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Pathogens
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Virulence Mechanisms of Rickettsiae
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Virulence Mechanisms of Rickettsiae

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: closed (10 December 2021) | Viewed by 20352

Special Issue Editor

Dr. Juan J. Martinez

E-Mail Website
Guest Editor
School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, United States
Interests: My research group is interested in understanding the mechanisms by which spotted fever group Rickettsia species interact with target mammalian host cells and how these interactions lead to disease initiation and progression in mammals. The overall goals of my research program are to identify bacterial and host proteins that can be targeted for efficacious therapeutic intervention.

Special Issue Information

Dear Colleagues,

Rickettsial species are pathogenic Gram-negative obligate intracellular bacteria that are often transmitted to humans and other mammals through tick salivary contents during the acquisition of a blood meal. In addition, some species in this class of pathogens are also transmitted to mammalian hosts through infected fecal content in contact with louse and flea bite sites. Once introduced into the mammalian hematogenous circulation, Rickettsiae must be able to survive in this normally bactericidal environment and ultimately spread to target organs and tissues.  Historically, some of the most severe diseases affecting humans and animals, including Rocky mountain spotted fever (RMSF), Mediterranean spotted fever (MSF), epidemic typhus, and murine typhus, are caused by rickettsial pathogens. As obligate intracellular bacteria, Rickettsia species rely on an infected host cell for the acquisition of nutrients and for the establishment of a permissive replicative niche.  Accordingly, a critical initial step in rickettsial pathogenesis is bacterial recognition of and attachment to target cells to mediate the internalization process. Recent advances in the genetic manipulation of Rickettsia species and related bacteria have opened new avenues of research for the identification and characterization of bona fide virulence determinants and of how these factors are potentially utilized to modulate target cell functions. Whereas the last few decades of research have furthered our understanding of how Rickettsia species can cause disease in infected mammals, there still remain unanswered questions regarding the molecular determinants that are responsible for the initiation of severe and often fatal diseases by these unique obligate intracellular bacteria. 

This Special Issue will focus on, but not exclusively, the following areas of research:

  1. Interactions of Rickettsia species and related pathogens with target host cells in mammals and vectors
  2. Modulation of immunologic responses to Rickettsia species in humans and mammals
  3. Development and refinement of animal models of disease
  4. Genetic manipulation of obligate intracellular bacteria
  5. Development of novel efficacious therapeutic strategies against rickettsial diseases

Dr. Juan J. Martinez
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Rickettsia
  • Anaplasma
  • Ehrlichia
  • Coxiella

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Published Papers (5 papers)

