Research Article: TLR–Dependent Control of Francisella tularensis Infection and Host Inflammatory Responses

Date Published: November 20, 2009

Publisher: Public Library of Science

Author(s): Allison L. Abplanalp, Ian R. Morris, Bijaya K. Parida, Judy M. Teale, Michael T. Berton, Jörg Hermann Fritz. http://doi.org/10.1371/journal.pone.0007920

Abstract: Francisella tularensis is the causative agent of tularemia and is classified as a Category A select agent. Recent studies have implicated TLR2 as a critical element in the host protective response to F. tularensis infection, but questions remain about whether TLR2 signaling dominates the response in all circumstances and with all species of Francisella and whether F. tularensis PAMPs are predominantly recognized by TLR2/TLR1 or TLR2/TLR6. To address these questions, we have explored the role of Toll-like receptors (TLRs) in the host response to infections with F. tularensis Live Vaccine Strain (LVS) and F. tularensis subspecies (subsp.) novicida in vivo.

Partial Text: Francisella tularensis is a Gram-negative, coccobacillus that replicates within macrophages, neutrophils, hepatocytes and type II lung epithelial cells [1]–[5], and causes the zoonotic disease tularemia in mammalian hosts [6]. Infection of humans occurs naturally by exposure to infected animal carcasses, insect bites, ingestion or inhalation. There are four subspecies (subsp.): tularensis (type A), holarctica (type B), mediasiatica, and novicida. Subsp. tularensis strains are highly virulent (LD50<10–100 CFU) [7], [8], and cause severe disease and death sporadically, predominantly in North America. Subsp. holarctica strains cause a more widespread but less severe disease in Northern Europe, Scandinavia and the former Soviet Union. Subsp. novicida is highly attenuated for humans, and is rarely isolated, but causes lethal disease in mice [9], [10]. Because of the high infectivity, virulence, and ability to be disseminated by aerosol, F. tularensis type A and B strains have been classified as Category A bioweapon agents [11]. A live attenuated vaccine strain (derived from a subsp. holarctica strain and known as LVS) was developed 50–60 years ago [12], but a lack of knowledge about the mechanisms of attenuation and concerns about reversion to virulence have prevented its licensure for use in the U.S. [6], [11]. Although LVS is attenuated in humans, it causes a disease in mice that is very similar to human tularemia, and thus it has been used extensively to model the human disease [13], [14]. The results of this study confirm and extend a recent study that demonstrated that TLR2 is critical for protection of mice against a primary pulmonary infection with F. tularensis LVS [32]. However, in contrast to a previous report [33], we show that the requirement for TLR2 is independent of the route of infection, since TLR2−/− mice had significantly decreased survival rates compared to controls following infection by either the intranasal or the intradermal route. MyD88 also contributes significantly to survival of a primary pulmonary LVS infection, consistent with its reported role in the intradermal infection [33]. The results of this study further demonstrate that the host protective response to primary infection with F. tularensis subsp. novicida is also dependent on TLR2/MyD88 signaling. Importantly, TLR2−/− macrophages are impaired in their ability to express pro-inflammatory cytokines and chemokines in response to F. tularensis LVS infection and pro-inflammatory cytokine expression is significantly impaired in vivo in the lungs of infected TLR2-deficient mice. Finally, this study revealed that neither TLR1−/− nor TLR6−/− mice were any more susceptible to LVS infection than control mice, although a previous study reported an exclusive role for TLR6 in the pro-inflammatory cytokine response of BM-derived dendritic cells to LVS in vitro[39]. Source: http://doi.org/10.1371/journal.pone.0007920

 

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