Francisella tularensis is best known as the zoonotic, highly infectious etiologi

c agent of the human disease, tularemia. There are three recognized species in t
he genus Francisella: F. tularensis, F. novicida, and F. philomiragia. All three
species can cause human infections, although F. novicida and F. philomiragia ra
rely do. Disease caused by F. tularensis can be mild but it usually is acute, se
vere and febrile; infection with a common North American strain can be life thre
atening.
Disease
Virulence Factors of the Bacterium
The possible mechanism(s) of Francisella pathogenesis in animals or humans have
been studied only for F. tularensis and the related attenuated vaccine strain (F
. tularensis LVS). No secreted toxins or other protein virulence factors of F. t
ularensis have been identified to date. Although all strains of F. tularensis ar
e Gram negative and have an LPS, the molecule essentially lacks traditional endo
toxic activity, as well as a number of immunomodulatory activities, including st
imulation of tumor necrosis factor (TNF) alpha production.
The only consistent virulence factor identified to date is the bacterial capsule
. Methods were developed for removing capsule from the virulent F. tularensis st
rain Schu S4 and were used to demonstrate that the resulting viable bacteria wer
e less virulent (LD50 reduced about 100-fold) in guinea pigs but not in mice. El
ectron microscopy demonstrated both the initial presence of a capsule and its re
moval following treatment, but it remains possible that other bacterial factors
were affected by treatment. The capsule itself was neither toxic nor immunogenic
, suggesting that its role in virulence was related more likely to protection of
the intact bacteria against host defenses. Similarly, loss of capsule by F. tul
arensis LVS, through manipulation of culture conditions, resulted in bacteria wi
th lowered virulence in mice. More directly, a capsule-deficient mutant of F. tu
larensis LVS, derived by chemical mutagenesis, was much less virulent than the p
arent strain in outbred mice. The loss of virulence was probably due to increase
d sensitivity of the mutant (designated LVSR) to killing by serum through activa
tion of the classical complement pathway. Paradoxically, LVSR also was less susc
eptible to intracellular oxygen-dependent killing by human polymorphonuclear leu
kocytes (PMNs), suggesting that host recognition of the capsule also was respons
ible for activation of PMNs. Other research demonstrated that LVSR also lacked m
uch of its LPS O antigen, which may be the basis for serum sensitivity. F. novic
ida, which apparently does not have a capsule, is nonetheless resistant to the b
actericidal action of serum; in contrast to LPS from F. tularensis, however, LPS
purified from F novicida appears to be endotoxic and may retain the ability to
stimulate nitric oxide production from macrophages. The relationship, if any, of
endotoxin activity to disease produced by F. novicida is unknown.
Disease progression and pathology have been described in monkey models of aeroso
l infection with both Type A and Type B F. tularensis. Even though monkeys appe
ar somewhat more susceptible to Francisella infection, the course of disease in
monkeys parallels that in humans. Infected monkeys exhibited an acute febrile il
lness with pneumonia when bacteria were introduced by aerosol. Bacteria multipli
ed readily in the lungs, disseminated to regional lymph nodes, and then spread t
o spleen and liver; surviving animals cleared bacteria within 2 months. The caus
e of death in lethal cases, however, was not specifically determined, but was ge
nerally assumed to follow overwhelming bacterial burden and liver failure. Speci
fic bacterial virulence factors responsible for disease progression, however, we
re not identified.