-␣, IL-1B, and CCL5 seem to be important in eliminating pathogenic rickettsiae (Feng and Walker, 2000;Valbuena et al, 2004;Sahni et al, 2013). Infection with R. rickettsii probably occurred in guinea pigs previously infected with 'Candidatus R. amblyommii', given transient temperature increase, antibody production, and visible orchitis (one animal), but the resulting immune response efficiently eliminated R. rickettsii to levels undetectable by PCR.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic potential of a Costa Rican strain of ‘Candidatus Rickettsia amblyommii’ in guinea pigs (Cavia porcellus) and protective immunity against Rickettsia rickettsii

Rivas

Moreira-Soto

Alvarado

et al. 2015

Ticks and Tick-borne Diseases

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'Candidatus Rickettsia amblyommii' is a spotted fever group rickettsia that is not considered pathogenic, although there is serologic evidence of possible infection in animals and humans. The aim of this study was to evaluate the pathogenic potential of a Costa Rican strain of 'Candidatus R. amblyommii' in guinea pigs and determine its capacity to generate protective immunity against a subsequent infection with a local strain of Rickettsia rickettsii isolated from a human case. Six guinea pigs were inoculated with 'Candidatus R. amblyommii' strain 9-CC-3-1 and two controls with cell culture medium. Health status was evaluated, and necropsies were executed at days 2, 4, and 13. Blood and tissues were processed by PCR to detect the gltA gene, and end titers of anti-'Candidatus R. amblyommii' IgG were determined by indirect immunofluorescence. To evaluate protective immunity, another 5 guinea pigs were infected with 'Candidatus R. amblyommii' (IGPs). After 4 weeks, these 5 IGPs and 3 controls (CGPs) were inoculated with pathogenic R. rickettsii. Clinical signs and titers of anti-Rickettsia IgG were determined. IgG titers reached 1:512 at day 13 post-infection with 'Candidatus R. amblyommii'. On day 2 after inoculation, two guinea pigs had enlarged testicles and 'Candidatus R. amblyommii' DNA was detected in testicles. Histopathology confirmed piogranulomatous orchitis with perivascular inflammatory infiltrate in the epididymis. In the protective immunity assay, anti-Rickettsia IgG end titers after R. rickettsii infection were lower in IGPs than in CGPs. IGPs exhibited only transient fever, while CGP showed signs of severe disease and mortality. R. rickettsii was detected in testicles and blood of CGPs. Results show that the strain 9-CC-3-1 of 'Candidatus R. amblyommii' was able to generate pathology and an antibody response in guinea pigs. Moreover, its capacity to generate protective immunity against R. rickettsii may modulate the epidemiology and severity of Rocky Mountain spotted fever in areas where both species circulate.

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“…and Shigella flexneri are also known to infect macrophages (18). However, macrophages are not the primary cells targeted during Rickettsial infections (209), and Shigella spp. induce macrophage cell death instead of replicating intracellularly as a strategy of pathogenesis (210–212).…”

Section: Infection Of Macrophages By Cytosolic Bacteriamentioning

confidence: 99%

Strategies Used by Bacteria to Grow in Macrophages

Mitchell

Chen²,

Portnoy

2016

Microbiol Spectr

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Intracellular bacteria are often clinically relevant pathogens that infect virtually every cell type found in host organisms. However, myeloid cells, especially macrophages, constitute the primary cells targeted by most species of intracellular bacteria. Paradoxically, macrophages possess an extensive antimicrobial arsenal and are efficient at killing microbes. In addition to their ability to detect and signal the presence of pathogens, macrophages sequester and digest microorganisms using the phagolysosomal and autophagy pathways or, ultimately, eliminate themselves through the induction of programmed cell death. Consequently, intracellular bacteria influence numerous host processes and deploy sophisticated strategies to replicate within these host cells. Although most intracellular bacteria have a unique intracellular life cycle, these pathogens are broadly categorized into intravacuolar and cytosolic bacteria. Following phagocytosis, intravacuolar bacteria reside in the host endomembrane system and, to some extent, are protected from the host cytosolic innate immune defenses. However, the intravacuolar lifestyle requires the generation and maintenance of unique specialized bacteria-containing vacuoles and involves a complex network of host-pathogen interactions. Conversely, cytosolic bacteria escape the phagolysosomal pathway and thrive in the nutrient-rich cytosol despite the presence of host cell-autonomous defenses. The understanding of host-pathogen interactions involved in the pathogenesis of intracellular bacteria will continue to provide mechanistic insights into basic cellular processes and may lead to the discovery of novel therapeutics targeting infectious and inflammatory diseases.

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Recent Molecular Insights into Rickettsial Pathogenesis and Immunity

Cited by 98 publications

References 180 publications

Secretome of obligate intracellularRickettsia

Secretome of obligate intracellularRickettsia

Pathogenic potential of a Costa Rican strain of ‘Candidatus Rickettsia amblyommii’ in guinea pigs (Cavia porcellus) and protective immunity against Rickettsia rickettsii

Strategies Used by Bacteria to Grow in Macrophages

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