2. Salmonella

Salmonella transmission

eating foods contaminated with small amounts of feces

Which genus of salmonella is most important clinically

Salmonella enterica

Which subspecies of S. enterica is most important clinically

Salmonella enterica subsp. enterica (I)

S. enterica subsp enterica I important clinical serovar nomenclature

Serovar names are capitalized, but not italicized

Salmonella Typhi

S. enterica serovars are based on 

O antigen from LPS 
H antigen from flagella 

O antigen is found in

LPS

H antigen is found in

Flagella

Most common Salmonella serovars worldwide

Enteritidis and Typhimurium

Typhoidal salmonella (TS)

group of serovars that cause typhoid fever
Ex: Typhi, Paratyphi, and Sendai

Non typhoidal Salmonella (NTS) 

All serovars that DO NOT cause typhoid fever 
Ex: Enteritidis, Typhimurium

Salmonella pathogenicity islands (SPIs)

Many of the genes that are unique
to Salmonella serovars are found on large
discrete genomic islands in the chromosome
VIRULENCE

How many SPIs are there and where do they come from

24 Salmonella pathogenicity
islands (SPIs) acquired by horizontal
gene transfer

Salmonella pathogenicity island-1 (SPI-1) is found

in all Salmonella species and subspecies (even S. bongori)

Salmonella pathogenicity island-1 (SPI-1) encodes

T3SS which is essential
for export of effector proteins that are
required for invasion of host cells

Salmonella pathogenicity island-2 (SPI-2) is found in

only in S. enterica

Salmonella pathogenicity island-2 (SPI-2) encodes

additional T3SS, that
secretes proteins that are essential for
intracellular survival and for preventing
acidification of the Salmonella containing vacuole (SCV)

How does the bacteria know where it is located in the intestinal tract

Bile salts serve as an important environmental cue to regulate the T3SS

S. typhi SP-1 T3SS1 regulation 

Expression of SP-1 T3SS1 and
invasion of epithelia cells is
increased

S typhimurium SP-1 T3SS1 regulation 

Expression of SP-1 T3SS1 and
invasion of epithelia cells is
repressed

How is oxygen used to regulate T3SS

The intestinal epithelium has more oxygen than the lumen

S. paratypi oxygen regulation

SPI-1 expression and epithelial
invasion is decreased in aerobic
conditions

S. typhimurium oxygen regulation

Expression of SPI-1 was similar
between aerobic and
microaerobic conditions

Aerobically grown bacteria are
more invasive at the intestinal
epithelium

S typhi temp regulation 

shows reduced invasion
and motility at fever temperatures
(42°C) and SPI-I is decreased, but SPI-2 is increased and intracellular replication increases

S. typhimurium temp regulation

invasion and
motility is not affected at fever
temperatures
SPI-2 is increased but intracellular replication doesn’t change.

S. Typhi Vi Capsule

a polysaccharide that inhibits IgM
binding and complement-mediated phagocytosis

S. Typhi Vi Capsule binds

human DC-SIGN activates RAF-1 (a kinase) that
ultimately leads to an increase in IL-10 and reduces
pro-inflammatory cytokines

upregulation of a capsule 

is associated with
increased virulence and invasive disease

Does S. paratyphi A have Vi capsule

No but it avoids IgM in other ways

How does S. paratyphi A avoid IgM

avoids IgM binding
and antibody-mediated complement
activation by expressing long O-chains of
LPS

Both S. Typhi and S. Paratyphi A avoid
antibody binding through

convergent
evolution

convergent
evolution

occurs when different species develop similar traits independently to adapt to similar environments or challenges.

TS and NTS motility

peritrichous (all over) flagella, which confer
motility

NTS flagella length

longer and make NTS
serovars more motile

NTS flagella modification

methylated, which
promotes adhesion to host cells

S. Typhimurium uses phase
variation

phase variation to switch between
expression of fliC and fljB (main
filament components of flagella)

S. Typhimurium flagella are also
involved in

chemotaxis to taxi
toward host molecules nitrate and
tetrathionate

Why would S. typhimurium want host molecules nitrate and
tetrathionate

are used as
alternate terminal electron acceptors
during anaerobic respiration and are only
produced by the host during
inflammation

NTS fimbriae

Serovars with wider host
range have more types of fimbriae
compared with the typhoid Salmonella

TS fimbriae

have very few fimbrial types and
are restricted to only the human host

Salmonella entry to host cell- Trigger mechanism

characterized by large membrane ruffles at the bacterial entry site

Salmonella entry to host cell- zipper mechanism

characterized by weak membrane
rearrangements

Membrane ruffling

Using T3SS, both genera inject bacterial
effectors to remodel host actin and induce
the formation of lamellipodia and
membrane ruffling

How does T3SS induce membrane ruffling

Using its T3SS1, Salmonella injects
SopE, SopE2, and SopB which
activate Rho GTPases (yellow in
figure) to allow actin cytoskeleton
remodeling

T3SS1 effectors SipA and SipC

bind directly to actin for remodeling to induce membrane ruffling

Spv operon 

Salmonella plasmid virulence) whose effectors alter host cell
cytoskeleton to enhance bacterial survival

SpvB toxin type

AB toxin without B domain

SpvB toxin action

ADP-ribosylates actin and prevents
actin polymerization

SpvB toxin effect

ADP-ribosylation of actin ultimately
blocks cell cycle progression, generally at
M phase. This leads to apoptosis

Which serovars have SpvB 

NTS

Typhoid toxin type

A2B5 toxin

Typoid toxin A domains

CdtB and PltA

Typoid toxin A domain- CdtB

nuclease that cleaves DNA and
ultimately leads to apoptosis of the host
cell

Typoid toxin A domain- PltA

Not confirmed but probably ADP-ribosylates
G proteins

Typhoid toxin discovery

first discovered in S. Typhi (how
it got its name)

Typhoid toxin CTD

has been shown to target specific
cell types like brain endothelial cells and immune
cells

ArtAB toxin

AB5 toxin that ADP-ribosylates G proteins

SboC/SeoC Toxin is found in

only in S. bongori

SboC/SeoC Toxin

ADP-ribosylate Src kinases in the
host and prevent phagocytosis

SboC

homologous to SeoC, which is found in S.
enterica arizonae and S. enterica salamae

Generally speaking, S. Typhimurium

triggers proinflammatory reactions

Generally speaking, S. Typhi

dampens the immune response

S. Typhimurium- proinflammation

host production of
proinflammatory
cytokines, such as IL-8,
TNF, and IL-1β starts a
cascade of events that lead
to the recruitment of
macrophages and
neutrophils, then 
inflamed tissues
provide nutrients and
electron acceptors that fuel
the replication

S. typhi- inflammation mitigation- Vi capsule

prevents IgM, decreases complement, less neutrophils recruited, decrease TLR4 recognition of LPS,

S. typhi- inflammation mitigation- flagella

is downregulated to decrease recognition and inflammation from the host immune system.

S. typhi- inflammation mitigation- typhoid toxin

reduces the number of
circulating neutrophils

Extensively drug resistant Salmonella Typhi- XDR

emerged in 2016 in Pakistan and are resistant to all antibiotic options 

Typhoid vaccine- 2 types

Inactivated and live