Faculty Collaboration Database

A Francisella tularensis Schu S4 purine auxotroph is highly attenuated in mice but offers limited protection against homologous intranasal challenge. PLoS One 2008 Jun 25;3(6):e2487

Date

06/26/2008

Pubmed ID

18575611

Pubmed Central ID

PMC2429968

DOI

10.1371/journal.pone.0002487

Scopus ID

2-s2.0-49649100202 (requires institutional sign-in at Scopus site)   64 Citations

Abstract

BACKGROUND: Francisella tularensis is a gram-negative coccobacillus that causes the febrile illness tularemia. Subspecies that are pathogenic for humans include those comprising the type A (subspecies tularensis) or type B (subspecies holarctica) biovars. An attenuated live vaccine strain (LVS) developed from a type B isolate has previously been used to vaccinate at-risk individuals, but offers limited protection against high dose (>1000 CFUs) challenge with type A strains delivered by the respiratory route. Due to differences between type A and type B F. tularensis strains at the genetic level, it has been speculated that utilization of an attenuated type A strain as a live vaccine might offer better protection against homologous respiratory challenge compared with LVS. Here, we report the construction and characterization of an unmarked Delta purMCD mutant in the highly virulent type A strain Schu S4.

METHODOLOGY/PRINCIPAL FINDINGS: Growth of Schu S4 Delta purMCD was severely attenuated in primary human peripheral blood monocyte-derived macrophages and in the A549 human lung epithelial cell line. The Schu S4 Delta purMCD mutant was also highly attenuated in mice when delivered via either the intranasal or intradermal infection route. Mice vaccinated intranasally with Schu S4 Delta purMCD were well protected against high dose intradermal challenge with virulent type A or type B strains of F. tularensis. However, intranasal vaccination with Schu S4 Delta purMCD induced tissue damage in the lungs, and conferred only limited protection against high dose Schu S4 challenge delivered by the same route. The level of protection observed was similar to that conferred following vaccination with wild-type LVS or the analogous LVS Delta purMCD mutant.

CONCLUSIONS/SIGNIFICANCE: Collectively, these results argue that development of the next generation live attenuated vaccine for Francisella should be based on use of the less pathogenic type B biovar rather than the more reactogenic type A biovar.

Author List

Pechous RD, McCarthy TR, Mohapatra NP, Soni S, Penoske RM, Salzman NH, Frank DW, Gunn JS, Zahrt TC

Authors

Dara W. Frank PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Nita H. Salzman MD, PhD Center Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Administration, Intranasal
Animals
Bacterial Vaccines
Cell Line
Francisella tularensis
Humans
Lung
Macrophages
Mice
Mutation
Purines
Virulence