Host innate recognition of an intestinal bacterial pathogen induces TRIF-dependent protective immunity

Sotolongo, John P.; España, Cecilia; Echeverry, Andrea; Siefker, David; Altman, Norman H.; Zaias, Julia; Santaolalla, Rebeca; Ruiz, Jose; Schesser, Kurt; Adkins, Becky; Fukata, Masayuki

doi:10.1084/jem.20110547

Cited by 44 publications

(56 citation statements)

References 43 publications

(53 reference statements)

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“…Although Trif LPS2 Ms responded to Th17 cells, overall suppression of bacterial growth in Trif LPS2 Ms was still significantly lower than that in WT Ms. This may be due to a fundamental phagocytic defect in Trif LPS2 Ms, as we showed in our earlier report (7). In addition, TRIF-mediated interaction of APCs to memory T cells seems to be crucial for memory immunity to eliminate Gram-negative pathogens in the secondary infection because memory T cells require CD28 costimulation for maximal expansion (34).…”

Section: Although a Majority Of Cd4mentioning

confidence: 49%

“…However, we previously showed defective neutrophil infiltration in Trif LPS2 mice (7). Increased numbers of Th17 cells in Trif LPS2 mice were also found in the Peyer's patches (PP) 4 days after oral infection with Y. enterocolitica (Fig.…”

Section: Lps2mentioning

confidence: 83%

“…Single-cell suspensions from the spleen, mesenteric lymph nodes (MLN), and Peyer's patches (PP) were prepared by mechanical disruption with 70-m nylon mesh. Peritoneal Ms were isolated as described previously (7). Exclusion of floating cells after 48 h incubation of peritoneal lavage allowed us to collect macrophages (over 97% of adherent cells expressed F4/80).…”

Section: Methodsmentioning

confidence: 99%

“…Our previous findings regarding the unique role of innate TRIF signaling in intestinal defense against Gram-negative bacteria along with the evidence that TRIF is required for induction of costimulatory molecules and major histocompatibility complex (MHC) class II antigens suggest that TRIF may play an important role at the innate and adaptive interface (7)(8)(9).…”

Section: H Ost Defense Against Bacterial Pathogens Utilizes Innate Phmentioning

confidence: 99%

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TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens

et al. 2015

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H ost defense against bacterial pathogens utilizes innate phagocytes and CD4 ϩ T cells, and successful interaction between innate and adaptive immunity establishes immunological memory. A fine interplay between innate and adaptive immune responses is necessary to eliminate pathogenic bacteria from the gastrointestinal tract without destruction of normal flora, mucosal barrier function, and gut homeostasis. However, the mechanisms regulating the interactions between innate and adaptive immunity during enteric bacterial infections have yet to be fully determined.Innate immunity covers immediate host defense against pathogens in a non-antigen-specific manner while the body is conducting initiation and calibration of adaptive immunity. In this system, pathogen-experienced antigen-presenting cells (APCs) induce differentiation of cytotoxic and helper T (Th) cells that form pathogen-specific acquired immunity. Multiple types of Th cells are generated in local lymphoid tissues during infection, while Th17 cell generation is dominant in the intestine (1). The antibacterial properties of Th17 cells have been observed in lung infections with Gram-negative extracellular bacteria (2, 3). In the intestine, however, the role of Th17 cells in host resistance to bacterial infection seems to be more complicated, as they may work as innate immune cells (4, 5). Although the importance of memory CD4 ϩ T cells in host defense against bacterial infection has been well established, the exact extent of coverage by memory Th17 cells has yet to be determined.TIR domain-containing adapter-inducing beta interferon (TRIF) is an adapter molecule that transduces intracellular signaling upon recognition of Gram-negative bacteria by Toll-like receptor 4 (TLR4) or double-stranded-RNA (dsRNA) viruses by TLR3 (6). Our previous findings regarding the unique role of innate TRIF signaling in intestinal defense against Gram-negative bacteria along with the evidence that TRIF is required for induction of costimulatory molecules and major histocompatibility complex (MHC) class II antigens suggest that TRIF may play an important role at the innate and adaptive interface (7-9).In this study, we sought to determine the role of TRIF signaling in establishing immunological memory as well as in conferring protective immunity against Gram-negative bacterial infection. We show that TRIF-deficient (Trif LPS2 ) mice failed to demonstrate increased resistance to secondary infection. TRIF deficiency resulted in the enhanced generation and maintenance of CD4 ϩ central memory T (T CM ) cells that expressed interleukin 17 (IL-17) in an antigen-specific manner. These IL-17 ϩ CD4 ϩ T cells facilitated neutrophil influx to the primary infection site and conferred on macrophages (Ms) full bactericidal function to eliminate Gram-negative pathogens only when TRIF signaling was present in innate immune cells. Therefore, our results highlight the importance of TRIF in regulating the balance between innate and adaptive immune responses to develop immune resistance to reinfecti...

