Type 1 and 5 secretion systems and associated toxins - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 506

a T1SS for delivery of antigens has been shown to induce protection and has
many advantages over other live-vaccine methods.
T5S proteins present a great opportunity to develop novel vaccines against
E. coli- mediated disease and T5SS proteins are already being used in current
vaccine strategies against other Gram-negative pathogens. The primary exam-
ple of T5SS protein vaccine is the acellular B. pertussis vaccine. For the last
50 years, efficacious whole-cell vaccines against whooping cough caused by
B. pertussis have been available. Acellular pertussis vaccines have also been
introduced that comprise from one to five proteins derived from B. pertussis ,
two of which are T5SS proteins. These proteins are the AT pertactin and the
TPS protein filamentous hemagglutinin (FHA). Of these proteins, high levels of
antibody to pertactin have the strongest correlation to a decreased likelihood of
acquiring pertussis ( Cherry et al., 1998; Hewlett and Halperin, 1998; Storsaeter
et al., 1998 ).
A similar strategy against ETEC is currently being explored where the vac-
cine would be comprised of protein subunits from multiple ETEC antigens.
To this end both AT and TPS proteins from ETEC strains are being tested for
immunogenicity and ability to protect from infection. The ETEC TPS pro-
tein EtpA has been found to be both immunogenic and protective in a murine
model ( Roy et al., 2008, 2009a ) while immune-proteomic studies identified not
only EtpA but AT proteins TibA, EatA, and Antigen 43 suggesting that these
proteins are expressed during infection both in mice and humans ( Roy et al.,
2010 ). Finally, immunization of mice with the passenger domains of two AT
proteins protected against subsequent intestinal colonization by ETEC ( Harris
et al., 2011 ).With many other T5SS proteins from a variety of Gram-negative
pathogens being found to be immunogenic ( Turner et al., 2002, 2006 ; Cainelli
Gebara et al., 2007; Litwin et al., 2007; Daigneault and Lo, 2009 ) and protec-
tive ( Marr et al., 2008; Alamuri et al., 2009; Winter and Barenkamp, 2009,
2010; Chan et al., 2011 ) it is highly likely that more T5SS-based vaccines will
be developed in the near future.
A further way that T5SS proteins are involved in vaccine delivery is exem-
plified by the live attenuated-vaccine strategy for Shigella. This application
involves deleting the T5SS virulence protein IcsA (crucial for intracellular
spread of Shigella ) to create a live-attenuated vaccine strain ( Venkatesan et al.,
2002; Venkatesan and Ranallo, 2006 ).
The T5SS can also be utilized for vaccine development by using the sys-
tem to display on the surface of bacterium, or secrete from the bacterium,
chimeric antigens. By replacing the passenger domain with a protein of
choice, the protein can be successfully secreted to the surface for display
( Ruiz-Perez et al., 2002; Ruiz-Olvera et al., 2003 ) or into the extracellular
milieu ( Sevastsyanovich et al., 2012 ). This strategy provides a simple way
to mass produce protein, or to develop live attenuated vaccines ( Zhu et al.,
2006; Chen and Schifferli, 2007 ).