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Complement opsonization of HIV-1 results in decreased antiviral and inflammatory responses in immature dendritic cells via CR3.

ABSTRACT: Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-β, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1β, IL-6, and TNF-α, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-κB pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.

SUBMITTER: Ellegard R

PROVIDER: S-EPMC4201991 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Complement opsonization of HIV-1 results in decreased antiviral and inflammatory responses in immature dendritic cells via CR3.

Ellegård Rada R Crisci Elisa E Burgener Adam A Sjöwall Christopher C Birse Kenzie K Westmacott Garrett G Hinkula Jorma J Lifson Jeffrey D JD Larsson Marie M

Journal of immunology (Baltimore, Md. : 1950) 20140924 9

Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HI ...[more]

PMID: 25252956

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Project description:UnlabelledHerpes simplex virus 2 (HSV-2) is one of the most common sexually transmitted infections globally, with a very high prevalence in many countries. During HSV-2 infection, viral particles become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of immune responses. In genital mucosa, the primary target cells for HSV-2 infection are epithelial cells, but resident immune cells, such as dendritic cells (DCs), are also infected. DCs are the activators of the ensuing immune responses directed against HSV-2, and the aim of this study was to examine the effects opsonization of HSV-2, either with complement alone or with complement and antibodies, had on the infection of immature DCs and their ability to mount inflammatory and antiviral responses. Complement opsonization of HSV-2 enhanced both the direct infection of immature DCs and their production of new infectious viral particles. The enhanced infection required activation of the complement cascade and functional complement receptor 3. Furthermore, HSV-2 infection of DCs required endocytosis of viral particles and their delivery into an acid endosomal compartment. The presence of complement in combination with HSV-1- or HSV-2-specific antibodies more or less abolished HSV-2 infection of DCs. Our results clearly demonstrate the importance of studying HSV-2 infection under conditions that ensue in vivo, i.e., conditions under which the virions are covered in complement fragments and complement fragments and antibodies, as these shape the infection and the subsequent immune response and need to be further elucidated.ImportanceDuring HSV-2 infection, viral particles should become coated with complement proteins and antibodies, both present in genital fluids, which could influence the activation of the immune responses. The dendritic cells are activators of the immune responses directed against HSV-2, and the aim of this study was to examine the effects of complement alone or complement and antibodies on HSV-2 infection of dendritic cells and their ability to mount inflammatory and antiviral responses. Our results demonstrate that the presence of antibodies and complement in the genital environment can influence HSV-2 infection under in vitro conditions that reflect the in vivo situation. We believe that our findings are highly relevant for the understanding of HSV-2 pathogenesis.

Project description:The complement system plays a key role in opsonization and immune clearance of engineered nanoparticles. Understanding the efficiency, inter-subject, and inter-strain differences of complement opsonization in preclinical species can help with translational nanomedicine development and improve our ability to model complement response in humans. Dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles and a wide range of non-magnetic iron oxide nanoparticle formulations are widely used in magnetic resonance imaging and as clinically approved iron supplements. Previously we found that opsonization of SPIO nanoworms (NW) with the third complement protein (C3) proceeds mostly via the alternative pathway in humans, and via the lectin pathway in mice. Here, we studied the pathway and efficiency of opsonization of 106 nm SPIO NW with C3 in different preclinical species and commonly used laboratory strains. In sera of healthy human donors (n = 6), C3 opsonization proceeded exclusively through the alternative pathway. On the other hand, the C3 opsonization in dogs (6 breeds), rats (4 strains) and mice (5 strains) sera was either partially or completely dependent on the complement Ca2+-sensitive pathways (lectin and/or classical). Specifically, C3 opsonization in sera of Long Evans rat strain, and mouse strains widely used in nanomedicine research (BALB/c, C57BL/6 J, and A/J) was only through the Ca2+-dependent pathways. Dogs and humans had the highest between-subject variability in C3 opsonization levels, while rat and mouse sera showed the lowest between-strain variability. Furthermore, using a panel of SPIO nanoparticles of different sizes and dextran coatings, we found that the level of C3 opsonization (C3 molecules per milligram Fe) in human sera was lower than in animal sera. At the same time, there was a strong predictive value of complement opsonization in dog and rat sera; nanoparticles with higher C3 deposition in animals showed higher deposition in humans, and vice versa. Notably, the opsonization decreased with decreasing size in all sera. The studies highlight the importance of the consideration of species and strains for predicting human complement responses (opsonization) towards nanomedicines.

Project description:BackgroundAtopy and viral respiratory tract infections synergistically promote asthma exacerbations. IgE cross-linking inhibits critical virus-induced IFN-α responses of plasmacytoid dendritic cells (pDCs), which can be deficient in patients with allergic asthma.ObjectiveWe sought to determine whether reducing IgE levels in vivo with omalizumab treatment increases pDC antiviral IFN-α responses in inner-city children with asthma.MethodsPBMCs and pDCs isolated from children with exacerbation-prone asthma before and during omalizumab treatment were stimulated ex vivo with rhinovirus and influenza in the presence or absence of IgE cross-linking. IFN-α levels were measured in supernatants, and mRNA expression of IFN-α pathway genes was determined by using quantitative RT-PCR (qRT-PCR) in cell pellets. FcεRIα protein levels and mRNA expression were measured in unstimulated cells by using flow cytometry and qRT-PCR, respectively. Changes in these outcomes and associations with clinical outcomes were analyzed, and statistical modeling was used to identify risk factors for asthma exacerbations.ResultsOmalizumab treatment increased rhinovirus- and influenza-induced PBMC and rhinovirus-induced pDC IFN-α responses in the presence of IgE cross-linking and reduced pDC surface FcεRIα expression. Omalizumab-induced reductions in pDC FcεRIα levels were significantly associated with a lower asthma exacerbation rate during the outcome period and correlated with increases in PBMC IFN-α responses. PBMC FcεRIα mRNA expression measured on study entry significantly improved an existing model of exacerbation prediction.ConclusionsThese findings indicate that omalizumab treatment augments pDC IFN-α responses and attenuates pDC FcεRIα protein expression and provide evidence that these effects are related. These results support a potential mechanism underlying clinical observations that allergic sensitization is associated with increased susceptibility to virus-induced asthma exacerbations.

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Complement opsonization of HIV-1 results in decreased antiviral and inflammatory responses in immature dendritic cells via CR3.

Publications

Complement opsonization of HIV-1 results in decreased antiviral and inflammatory responses in immature dendritic cells via CR3.

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