MyD88 Signaling Is Indispensable for Primary Influenza A Virus Infection but Dispensable for Secondary Infection

Seo, Sang Uk; Kwon, Hyung Joon; Song, Joo Hye; Byun, Young Ho; Seong, Baik Lin; Kawai, Taro; Akira, Shizuo; Kweon, Mi Na

doi:10.1128/jvi.01675-10

Cited by 85 publications

(91 citation statements)

References 61 publications

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“…Although epithelial cells primarily signal as a result of intracellular detection, APCs-with their ability to phagocytose and high basal expression of TLRs-can produce cytokines through either pathway (49). In agreement with past studies demonstrating that myeloid differentiation primary response gene 88 signaling is not required to control early virus infection (50,51), our results indicate that virus replication and activation of RIG-I is the primary source of virus-induced signaling regardless of the cellular source. It is perplexing that inhibition of virus replication within immune cells leads to such drastic defects in overall IFN-I production, given that IAV replication predominates in lung epithelia, where virus fitness is not altered.…”

Section: Discussionsupporting

confidence: 79%

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Langlois¹,

Varble²,

Chua³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A coordinated innate and adaptive immune response, orchestrated by antigen presenting cells (APCs), is required for effective clearance of influenza A virus (IAV). Although IAV primarily infects epithelial cells of the upper respiratory tract, APCs are also susceptible. To determine if virus transcription in these cells is required to generate protective innate and adaptive immune responses, we engineered IAV to be selectively attenuated in cells of hematopoietic origin. Incorporation of hematopoietic-specific miR-142 target sites into the nucleoprotein of IAV effectively silenced virus transcription in APCs, but had no significant impact in lung epithelial cells. Here we demonstrate that inhibiting IAV replication in APCs in vivo did not alter clearance, or the generation of IAV-specific CD8 T cells, suggesting that cross-presentation is sufficient for cytotoxic T lymphocyte activation. In contrast, loss of in vivo virus infection, selectively in APCs, resulted in a significant reduction of retinoic acid-inducible gene I-dependent type I IFN (IFN-I). These data implicate the formation of virus replication intermediates in APCs as the predominant trigger of IFN-I in vivo. Taking these data together, this research describes a unique platform to study the host response to IAV and provides insights into the mechanism of antigen presentation and the induction of IFN-I.

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Section: Discussionsupporting

confidence: 79%

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Langlois¹,

Varble²,

Chua³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Immune markers used to determine the efficacy of vaccination are commonly based on the primary immune response against Brucella. However, it has been often observed in several other infectious models (23)(24)(25)(26)(27)(28)(29) that the primary and secondary responses do not necessarily use same classes of effector mechanisms. In a recent study (55) using a large panel of gene-deficient mice, we attempted to clearly identify the effector cells and signaling pathways implicated in the primary immune response against B. melitensis infection.…”

Section: Discussionmentioning

confidence: 99%

“…Rare studies (19)(20)(21)(22) have tried to characterize the nature of the protective immune response induced by vaccination and thus identify potential protective immune markers for the development of a rational strategy to select candidate vaccines. These markers cannot be deduced from studies of the primary immune response against Brucella, because, as shown in other infectious models (23)(24)(25)(26)(27)(28)(29), primary and secondary immune responses frequently implicate different classes of effectors.…”

mentioning

confidence: 99%

Humoral Immunity and CD4+ Th1 Cells Are Both Necessary for a Fully Protective Immune Response upon Secondary Infection with Brucella melitensis

Vitry

Mambres

Trez

et al. 2014

The Journal of Immunology

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Brucella spp are intracellular bacteria that cause brucellosis, one of the most common zoonoses in the world. Given the serious medical consequences of this disease, a safe and effective human vaccine is urgently needed. Efforts to develop this vaccine have been hampered by our lack of understanding of what constitutes a protective memory response against Brucella. In this study, we characterize the cells and signaling pathways implicated in the generation of a protective immune memory response following priming by the injection of heat-killed or live Brucella melitensis 16M. Using a panel of gene-deficient mice, we demonstrated that during a secondary recall response, both the Brucella-specific humoral response and CD4+ Th1 cells must act together to confer protective immunity in the spleen to B. melitensis infection. Humoral protective immunity is induced by the inoculation of both heat-killed and live bacteria, and its development does not require T cells, MyD88/IL-12p35 signaling pathways, or an activation-induced deaminase–mediated isotype switch. In striking contrast, the presence of memory IFN-γ–producing CD4+ Th1 cells requires the administration of live bacteria and functional MyD88/IL-12p35 pathways. In summary, our work identifies several immune markers closely associated with protective immune memory and could help to define a rational strategy to obtain an effective human vaccine against brucellosis.

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“…These innate immune receptors initiate an antigenspecific adaptive immune response by the induction of IFN-␣/␤ and proinflammatory cytokines. Thus, it is possible that in the absence of TLR7, the collective signaling through other PRRs is sufficient to facilitate the induction of adaptive immunity during virus infection (4,10,35,38,52). In the context of immunization with split inactivated influenza vaccine, the vaccine components are confined to the major histocompatibility complex class II endocytic pathway.…”

Section: Fig 3 Tlr7mentioning

confidence: 99%

TLR7 Recognition Is Dispensable for Influenza Virus A Infection but Important for the Induction of Hemagglutinin-Specific Antibodies in Response to the 2009 Pandemic Split Vaccine in Mice

Jeisy-Scott

Kim

Davis

et al. 2012

J Virol

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Recognition of pathogen-associated molecular patterns by pattern recognition receptors of the innate immune system is crucial for the initiation of innate and adaptive responses and for immunological memory. We investigated the role of TLR7 in the induction of adaptive immunity and long-term memory following influenza virus infection and vaccination in C57BL/6 mice. During infection with influenza A/PR8/34 virus, the absence of either TLR7 or MyD88 leads to reduced virus-specific antibodies in the serum and antibody-secreting cells in their secondary lymphoid organs, particularly in bone marrow. In spite of this, the absence of TLR7/MyD88 signaling did not impair the production of protective antibodies. Following immunization with the 2009 pandemic inactivated split vaccine, TLR7 −/− mice had significantly lower levels of germinal center formation, antibody-secreting cells, and circulating influenza virus-specific antibodies than control animals. Consequently, TLR7 −/− mice failed to develop protective immunological memory upon challenge. Furthermore, the immunogenicity of the split vaccine was likely due to TLR7 recognition of virion RNA, as its removal from the split vaccine significantly reduced the levels of influenza virus-specific antibodies and compromised the vaccine protective efficacy in mice. Taken together, our data demonstrate that TLR7 plays an important role in vaccine-induced humoral immune responses to influenza virus through the interaction with viral RNA present in the split vaccine.

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MyD88 Signaling Is Indispensable for Primary Influenza A Virus Infection but Dispensable for Secondary Infection

Cited by 85 publications

References 61 publications

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Humoral Immunity and CD4+ Th1 Cells Are Both Necessary for a Fully Protective Immune Response upon Secondary Infection with Brucella melitensis

TLR7 Recognition Is Dispensable for Influenza Virus A Infection but Important for the Induction of Hemagglutinin-Specific Antibodies in Response to the 2009 Pandemic Split Vaccine in Mice

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