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IFN-? increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells.

ABSTRACT: Increased levels of interferon-? (IFN-?) are routinely observed in the respiratory tract following influenza virus infection, yet its potential role remains unclear. We now demonstrate that influenza-induced IFN-? restricts protective innate lymphoid cell group II (ILC2) function in the lung following challenge with the pandemic H1N1 A/CA/04/2009 (CA04) influenza virus. Specifically, IFN-? deficiency resulted in enhanced ILC2 activity, characterized by increased production of interleukin (IL)-5 and amphiregulin, and improved tissue integrity, yet no change in ILC2 numbers, viral load or clearance. We further found that IFN-?-deficient mice, as well as wild-type animals treated with neutralizing anti-IFN-? antibody, exhibited decreased susceptibility to lethal infection with H1N1 CA04 influenza virus, and moreover that survival was dependent on the presence of IL-5. The beneficial effects of IFN-? neutralization were not observed in ILC2-deficient animals. These data support the novel concept that IFN-? can have a detrimental role in the pathogenesis of influenza through a restriction in ILC2 activity. Thus, regulation of ILC2 activity is a potential target for post-infection therapy of influenza.

SUBMITTER: Califano D

PROVIDER: S-EPMC5693789 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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IFN-γ increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells.

Califano D D Furuya Y Y Roberts S S Avram D D McKenzie A N J ANJ Metzger D W DW

Mucosal immunology 20170517 1

Increased levels of interferon-γ (IFN-γ) are routinely observed in the respiratory tract following influenza virus infection, yet its potential role remains unclear. We now demonstrate that influenza-induced IFN-γ restricts protective innate lymphoid cell group II (ILC2) function in the lung following challenge with the pandemic H1N1 A/CA/04/2009 (CA04) influenza virus. Specifically, IFN-γ deficiency resulted in enhanced ILC2 activity, characterized by increased production of interleukin (IL)-5 ...[more]

PMID: 28513592

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Project description:Objectives:Innate lymphoid cells (ILCs) share many characteristics with CD4+ T cells, and group 1 ILCs share a requirement for T-bet and the ability to produce IFN? with T helper 1 (Th1) cells. Given this similarity, and the importance of Th1 cells for protection against intracellular protozoan parasites, we aimed to characterise the role of group 1 ILCs during Plasmodium infection. Methods:We quantified group 1 ILCs in peripheral blood collected from subjects infected with with Plasmodium falciparum 3D7 as part of a controlled human malaria infection study, and in the liver and spleens of Pc AS-infected mice. We used genetically-modified mouse models, as well as cell-depletion methods in mice to characterise the role of group 1 ILCs during Pc AS infection. Results:In a controlled human malaria infection study, we found that the frequencies of circulating ILC1s and NK cells decreased as infection progressed but recovered after volunteers were treated with antiparasitic drug. A similar observation was made for liver and splenic ILC1s in P. chabaudi chabaudi AS (Pc AS)-infected mice. The decrease in mouse liver ILC1 frequencies was associated with increased apoptosis. We also identified a population of cells within the liver and spleen that expressed both ILC1 and NK cell markers, indicative of plasticity between these two cell lineages. Studies using genetic and cell-depletion approaches indicated that group 1 ILCs have a limited role in antiparasitic immunity during Pc AS infection in mice. Discussion:Our results are consistent with a previous study indicating a limited role for natural killer (NK) cells during Plasmodium chabaudi infection in mice. Additionally, a recent study reported the redundancy of ILCs in humans with competent B and T cells. Nonetheless, our results do not rule out a role for group 1 ILCs in human malaria in endemic settings given that blood stage infection was initiated intravenously in our experimental models, and thus bypassed the liver stage of infection, which may influence the immune response during the blood stage. Conclusion:Our results show that ILC1s are lost early during mouse and human malaria, and this observation may help to explain the limited role for these cells in controlling blood stage infection.

Project description:BackgroundThe cardiovascular effects of pulmonary exposure to engineered nanomaterials (ENM) are poorly understood, and the reproductive consequences are even less understood. Inflammation remains the most frequently explored mechanism of ENM toxicity. However, the key mediators and steps between lung exposure and uterine health remain to be fully defined. The purpose of this study was to determine the uterine inflammatory and vascular effects of pulmonary exposure to titanium dioxide nanoparticles (nano-TiO2). We hypothesized that pulmonary nano-TiO2 exposure initiates a Th2 inflammatory response mediated by Group II innate lymphoid cells (ILC2), which may be associated with an impairment in uterine microvascular reactivity.MethodsFemale, virgin, Sprague-Dawley rats (8-12 weeks) were exposed to 100 ?g of nano-TiO2 via intratracheal instillation 24 h prior to microvascular assessments. Serial blood samples were obtained at 0, 1, 2 and 4 h post-exposure for multiplex cytokine analysis. ILC2 numbers in the lungs were determined. ILC2s were isolated and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) levels were measured. Pressure myography was used to assess vascular reactivity of isolated radial arterioles.ResultsPulmonary nano-TiO2 exposure was associated with an increase in IL-1ß, 4, 5 and 13 and TNF- ? 4 h post-exposure, indicative of an innate Th2 inflammatory response. ILC2 numbers were significantly increased in lungs from exposed animals (1.66?±?0.19%) compared to controls (0.19?±?0.22%). Phosphorylation of the transactivation domain (Ser-468) of NF-?B in isolated ILC2 and IL-33 in lung epithelial cells were significantly increased (126.8?±?4.3% and 137?±?11% of controls respectively) by nano-TiO2 exposure. Lastly, radial endothelium-dependent arteriolar reactivity was significantly impaired (27?±?12%), while endothelium-independent dilation (7?±?14%) and ?-adrenergic sensitivity (8?±?2%) were not altered compared to control levels. Treatment with an anti- IL-33 antibody (1 mg/kg) 30 min prior to nano-TiO2 exposure resulted in a significant improvement in endothelium-dependent dilation and a decreased level of IL-33 in both plasma and bronchoalveolar lavage fluid.ConclusionsThese results provide evidence that the uterine microvascular dysfunction that follows pulmonary ENM exposure may be initiated via activation of lung-resident ILC2 and subsequent systemic Th2-dependent inflammation.

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IFN-? increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells.

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IFN-γ increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells.

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