Recruitment of dendritic cell progenitors to foci of influenza A virus infection sustains immunity.
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ABSTRACT:
SUBMITTER: Cabeza-Cabrerizo M
PROVIDER: S-EPMC7612017 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recruitment of dendritic cell progenitors to foci of influenza A virus infection sustains immunity
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Project description:Type I and type III interferon (IFN) are important in regulating responses to viral infection. Type I IFN signaling is know to contribute to dendritic cell (DC) function, but the contribution of type III IFN remains unknown. To determine changes in migratory dendritic cell gene expression during influenza A virus (IAV) in the presence or absence of type I or type III (IFN) receptors, C57Bl/6 (WT) mice, mice lacking the type I IFN receptor (Ifnar-/-), and mice lacking the type III IFN receptor (Ifnlr-/-) were infected intranasally with 40 plaque forming units (PFU) IAV H1N1 strain A/PR/8/34 or mock infected. On day 4, lung-draining lymph nodes (dLN) were harvested, conventional DC were isolated, and mRNA sequencing (mRNAseq) was performed.
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Project description:The development of influenza A virus (IAV) vaccines capable of inducing cytotoxic CD8 T cell responses could potentially provide superior, long-term protection against multiple, heterologous strains of IAV. Although prior studies demonstrated the effectiveness of baculovirus-derived virus-like particle (VLP) vaccination in generating Ab-mediated protection, the role that CD8 T cell immunity plays in overall VLP-mediated protection is less-well understood. In this article, we demonstrate that intranasal vaccination of mice with a VLP containing the hemagglutinin and matrix 1 proteins of IAV/PR/8/34 leads to a significant increase in hemagglutinin 533-specific CD8 T cells in the lungs and protection following subsequent homologous challenge with IAV. VLP-mediated protection was significantly reduced by CD8 T cell depletion, indicating a critical role for CD8 T cells in protective immunity. Importantly, our results show that VLP vaccine-induced CD8 T cell-mediated protection is not limited to homologous IAV strains. VLP vaccination leads to an increase in protection following heterosubtypic challenge with a strain of IAV that avoids vaccine-induced neutralizing Abs but contains conserved, immunodominant CD8 T cell epitopes. Overall, our results demonstrate the ability of influenza protein-containing VLPs to prime IAV-specific CD8 T cell responses that contribute to protection from homo- and heterosubtypic IAV infections. These results further suggest that vaccination strategies focused on the development of cross-protective CD8 T cell responses may contribute to the development of "universal" IAV vaccines.
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Project description:Exaggerated inflammatory responses during influenza A virus (IAV) infection are typically associated with severe disease. Neutrophils are among the immune cells that can drive this excessive and detrimental inflammation. In moderation, however, neutrophils are necessary for optimal viral control. In this study, we explore the role of the nucleotide-binding domain leucine-rich repeat containing receptor family member Nlrp12 in modulating neutrophilic responses during lethal IAV infection. Nlrp12-/- mice are protected from lethality during IAV infection and show decreased vascular permeability, fewer pulmonary neutrophils, and a reduction in levels of neutrophil chemoattractant CXCL1 in their lungs compared with wild-type mice. Nlrp12-/- neutrophils and dendritic cells within the IAV-infected lungs produce less CXCL1 than their wild-type counterparts. Decreased CXCL1 production by Nlrp12-/- dendritic cells was not due to a difference in CXCL1 protein stability, but instead to a decrease in Cxcl1 mRNA stability. Together, these data demonstrate a previously unappreciated role for Nlrp12 in exacerbating the pathogenesis of IAV infection through the regulation of CXCL1-mediated neutrophilic responses.
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Project description:Leishmania infantum is a protozoan parasite that causes visceral leishmaniasis (VL). This infection triggers dendritic cell (DC) activation through the recognition of microbial products by Toll-like receptors (TLRs). Among the TLRs, TLR9 is required for DC activation by different Leishmania species. We demonstrated that TLR9 is upregulated in vitro and in vivo during infection. We show that C57BL/6 mice deficient in TLR9 expression (TLR9(-/-) mice) are more susceptible to infection and display higher parasite numbers in the spleen and liver. The increased susceptibility of TLR9(-/-) mice was due to the impaired recruitment of neutrophils to the infection foci associated with reduced levels of neutrophil chemoattractants released by DCs in the target organs. Moreover, both Th1 and Th17 cells were also committed in TLR9(-/-) mice. TLR9-dependent neutrophil recruitment is mediated via the MyD88 signaling pathway but is TIR domain-containing adapter-inducing interferon beta (TRIF) independent. Furthermore, L. infantum failed to activate both plasmacytoid and myeloid DCs from TLR9(-/-) mice, which presented reduced surface costimulatory molecule expression and chemokine release. Interestingly, neutrophil chemotaxis was affected both in vitro and in vivo when DCs were derived from TLR9(-/-) mice. Our results suggest that TLR9 plays a critical role in neutrophil recruitment during the protective response against L. infantum infection that could be associated with DC activation.
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Project description:Pertussis (whooping cough) is frequently complicated by concomitant infections with respiratory viruses. Here we report the effect of Bordetella pertussis infection on subsequent influenza virus (PR8) infection in mouse models and the role of pertussis toxin (PT) in this effect. BALB/c mice infected with a wild-type strain of B. pertussis (WT) and subsequently (up to 14 days later) infected with PR8 had significantly increased pulmonary viral titers, lung pathology and mortality compared to mice similarly infected with a PT-deficient mutant strain (?PT) and PR8. Substitution of WT infection by intranasal treatment with purified active PT was sufficient to replicate the exacerbating effects on PR8 infection in BALB/c and C57/BL6 mice, but the effects of PT were lost when toxin was administered 24 h after virus inoculation. PT had no effect on virus titers in primary cultures of murine tracheal epithelial cells (mTECs) in vitro, suggesting the toxin targets an early immune response to increase viral titers in the mouse model. However, type I interferon responses were not affected by PT. Whole genome microarray analysis of gene expression in lung tissue from PT-treated and control PR8-infected mice at 12 and 36 h post-virus inoculation revealed that PT treatment suppressed numerous genes associated with communication between innate and adaptive immune responses. In mice depleted of alveolar macrophages, increase of pulmonary viral titers by PT treatment was lost. PT also suppressed levels of IL-1?, IL-12, IFN-?, IL-6, KC, MCP-1 and TNF-? in the airways after PR8 infection. Furthermore PT treatment inhibited early recruitment of neutrophils and NK cells to the airways. Together these findings demonstrate that infection with B. pertussis through PT activity predisposes the host to exacerbated influenza infection by countering protective innate immune responses that control virus titers.
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