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Research

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19 pages, 4511 KiB  
Article
Rickettsia parkeri with a Genetically Disrupted Phage Integrase Gene Exhibits Attenuated Virulence and Induces Protective Immunity against Fatal Rickettsioses in Mice
by Esteban Arroyave, Ilirjana Hyseni, Nicole Burkhardt, Yong-Fang Kuo, Tian Wang, Ulrike Munderloh and Rong Fang
Pathogens 2021, 10(7), 819; https://doi.org/10.3390/pathogens10070819 - 30 Jun 2021
Cited by 7 | Viewed by 2915
Abstract
Although rickettsiae can cause life-threatening infections in humans worldwide, no licensed vaccine is currently available. To evaluate the suitability of live-attenuated vaccine candidates against rickettsioses, we generated a Rickettsia parkeri mutant RPATATE_0245::pLoxHimar (named 3A2) by insertion of a modified pLoxHimar transposon into the [...] Read more.
Although rickettsiae can cause life-threatening infections in humans worldwide, no licensed vaccine is currently available. To evaluate the suitability of live-attenuated vaccine candidates against rickettsioses, we generated a Rickettsia parkeri mutant RPATATE_0245::pLoxHimar (named 3A2) by insertion of a modified pLoxHimar transposon into the gene encoding a phage integrase protein. For visualization and selection, R. parkeri 3A2 expressed mCherry fluorescence and resistance to spectinomycin. Compared to the parent wild type (WT) R. parkeri, the virulence of R. parkeri 3A2 was significantly attenuated as demonstrated by significantly smaller size of plaque, failure to grow in human macrophage-like cells, rapid elimination of Rickettsia and ameliorated histopathological changes in tissues in intravenously infected mice. A single dose intradermal (i.d.) immunization of R. parkeri 3A2 conferred complete protection against both fatal R. parkeri and R. conorii rickettsioses in mice, in association with a robust and durable rickettsiae-specific IgG antibody response. In summary, the disruption of RPATATE_0245 in R. parkeri resulted in a mutant with a significantly attenuated phenotype, potent immunogenicity and protective efficacy against two spotted fever group rickettsioses. Overall, this proof-of-concept study highlights the potential of R. parkeri mutants as a live-attenuated and multivalent vaccine platform in response to emergence of life-threatening spotted fever rickettsioses. Full article
(This article belongs to the Special Issue Virulence Mechanisms of Rickettsiae)
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14 pages, 2376 KiB  
Article
Significant Growth by Rickettsia Species within Human Macrophage-Like Cells Is a Phenotype Correlated with the Ability to Cause Disease in Mammals
by M. Nathan Kristof, Paige E. Allen, Lane D. Yutzy, Brandon Thibodaux, Christopher D. Paddock and Juan J. Martinez
Pathogens 2021, 10(2), 228; https://doi.org/10.3390/pathogens10020228 - 19 Feb 2021
Cited by 15 | Viewed by 4786
Abstract
Rickettsia are significant sources of tick-borne diseases in humans worldwide. In North America, two species in the spotted fever group of Rickettsia have been conclusively associated with disease of humans: Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, and Rickettsia [...] Read more.
Rickettsia are significant sources of tick-borne diseases in humans worldwide. In North America, two species in the spotted fever group of Rickettsia have been conclusively associated with disease of humans: Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, and Rickettsia parkeri, the cause of R. parkeri rickettsiosis. Previous work in our lab demonstrated non-endothelial parasitism by another pathogenic SFG Rickettsia species, Rickettsia conorii, within THP-1-derived macrophages, and we have hypothesized that this growth characteristic may be an underappreciated aspect of rickettsial pathogenesis in mammalian hosts. In this work, we demonstrated that multiple other recognized human pathogenic species of Rickettsia, including R. rickettsii, R. parkeri, Rickettsia africae, and Rickettsiaakari can grow within target endothelial cells as well as within PMA-differentiated THP-1 cells. In contrast, Rickettsia bellii, a Rickettsia species not associated with disease of humans, and R. rickettsii strain Iowa, an avirulent derivative of pathogenic R. rickettsii, could invade both cell types but proliferate only within endothelial cells. Further analysis revealed that similar to previous studies on R. conorii, other recognized pathogenic Rickettsia species could grow within the cytosol of THP-1-derived macrophages and avoided localization with two different markers of lysosomal compartments; LAMP-2 and cathepsin D. R. bellii, on the other hand, demonstrated significant co-localization with lysosomal compartments. Collectively, these findings suggest that the ability of pathogenic rickettsial species to establish a niche within macrophage-like cells could be an important factor in their ability to cause disease in mammals. These findings also suggest that analysis of growth within mammalian phagocytic cells may be useful to predict the pathogenic potential of newly isolated and identified Rickettsia species. Full article
(This article belongs to the Special Issue Virulence Mechanisms of Rickettsiae)
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8 pages, 979 KiB  
Article
Molecular Characteristics of Rickettsia in Ticks Collected along the Southern Border of Mongolia
by Michael E. von Fricken, Matthew A. Voorhees, Jeffrey W. Koehler, Carmen Asbun, Brandon Lam, Barbara Qurollo, Kathryn M. Hogan, Uyanga Baasandagva, Battsetseg Jigjav and Randal J. Schoepp
Pathogens 2020, 9(11), 943; https://doi.org/10.3390/pathogens9110943 - 13 Nov 2020
Cited by 9 | Viewed by 2591
Abstract
Tick-borne infections are a significant threat to public health, particularly in regions where individuals frequently enter tick habitats. Roughly 26% of the population in Mongolia practice nomadic pastoralism and are considered at high risk of exposure to ticks and the diseases they carry. [...] Read more.
Tick-borne infections are a significant threat to public health, particularly in regions where individuals frequently enter tick habitats. Roughly 26% of the population in Mongolia practice nomadic pastoralism and are considered at high risk of exposure to ticks and the diseases they carry. This study tested ticks from Mongolia’s southern border for Rickettsia spp. to better understand the epidemiology of tick-borne diseases in the region. Dermacentor nuttalli and Hyalomma asiaticum ticks (n = 4022) were pooled and tested for Rickettsia spp. by real-time PCR. Melt-curve analyses and Sanger sequencing were used to identify Rickettsia species. Approximately 64% of the 786 tick pools tested positive for Rickettsia bacteria. Melt curve analyses identified four different Rickettsia species circulating in these tick pools. Amplicon sequencing of the ompA gene identified Rickettsia spp. that closely resembled R. raoultii and R. sibirica. Dermacentor nuttalli ticks from Govi-Altai had the highest maximum likelihood estimation infection rate 48.4% (95% CI: 41.7–56.5%), while Hyalommaasiaticum collected in Omnogovi had a rate of 7.6% (95% CI: 6.2–9.2%). The high detection of Rickettsia suggests a substantial risk of infection in southern Mongolia. Further studies are necessary to investigate the clinical burden of tick-borne diseases in Mongolia. Full article
(This article belongs to the Special Issue Virulence Mechanisms of Rickettsiae)
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15 pages, 5018 KiB  
Article
Comparative Analysis of Infection by Rickettsia rickettsii Sheila Smith and Taiaçu Strains in a Murine Model
by Eliane Esteves, Chanida Fongsaran, Ingeborg M. Langohr, Sean P. Riley, Marcelo B. Labruna, Sirlei Daffre, Andréa C. Fogaça and Kevin R. Macaluso
Pathogens 2020, 9(9), 744; https://doi.org/10.3390/pathogens9090744 - 10 Sep 2020
Cited by 6 | Viewed by 3879
Abstract
Rocky Mountain spotted fever (RMSF) is a life-threatening tick-borne disease caused by Rickettsia rickettsii, which is widely distributed throughout the Americas. Over 4000 cases of RMSF are recorded annually in the United States, while only around 100 cases are reported in Brazil. [...] Read more.
Rocky Mountain spotted fever (RMSF) is a life-threatening tick-borne disease caused by Rickettsia rickettsii, which is widely distributed throughout the Americas. Over 4000 cases of RMSF are recorded annually in the United States, while only around 100 cases are reported in Brazil. Conversely, while case fatality rates in the United States oscillate around 5%, in Brazil they can surpass 70%, suggesting that differences in tick vectoring capacity, population sensitivity, and/or variability in virulence of the rickettsial strains may exist. In this study, we compared the susceptibility of C3H/HeN mice to two highly virulent strains of R. rickettsii, one from the United States (Sheila Smith) and the other from Brazil (Taiaçu). Animals inoculated with the Taiaçu strain succumbed to infection earlier and exhibited severe histological lesions in both liver and spleen sooner than mice infected with the Sheila Smith strain. These differences in survival and signs of the disease are not related to a greater proliferation of the Taiaçu strain, as there were no significant differences in the rickettsial load in mice tissues inoculated with either strain. The present study is the first step to experimentally assess differences in fatality rates of RMSF in two different regions of the American continent. Full article
(This article belongs to the Special Issue Virulence Mechanisms of Rickettsiae)
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Review

