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EcoSal Plus

Domain 8:

Pathogenesis

Live Attenuated Human Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity

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  • Authors: James E. Galen1, Amanda D. Buskirk3, Sharon M. Tennant5, and Marcela F. Pasetti7
  • Editors: Michael S. Donnenberg9, Andreas J. Bäumler10
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD 21201; 2: Division of Geographic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; 3: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore MD 21201; 4: Division of Infectious Diseases and Tropical Pediatrics, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201; 5: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore MD 21201; 6: Division of Geographic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201; 7: Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, Baltimore MD 21201; 8: Division of Infectious Diseases and Tropical Pediatrics, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201; 9: University of Maryland, School of Medicine, Baltimore, MD; 10: University of California—Davis, Davis, CA
  • Received 13 May 2016 Accepted 10 June 2016 Published 03 November 2016
  • Address correspondence to James E. Galen, jgalen@medicine.umaryland.edu
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  • Abstract:

    Salmonellosis, caused by members of the genus , is responsible for considerable global morbidity and mortality in both animals and humans. In this review, we will discuss the pathogenesis of serovar Typhi and serovar Typhimurium, focusing on human infections. We will trace the path of through the body, including host entry sites, tissues and organs affected, and mechanisms involved in both pathogenesis and stimulation of host immunity. Careful consideration of the natural progression of disease provides an important context in which attenuated live oral vaccines can be rationally designed and developed. With this in mind, we will describe a series of attenuated live oral vaccines that have been successfully tested in clinical trials and demonstrated to be both safe and highly immunogenic. The attenuation strategies summarized in this review offer important insights into further development of attenuated vaccines against other for which live oral candidates are currently unavailable.

  • Citation: Galen J, Buskirk A, Tennant S, Pasetti M. 2016. Live Attenuated Human Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0010-2016

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Immune System Proteins
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ecosalplus.ESP-0010-2016.citations
ecosalplus/7/1
content/journal/ecosalplus/10.1128/ecosalplus.ESP-0010-2016
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/content/journal/ecosalplus/10.1128/ecosalplus.ESP-0010-2016
2016-11-03
2017-03-26

Abstract:

Salmonellosis, caused by members of the genus , is responsible for considerable global morbidity and mortality in both animals and humans. In this review, we will discuss the pathogenesis of serovar Typhi and serovar Typhimurium, focusing on human infections. We will trace the path of through the body, including host entry sites, tissues and organs affected, and mechanisms involved in both pathogenesis and stimulation of host immunity. Careful consideration of the natural progression of disease provides an important context in which attenuated live oral vaccines can be rationally designed and developed. With this in mind, we will describe a series of attenuated live oral vaccines that have been successfully tested in clinical trials and demonstrated to be both safe and highly immunogenic. The attenuation strategies summarized in this review offer important insights into further development of attenuated vaccines against other for which live oral candidates are currently unavailable.

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Figure 1

Infection with is initiated following oral ingestion of contaminated food or water (A). must then overcome potentially lethal levels of inorganic acid (H+) which produce pHs as low as 2 in the stomach of healthy adults (B). organisms surviving the extreme acidic conditions of the stomach eventually drain into the small intestine, the portal for invasion into deeper tissues and development of systemic disease (C). invade tissues of both villus epithelial tissue as well as lymphoid Peyer’s patches. Following transit of invading out of the lumen and across the epithelial barrier of the small intestine, bacteria eventually gain transient access to the bloodstream to eventually colonize deep tissues including the liver (D), spleen, and bone marrow. It is at this stage that infection with Typhimurium is typically halted and does not progress to systemic disease in immunologically competent humans. However, Typhi can be released from deep tissues back into the bloodstream, triggering a more substantial secondary bacteremia which precedes the onset of classic typhoid fever. In rare cases, typhoid fever can progress to an asymptomatic chronic infection in which Typhi can migrate down the hepatic ducts of the liver and into the gallbladder (E), setting up a convalescent carrier state in which very high levels of organisms can be intermittently released back into the small intestine, passing through the large intestine (F) and being released in the feces (G).

Citation: Galen J, Buskirk A, Tennant S, Pasetti M. 2016. Live Attenuated Human Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0010-2016
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Figure 2

Invasion of into deeper tissues of the human host occurs primarily in the small intestine (A) and is triggered by environmental signals including osmolarity. Villi of the small intestine possess a gradient of osmolarity, which is highest at the luminal surface of villi and decreases to physiological osmolarity in the lower crypts of the villus. Incoming luminal sense the high osmolarity of villus surfaces that induce invasion (B). High osmolarity in the lumen upregulates , which in turn represses synthesis of Vi in Typhi to enhance invasion; this negative control is further strengthened by the osmotic repression of , which is a positive activator of Vi synthesis (C). In addition, high osmolarity signals OmpR to upregulate Pathogenicity Island 1 (SPI-1) to inject effector proteins into target eukaryotic cells, resulting in ruffling of the outer membrane and engulfment of invading bacteria. Transepithelial migration then reduces the osmolarity to physiological levels, repressing and activating for induction of Vi synthesis. TviA is also a repressor of flagellar synthesis; therefore, Typhi is motile in the intestinal lumen when TviA is repressed (C, top left), but replaces flagella with the Vi capsule upon entry into host tissue (C, bottom left).

Citation: Galen J, Buskirk A, Tennant S, Pasetti M. 2016. Live Attenuated Human Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0010-2016
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Tables

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Table 1

Selected candidate live oral vaccines against human disease tested in phase 1/phase 2 clinical trials

Citation: Galen J, Buskirk A, Tennant S, Pasetti M. 2016. Live Attenuated Human Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity, EcoSal Plus 2016; doi:10.1128/ecosalplus.ESP-0010-2016

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