Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi

Song, Jeongmin; Wilhelm, Cara L.; Wangdi, Tamding; Maira-Litrán, Tomas; Lee, Seung Joo; Raetz, Megan; Sturge, Carolyn R.; Mirpuri, Julie; Pei, Jimin; Grishin, Nick V.; McSorley, Stephen J.; Gewirtz, Andrew T.; Bäumler, Andreas J.; Pier, Gerald B.; Galán, Jorge E.; Yarovinsky, Felix

doi:10.1016/j.cell.2016.02.015

Cited by 23 publications

(31 citation statements)

References 6 publications

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“…While this model would be a great step forward for Salmonella Typhi vaccine testing, issues have arisen surrounding its reproducibility. It has since been reported that five separate groups at four institutions have been unable to replicate these results (68). While standing by their results, the original authors have also noted high variability in the susceptibility of the tlr11 Ϫ/Ϫ mice over time (69).…”

Section: Systemic Infection Small Animal Modelsmentioning

confidence: 71%

Animal Models for Salmonellosis: Applications in Vaccine Research

Higginson

Simon

Tennant

2016

Clin Vaccine Immunol

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Salmonellosis remains an important cause of human disease worldwide. While there are several licensed vaccines for Salmonella enterica serovar Typhi, these vaccines are generally ineffective against other Salmonella serovars. Vaccines that target paratyphoid and nontyphoidal Salmonella serovars are very much in need. Preclinical evaluation of candidate vaccines is highly dependent on the availability of appropriate scientific tools, particularly animal models. Many different animal models exist for various Salmonella serovars, from whole-animal models to smaller models, such as those recently established in insects. Here, we discuss various mouse, rat, rabbit, calf, primate, and insect models for Salmonella infection, all of which have their place in research. However, choosing the right model is imperative in selecting the best vaccine candidates for further clinical testing. In this minireview, we summarize the various animal models that are used to assess salmonellosis, highlight some of the advantages and disadvantages of each, and discuss their value in vaccine development.A nimal models are indispensable tools for assessing candidate vaccines, with preclinical animal safety, immunogenicity, and efficacy data being prerequisite for regulatory agencies such as the U.S. Food and Drug Administration (FDA) prior to undertaking early-stage clinical trials. However, not all animal models are created equal. While some models are highly robust and closely mimic clinical infection, others are contrived and far removed from clinical relevance. Choosing the right animal model for the vaccine under investigation is imperative in determining its safety and/or effectiveness.Salmonella spp. are often used as model organisms to study bacterial pathogenesis and host-microbe interactions, due to the ability of certain Salmonella serovars to readily infect animals. As such, there are a myriad of animal models available to vaccine developers. These range from colonization or lethality models to those involving complex surgical techniques (Table 1). The choice of model is often related not only to relevance but also cost, ethics, housing requirements, and the availability of appropriate technical expertise. While most researchers utilize one model or another, integration of data from multiple animal models can provide a more complete understanding of the safety of a candidate vaccine and/or predict how a potential vaccine may perform in humans. In this minireview, we provide background on Salmonella clinical syndromes and pathogenesis and then summarize the various animal models that have been used for Salmonella vaccine research. We include a brief discussion of the technical aspects, advantages, and limitations of each model, followed by a review of the literature surrounding its use in vaccine evaluation. While there has been considerable development for veterinary Salmonella vaccines, here we will focus solely on vaccines and models for human salmonellosis.

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Section: Systemic Infection Small Animal Modelsmentioning

confidence: 71%

Animal Models for Salmonellosis: Applications in Vaccine Research

Higginson

Simon

Tennant

2016

Clin Vaccine Immunol

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“…This variable susceptibility of Tlr11 -/- mice could be due to the parasite strains used for infection, i.e ME49 versus Pru, which can elicit a different immune response (65). Alternatively, the different susceptibility of Tlr11 -/- mice could be explained by variations in the microbiota in these mice, as they were housed in different colonies (5, 42, 43, 57, 66)(43). Acute mortality of mice upon Toxoplasma infection depends on the route of infection and virulence of the parasite strain (67).…”

Section: Discussionmentioning

confidence: 99%

“…To generate the Tlr11 -/- mouse colony, two 4-week-old Tlr11 -/- male mice (42, 66) were bred with wild-type female C57BL/6 mice (Jackson laboratories). The Tlr11 +/- F1 progeny mice were subsequently crossed to obtain Tlr11 -/- mice.…”