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Section: Although a Majority Of Cd4mentioning

confidence: 49%

Section: Lps2mentioning

confidence: 83%

Section: Methodsmentioning

confidence: 99%

Section: H Ost Defense Against Bacterial Pathogens Utilizes Innate Phmentioning

confidence: 99%

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TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens

et al. 2015

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“…To date, more than 10 TLRs have been identified in mice (14). The importance of these pathways in macrophage killing of invading pathogens has been demonstrated in various studies (15)(16)(17)(18). Although TLR4 signaling can take place through both pathways, the majority of genes expressed in LPS-activated macrophages appear to use a TRIF-dependent pathway, implying that the TRIF-dependent pathway may serve as a pivotal regulator of host defense against Gram-negative pathogens (19).…”

mentioning

confidence: 99%

Sterile-α- and Armadillo Motif-Containing Protein Inhibits the TRIF-Dependent Downregulation of Signal Regulatory Protein α To Interfere with Intracellular Bacterial Elimination in Burkholderia pseudomallei-Infected Mouse Macrophages

Baral

Utaisincharoen

2013

Infect Immun

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Burkholderia pseudomallei, the causative agent of melioidosis, evades macrophage killing by suppressing the TRIF-dependent pathway, leading to inhibition of inducible nitric oxide synthase (iNOS) expression. We previously demonstrated that virulent wild-type B. pseudomallei inhibits the TRIF-dependent pathway by upregulating sterile-␣-and armadillo motif-containing protein (SARM) and by inhibiting downregulation of signal regulatory protein ␣ (SIRP␣); both molecules are negative regulators of Toll-like receptor signaling. In contrast, the less virulent lipopolysaccharide (LPS) mutant of B. pseudomallei is unable to exhibit these features and is susceptible to macrophage killing. However, the functional relationship of these two negative regulators in the evasion of macrophage defense has not been elucidated. We demonstrated here that SIRP␣ downregulation was observed after inhibition of SARM expression by small interfering RNA in wild-type-infected macrophages, indicating that SIRP␣ downregulation is regulated by SARM. Furthermore, this downregulation requires activation of the TRIF signaling pathway, as we observed abrogation of SIRP␣ downregulation as well as restricted bacterial growth in LPS mutant-infected TRIF-depleted macrophages. Although inhibition of SARM expression is correlated to SIRP␣ downregulation and iNOS upregulation in gamma interferon-activated wild-type-infected macrophages, these phenomena appear to bypass the TRIF-dependent pathway. Similar to live bacteria, the wild-type LPS is able to upregulate SARM and to prevent SIRP␣ downregulation, implying that the LPS of B. pseudomallei may play a crucial role in regulating the expression of these two negative regulators. Altogether, our findings show a previously unrecognized role of B. pseudomallei-induced SARM in inhibiting SIRP␣ downregulation-mediated iNOS upregulation, facilitating the ability of the bacterium to multiply in macrophages.

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Yersinia Activation of Type I Interferon

Dhariwala

Anderson

2014

Bacterial Activation of Type I Interferons

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Host innate recognition of an intestinal bacterial pathogen induces TRIF-dependent protective immunity

Abstract: TRIF signaling triggers the amplification of macrophage bactericidal activity sufficient to eliminate invading intestinal pathogens through the sequential induction of IFN-β and IFN-γ from macrophages and NK cells, respectively.

Cited by 44 publications

References 43 publications

TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens

TIR Domain-Containing Adapter-Inducing Beta Interferon (TRIF) Mediates Immunological Memory against Bacterial Pathogens

Sterile-α- and Armadillo Motif-Containing Protein Inhibits the TRIF-Dependent Downregulation of Signal Regulatory Protein α To Interfere with Intracellular Bacterial Elimination in Burkholderia pseudomallei-Infected Mouse Macrophages

Yersinia Activation of Type I Interferon

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