Meningitis-associated Escherichia coli - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 297

FIGURE 10.1 Transmission electron micrograph of human brain microvascular endothelial
cell monolayer infected with meningitis-causing E. coli K1 strain RS218 (018:K1, B2 group).
Cellular protrusions surround internalizing E. coli (left) and internalized E. coli are found within
membrane-bound vacuoles (right). Scale bar = 1 µm. (Adapted from Kim, 2003 , figure 3.)
enclosed vacuole without intracellular multiplication and without any change
in the integrity of the HBMEC monolayer ( Nemani et al., 1999 ; Stins et al.,
2001 ; Kim, 2003 ). No free bacteria are found in the cytoplasm of HBMEC or
between adjacent HBMEC.
The in vivo blood-brain barrier model has been developed by induc-
ing hematogenous meningitis in infant rats and mice. In this animal model,
E. coli is administered orally, subcutaneously, intracardially, or intravenously,
resulting in bacteremia and subsequent entry into the CNS ( Kim et al., 1992 ;
Huang et al., 1995, 1999 ; Wang et al., 1999 ; Hoffman et al., 2000 ; Khan et al.,
2002 ; Wang and Kim, 2002 ; Wang et al., 2004 ; Zhu et al., 2010a,b ). Studies in
experimental hematogenous meningitis models indicate that the primary site
of entry into the CNS for circulating E. coli is the cerebral vasculature, not the
choroid plexus ( Kim et al., 1992 ). E. coli entry into the CNS was documented
without any change in the blood-brain barrier permeability as well as without
concomitant presence of host inflammatory cells (e.g. PMNs, macrophages)
( Kim et al., 1992, 1997 ), excluding the possibility that E. coli penetrates into
the brain using the paracellular mechanism or the Trojan-horse mechanism via
transmigration of E. coli -infected phagocytic cells. Taken together, these find-
ings indicate a transcellular penetration of meningitis-causing E. coli K1 across
the blood-brain barrier.
It is important to point out that E. coli is an enteric organism and there are no
data supporting the concept that E. coli meningitis occurs following inhalation
or intranasal spread ( Mittal et al., 2010 ) and also there are no data indicating
that an exposure to passive smoking (e.g. nicotine) increases the development
of E. coli meningitis ( Chi et al., 2011 ).
Studies with the above-mentioned in vitro and in vivo models of the blood-
brain barrier have demonstrated that successful traversal of the blood-brain bar-
rier by circulating E. coli requires (a) a high degree of bacteremia; (b) E. coli
binding to and invasion of HBMEC; and (c) traversal of the blood-brain barrier
as live bacteria ( Kim et al., 1992 ; Hoffman et al., 1999 ; Kim 2001, 2002, 2003,
2008, 2010, 2012 ) ( Table 10.1 ).