Section: Methodsmentioning

confidence: 99%

ToxoplasmaGRA15 and GRA24 are important activators of the host innate immune response in the absence of TLR11

Mukhopadhyay

Arranz-Solís

2020

Preprint

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15The murine innate immune response against Toxoplasma gondii is predominated by the 16 interaction of TLR11/12 with Toxoplasma profilin. However, mice lacking Tlr11 or 17 humans, who do not have functional TLR11 or TLR12, still elicit a strong innate immune 18 93 and GRA24 drive the classical activation of macrophages (M1) via the activation of 94 NFκB and p38 MAPK (35, 37, 38). By contrast, the polymorphic kinase ROP16 from 95 type I and type III strains drives the alternative activation of macrophages (M2) via the 96 phosphorylation of the STAT6 and STAT3 transcription factors (37, 39, 40). It is likely 97 that the deliberate activation of the immune response by Toxoplasma effectors is a 98 strategy to limit its virulence thereby promoting the survival of its host and the formation 99 of tissue cysts, which are the only stages in the intermediate host that are orally 100 infectious. 101Given the large impact of GRA15 and GRA24 on macrophage gene expression 102 and production of IL12 and IL1β, it seems surprising that their in vivo effect on parasite 103 virulence is relatively minor (31, 35). Mice infected with type II Δgra15 or Δgra24 104 parasites had elevated parasite numbers early after infection, but as the infection 105 progressed, parasite burden and host susceptibility were no different from those 106 following wild-type type II strain infections (31, 35, 41). Increased type II Δgra15 early 107 parasite burdens were associated with decreased IL12 and IFNγ levels 2 days after 108 infection (31). Similar results were obtained after infection of mice with the Δgra24 strain 109 (35). Possibly, the effects of GRA15 and GRA24 in these studies were masked by 110 profilin: as the infection progresses and parasites lyse out of host cells, PAMPS, such 111 as profilin, are released and activate TLR11/12. At this stage, IL12/IL1β and subsequent 112 IFNγ production are probably no longer dependent on GRA15 and GRA24. However, 113 humans and many animals do not have functional TLR11/12 or IFNγ-inducible IRGs 114 (17), and therefore Toxoplasma virulence of a particular strain in mice might not 115 correlate with virulence in other species. In Tlr11 -/mice, neutrophils are the main 116 producers of IFNγ with a minor role of NK and T cells (42). The production of IFNγ by 117 neutrophils is dependent on IL1β and TNFα, but not on IL12 (42). In addition, IL18 118 secreted upon inflammasome activation plays a key role in the IFNγ response from 119 CD4 + T cells and the subsequent disease outcome in Tlr11 -/mice (43). Thus, GRA15 120 and GRA24, by inducing IL1β, IL18, TNFα and IL12, might play an important role in the 121 production of IFNγ in hosts lacking TLR11. Herein, we tested this hypothesis by 122 infecting Tlr11 -/mice with wild-type, Δgra15, Δgra24 and Δgra15/24 parasites. Our data 123 indicate that although parasites that do not express GRA15 and/or GRA24 induced 124 significantly less inflammatory cytokines, a significant increase in virulence compared to 125 wild-type was only observed after subcutaneous infecti...

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“…Notably, multiple groups, including the group that originally characterized the model, have recently reported that the original S. Typhi infection model in the TLR11 −/− is not reproducible and that these mice may not actually be susceptible to infection with S . Typhi [49,50]. As such TLR11 −/− mice are likely not a suitable model for the study of S .…”

Section: Overview Of Salmonella Infectionmentioning

confidence: 99%

Salmonella infection: Interplay between the bacteria and host immune system

2017

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Salmonella infection causes morbidity and mortality throughout the world with the host immune response varying depending on whether the infection is acute and limited, or systemic and chronic. Additionally, Salmonella bacteria have evolved multiple mechanisms to avoid or subvert immunity to its own benefit and often the anatomical location of infection plays a role in both the immune response and bacterial fate. Here, we provide an overview of the interplay between the immune system and Salmonella, while discussing how different host and bacterial factors influence the outcome of infection.

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Absence of TLR11 in Mice Does Not Confer Susceptibility to Salmonella Typhi

Cited by 23 publications

References 6 publications

Animal Models for Salmonellosis: Applications in Vaccine Research

Animal Models for Salmonellosis: Applications in Vaccine Research

ToxoplasmaGRA15 and GRA24 are important activators of the host innate immune response in the absence of TLR11

Salmonella infection: Interplay between the bacteria and host immune system

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