Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 768

which is a serious public health problem in developing countries. Nontyphoidal
salmonella are responsible for more deaths in USA than any other foodborne patho-
gen, with a mortality rate of nearly 1% and an estimated total number of annual
cases of one to three millions. In infants, in the elderly, in immunocompromised or
in response to certain serovar, nontyphoidal salmonella can also result in bacteri-
emia and establishment of secondary focal infections (meningithis, septic arthritis,
or pneumonia) (McCormick 2004 ).
Most infections with Salmonella are contracted through contaminated food or
water (Groisman 1997 ) and although it is very rare, direct person to person trans-
mission can occur. Once ingested, most organisms are killed by the low pH of the
stomach, but those that persist target the colon and small intestine (distal illeum) as
a portal entry to the host (Galán et al. 1992 ). In mice, the primary sites of Salmonella
invasion are the ileal Peyer's patches and possibly also the cecal lymphoid patches
(Carter and Collins 1974 ). The follicle-associated epithelium overlying these gut-
associated lymphoid tissues includes the specialized antigen-sampling M cells,
which are a major site of invasion by diverse pathogens (Giannasca and Neutra
1993 ). Interaction of salmonellae with intestinal M cells is accompanied by loss of
cell surface microvilli and remodelling of the apical membrane to form structures
resembling membrane ruffles, and massive uptake of extracellular fluid in the form
of macropinosomes (Clark et al. 1996 ; Finlay 1994 ; García del Portillo and Finlay
1994 ). Bacterial invasion correlates with the appearance of transient Salmonella -
surface appendage-like structures termed “invasomes” (Ginocchio et al. 1994 ),
formation of filamentous endocytic vacuoles that contain lysosomal membrane
glycoproteins (García del Portillo et al. 1993 ) and the intracellularly replicating
bacteria.
Salmonella spp. pass through the intestinal epithelial barrier to gain access to
mesenteric lymph nodes from which point the bacteria are eventually transported
to the bloodstream and more distant sites of infection such as the liver and spleen
(Hook 1990 ). Once colonized, the bacteria may then potentially disseminate to
the lungs, gallbladder, kidneys or central nervous system. The nontyphoid spe-
cies of Salmonella tend to produce a more localized response where they elicit
an acute inflammatory response through dendritic cells that manifests itself as
fever, diarrhea and abdominal cramping. This inflammatory host response can
actually benefit the intestinal pathogens and contribute to the nature and severity
of the infection by establishing a competitive advantage against the native flora
(Owens and Warren 2010 ). However, the typhi serotype can develop the more
invasive disease resulting in bacteremia. The severity of disease is related to
the serotype, number of organisms, and host factors (Finlay 1994 ; Owens and
Warren 2010 ).
Soon after entry, the Salmonella-containing vacuole (SCV) displays markers of
early endosomes. The SCV recruits Rab7 and a subset of lysosomal markers
(LAMP1 and vATPase) by selective fusion with late endosomes and/or lysosomes.
A small portion of intracellular Salmonella exits the SCV and resides in the host
cytoplasm. These bacteria are targeted for ubiquitination (Perrin et al. 2004 ) and
subsequently cleared by autophagy (Birmingham et al. 2006 ).