Subversion of Host Recognition and Defense Systems by Francisella spp. Crystal L. Jones, Emory University Brooke A. Napier, Emory University Timothy R. Sampson, Emory University Anna C. Llewellyn, Emory University Max R. Schroeder, Emory University David S Weiss, Emory University Journal Title: Microbiology and Molecular Biology Reviews Volume: Volume 76, Number 2 Publisher: American Society for Microbiology | 2012-06, Pages 383-404 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.1128/MMBR.05027-11 Permanent URL: http://pid.emory.edu/ark:/25593/f813h Final published version: http://dx.doi.org/10.1128%2FMMBR.05027-11 Copyright information: © 2012 American Society for Microbiology. All Rights Reserved. Accessed October 1, 2021 1:23 PM EDT Subversion of Host Recognition and Defense Systems by Francisella spp. Crystal L. Jones,a Brooke A. Napier,a Timothy R. Sampson,a Anna C. Llewellyn,a Max R. Schroeder,a and David S. Weissb,c Department of Microbiology and Immunology, Microbiology and Molecular Genetics Program,a Emory Vaccine Center,b and Division of Infectious Diseases, Department of Medicine,c Emory University, Atlanta, Georgia, USA INTRODUCTION ............................................................................................................................................383 SUBVERSION OF HOST DEFENSES .........................................................................................................................384 Complement and Antibody ..............................................................................................................................384 Antimicrobial Peptides ...................................................................................................................................387 Mechanisms of Entry and Fate of Intracellular Francisella ................................................................................................388 Phagosomal Acidification ................................................................................................................................390 Inhibition of Reactive Oxygen Species ...................................................................................................................390 Francisella Escape from the Phagosome .................................................................................................................391 Toll-Like Receptors .......................................................................................................................................391 Cytosolic Defenses .......................................................................................................................................393 Nutritional Defenses......................................................................................................................................394 Modulation of Adaptive Immune Responses.............................................................................................................396 CONCLUDING REMARKS ...................................................................................................................................398 ACKNOWLEDGMENTS......................................................................................................................................399 REFERENCES ................................................................................................................................................399 INTRODUCTION model system to study Francisella virulence. Finally, Francisella tularensis subsp. mediasiatica is a species of intermediate virulence rancisella tularensis was first identified as the causative agent of Fa fatal plague-like disease in a population of ground squirrels in humans and is found in Central Asia, while Francisella philomi- in Tulare County, CA, in 1911 (147). Originally called Bacterium ragia and Francisella noatunensis can cause infections in aquatic tularense, it was later renamed Francisella tularensis in honor of organisms, including wild and farmed fish (57). Throughout this Edward Francis, who spent his career extensively studying and paper we will refer to “Francisella” when discussing general char- characterizing the transmission and growth of this bacterium acteristics shared by numerous species and subspecies and will (209). Although it causes disease in squirrels, rabbits, and numer- otherwise refer to specific species and subspecies by name. It is ous other mammals, no animal has been identified as a reservoir. important to note that there are significant differences between Instead, the reservoir may be freshwater or amoebae living highly virulent and less pathogenic strains in terms of the require- therein. As there is no person-to-person spread, F. tularensis is ments of genes for pathogenesis, susceptibilities to host defenses, acquired primarily by humans via arthropod vectors or zoonotic and the types of immune responses induced. Therefore, caution transmission, though it can also be transmitted by inhalation of must be used when interpreting results from experiments using aerosolized bacteria or ingestion of contaminated food or water less pathogenic species and drawing conclusions about the char- (2). Inhalation of F. tularensis causes the most severe infections, acteristics of highly virulent species. and only 10 bacteria can lead to a potentially fatal disease. This F. tularensis subspecies are the etiological agents of the disease high infectivity, along with its ease of aerosolization, have led to its tularemia, also known as rabbit fever. Tularemia is characterized history of weaponization (209). by a 3- to 5-day incubation period (209) during which the bacteria Francisella species are endemic only in the Northern Hemi- replicate almost “silently” in macrophages and other types of host sphere. F. tularensis subsp. tularensis (F. tularensis) is the most cells. The eventual release of bacteria from these cells may coincide virulent etiologic agent of tularemia in humans and is the primary with the presentation of flu-like symptoms. There are several disease-causing Francisella species in North America. Francisella manifestations of tularemia, each dependent on the route of ac- tularensis subsp. holarctica (F. holarctica) is responsible for the quisition (159). The most common form of tularemia is ul- majority of reported cases of tularemia in Europe and Asia. The ceroglandular disease, which can result from insect bites or from current vaccine is an attenuated live vaccine strain (LVS) derived contact with infected animal tissues following mechanical damage from virulent F. holarctica by serial passage. LVS causes a very mild to the skin. A cutaneous ulcer develops at the site of infection, and infection in humans but can cause a lethal infection in mice and is therefore commonly used as a model to study Francisella patho- genesis. The closely related Francisella novicida species rarely Address correspondence to David S. Weiss, [email protected]. causes disease in humans, though some cases have been docu- C.L.J., B.A.N., and T.R.S. contributed equally to this article. mented (31, 125). However, F. novicida is highly virulent in mice, Copyright © 2012, American Society for Microbiology. All Rights Reserved. has over 98% identity to F. tularensis at the DNA level (188), doi:10.1128/MMBR.05027-11 shares many of the same virulence genes (43), and is also used as a June 2012 Volume 76 Number 2 Microbiology and Molecular Biology Reviews p. 383–404 mmbr.asm.org 383 Jones et al. cluding the inflammasome) with which the bacteria must con- tend. In order to replicate in this host compartment, Francisella must also obtain the nutrients required to sustain its rapid cell division and actively counteract host defenses aimed at limiting nutrient availability. In addition to subverting extracellular and intracellular de- fenses to facilitate replication, Francisella suppresses the activation of adaptive immune defenses that have the capability of destroy- ing infected host cells. For example, CD8 T cells can directly lyse infected host cells, clearing these havens for bacterial replication. They and other cells also secrete the cytokine gamma interferon (IFN-␥), which can activate strong defenses in host cells, allowing them to resist Francisella replication. Therefore, Francisella uses several strategies to skew adaptive responses and block IFN-␥ sig- naling to help preserve its replication niche in infected host cells (35, 119, 166, 189). Here we review the multitude of ways in which Francisella subverts host defenses at each of the stages of intracel- FIG 1 Stages of Francisella pathogenesis in the macrophage. Francisella can be lular infection as well as its effects on adaptive immune responses. detected by multiple macrophage receptors (see “Mechanisms of Entry and Fate of Intracellular Francisella” below) and is engulfed by a unique pseudopod SUBVERSION OF HOST DEFENSES loop mechanism. It then traffics to an early phagosome called the Francisella- containing phagosome (FCP). Francisella uses multiple mechanisms to evade Following its transmission, Francisella must resist extracellular host defenses in this harsh environment (inset). Francisella blocks the NADPH host defenses prior to entry into host cells. Furthermore, there is oxidase and also detoxifies reactive oxygen species (ROS). It can also resist the evidence that a potentially important extracellular phase exists action of antimicrobial peptides (AMPs). Francisella does not signal through