Enterotoxigenic Escherichia coli - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 193

Interestingly, increased fecal levels of IL-8 have been associated with more
rapid resolution of ETEC infections ( Long et al., 2010 ), suggesting this element
of innate immunity is relevant in clearing organisms from the small intestine.
Recent studies have demonstrated that LT plays a role in promoting intesti-
nal colonization by ETEC ( Allen et al., 2006 ). One possible avenue by which
LT might affect colonization is by interfering with innate immune effectors
at the mucosal surface. Interestingly, increases in cAMP inhibit activation of
a number of cytokines ( Hajishengallis et al., 2004 ) including TNFα and IL-8
( Huang et al., 2004 ), as well as intestinal antimicrobial peptides including
beta-defensin-1 and cathelicidin ( O'Neil et al., 1999 ; Chakraborty et al., 2008 )
by interfering with NF-κB-mediated ( Parry and Mackman, 1997 ) modulation of
pathogen-associated molecular pattern (PAMP) responses.
Adaptive immune responses to ETEC
Multiple studies have documented striking age-associated declines in the inci-
dence of symptomatic ETEC infections strongly suggesting that naturally
occurring infections provide substantial protection against subsequent episodes
of disease ( Abu-Elyazeed et al., 1999 ; Qadri et al., 2007 ). Most studies of
immune responses to ETEC have centered on responses to the CFs and LT.
However, the precise nature of the protective antigens following ETEC infec-
tions is not really clear. While some studies have suggested that infection with
strains expressing a particular CF is protective against subsequent infection
with strains expressing homologous CFs ( Qadri et al., 2007 ), other studies
have failed to demonstrate a clear association with CF antigens and protection
( Steinsland et al., 2003, 2004 ), and have implicated other as yet unspecified
antigens as a possible source of protection ( Steinsland et al., 2003 ). Similarly,
there is no robust serologic correlate of protection from studies performed to
date ( Rao et al., 2005 ). Clearly, as shown by recent immuno-proteomic studies,
the immune response to ETEC is extraordinarily complex, and involves rec-
ognition of multiple antigens in addition to LT and the CFs ( Roy et al., 2010 ),
including more recently discovered antigens such as the EtpA adhesin and the
passenger domain of the EatA autotransporter.
CONTROL AND PREVENTION
ETEC vaccine development
Despite four decades of ETEC vaccine development effort, there is at pres-
ent no vaccine against ETEC that has demonstrated sustained, broad-based
protection in any of the target populations at risk, most importantly children
in developing countries ( Svennerholm and Tobias, 2008 ). Vaccinology efforts
to date have focused on a limited number of antigens, primarily the CFs, LT,
and more recently ST ( Taxt et al., 2010 ) toxoids. This strategy attempts to
achieve broad coverage by incorporating the most widely distributed CFs, and
inducing toxin-neutralizing immunity. Unfortunately, antigenic heterogeneity