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22 pages, 1392 KiB  
Review
Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria
by Paige E. Allen and Juan J. Martinez
Pathogens 2020, 9(8), 614; https://doi.org/10.3390/pathogens9080614 - 28 Jul 2020
Cited by 16 | Viewed by 4494
Abstract
Lipids are a broad group of molecules required for cell maintenance and homeostasis. Various intracellular pathogens have developed mechanisms of modulating and sequestering host lipid processes for a large array of functions for both bacterial and host cell survival. Among the host cell [...] Read more.
Lipids are a broad group of molecules required for cell maintenance and homeostasis. Various intracellular pathogens have developed mechanisms of modulating and sequestering host lipid processes for a large array of functions for both bacterial and host cell survival. Among the host cell lipid functions that intracellular bacteria exploit for infection are the modulation of host plasma membrane microdomains (lipid rafts) required for efficient bacterial entry; the recruitment of specific lipids for membrane integrity of intracellular vacuoles; and the utilization of host lipid droplets for the regulation of immune responses and for energy production through fatty acid β-oxidation and oxidative phosphorylation. The majority of published studies on the utilization of these host lipid pathways during infection have focused on intracellular bacterial pathogens that reside within a vacuole during infection and, thus, have vastly different requirements for host lipid metabolites when compared to those intracellular pathogens that are released into the host cytosol upon infection. Here we summarize the mechanisms by which intracellular bacteria sequester host lipid species and compare the modulation of host lipid pathways and metabolites during host cell infection by intracellular pathogens residing in either a vacuole or within the cytosol of infected mammalian cells. This review will also highlight common and unique host pathways necessary for intracellular bacterial growth that could potentially be targeted for therapeutic intervention. Full article
(This article belongs to the Special Issue Virulence Mechanisms of Rickettsiae)
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