Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling

Puttur, Franz; Francozo, Marcela; Solmaz, Gülhas; Bueno, Carlos Alberto; Lindenberg, Marc; Gohmert, Melanie; Swallow, Maxine; Tufa, Dejene M.; Jacobs, Roland; Lienenklaus, Stefan; Kühl, Anja A.; Borkner, Lisa; Čičin-Šain, Luka; Holzmann, B.; Wagner, Hermann; Berod, Luciana; Sparwasser, Tim

doi:10.1016/j.celrep.2016.09.055

Cited by 32 publications

(34 citation statements)

References 61 publications

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“…Murine cDC on the other hand can be infected with MCMV but produce smaller amounts of type I IFNs (20,28). In vivo experiments have shown that DC contribute to the control of CMV infection by indirect mechanisms inducing antiviral responses of NK and T cells (27,(29)(30)(31). More recently, we showed direct repression of MCMV infection and spread by bone marrow-derived DC (mDC) (22) in coculture with infected endothelial and fibroblast cells.…”

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confidence: 94%

“…Nevertheless, there are significant similarities between CMVs of different species at the level of viral genes and their functions (23)(24)(25), and the murine CMV (MCMV) is widely used as model of virus-host in vivo interactions. Murine pDC are the major source of a type I interferon response to MCMV infection (26) yet do not support a replicative infection (27). Murine cDC on the other hand can be infected with MCMV but produce smaller amounts of type I IFNs (20,28).…”

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confidence: 99%

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Myeloid Dendritic Cells Repress Human Cytomegalovirus Gene Expression and Spread by Releasing Interferon-Unrelated Soluble Antiviral Factors

Kasmapour

Kubsch

Rand

et al. 2018

J Virol

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Cytomegalovirus (CMV) is a betaherpesvirus that latently infects most adult humans worldwide and is a major cause of morbidity and mortality in immunocompromised hosts. Latent human CMV (HCMV) is believed to reside in precursors of myeloid-lineage leukocytes and monocytes, which give rise to macrophages and dendritic cells (DC). We report here that human monocyte-derived DC (mo-DC) suppress HCMV infection in coculture with infected fibroblast target cells in a manner dependent on the effector-to-target ratio. Intriguingly, optimal activation of mo-DC was achieved under coculture conditions and not by direct infection with HCMV, implying that mo-DC may recognize unique molecular patterns on, or within, infected fibroblasts. We show that HCMV is controlled by secreted factors that act by priming defenses in target cells rather than by direct viral neutralization, but we excluded a role for interferons (IFNs) in this control. The expression of lytic viral genes in infected cells and the progression of infection were significantly slowed, but this effect was reversible, indicating that the control of infection depended on the transient induction of antiviral effector molecules in target cells. Using immediate early or late-phase reporter HCMVs, we show that soluble factors secreted in the cocultures suppress HCMV replication at both stages of the infection and that their antiviral effects are robust and comparable in numerous batches of mo-DC as well as in primary fibroblasts and stromal cells. Human cytomegalovirus is a widespread opportunistic pathogen that can cause severe disease and complications in vulnerable individuals. This includes newborn children, HIV AIDS patients, and transplant recipients. Although the majority of healthy humans carry this virus throughout their lives without symptoms, it is not exactly clear which tissues in the body are the main reservoirs of latent virus infection or how the delicate balance between the virus and the immune system is maintained over an individual's lifetime. Here, for the first time, we provide evidence for a novel mechanism of direct virus control by a subset of human innate immune cells called dendritic cells, which are regarded as a major site of virus latency and reactivation. Our findings may have important implications in HCMV disease prevention as well as in development of novel therapeutic approaches.

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confidence: 94%

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confidence: 99%

Myeloid Dendritic Cells Repress Human Cytomegalovirus Gene Expression and Spread by Releasing Interferon-Unrelated Soluble Antiviral Factors

Kasmapour

Kubsch

Rand

et al. 2018

J Virol

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“…The mechanisms accounting for the activation of cDC also remain to be determined. cDCs could be either directly activated via TLR9 ligation (53) or indirectly activated with other cell types mediating the signaling between CpG-B and cDC activation. In contrast to previous observations (20), we excluded a possible role for IFN-I in the activation of cDC after i.t.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral CpG-B Promotes Antitumoral Neutrophil, cDC, and T-cell Cooperation without Reprograming Tolerogenic pDC

et al. 2018

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Cancer immunotherapies utilize distinct mechanisms to harness the power of the immune system to eradicate cancer cells. Therapeutic vaccines, aimed at inducing active immune responses against an existing cancer, are highly dependent on the immunological microenvironment, where many immune cell types display high levels of plasticity and, depending on the context, promote very different immunologic outcomes. Among them, plasmacytoid dendritic cells (pDC), known to be highly immunogenic upon inflammation, are maintained in a tolerogenic state by the tumor microenvironment. Here, we report that intratumoral (i.t.) injection of established solid tumors with CpG oligonucleotides-B (CpG-B) inhibits tumor growth. Interestingly, control of tumor growth was independent of tumor-associated pDC, which remained refractory to CpG-B stimulation and whose depletion did not alter the efficacy of the treatment. Instead, tumor growth inhibition subsequent to i.t. CpG-B injection depended on the recruitment of neutrophils into the milieu, resulting in the activation of conventional dendritic cells, subsequent increased antitumor T-cell priming in draining lymph nodes, and enhanced effector T-cell infiltration in the tumor microenvironment. These results reinforce the concept that i.t. delivery of TLR9 agonists alters the tumor microenvironment by improving the antitumor activity of both innate and adaptive immune cells. Intratumoral delivery of CpG-B disrupts the tolerogenic tumor microenvironment and inhibits tumor growth. .

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“…Conversely, murine TLR9 is expressed abundantly in myeloid immune cells and can also result in IFN-γ production and the recruitment of NK, αβ-, and γδ-T cells (Hartmann, 2017; Hornung et al, 2002; Krug et al, 2004; Walker et al, 2010). For example, it has been shown that CMV infection in mice activates a TLR9/MyD88 response that occurs selectively in CD11 + dendritic cells (Krug et al, 2004; Puttur et al, 2016). Other DNA viruses that have been implicated in activating an innate immune response through TLR9 are Varicella zoster virus (VZV), Epstein-Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), vaccinia virus (VV), adenovirus (AdV), and human CMV (Appledorn et al, 2008; Basner-Tschakarjan et al, 2006; Fiola et al, 2010; Lim et al, 2006; Samuelsson et al, 2008; Varani et al, 2007; West et al, 2011; Yu et al, 2011).…”

Section: Intracellular Recognition Of Dnamentioning

confidence: 99%

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Matz

Guzman

Goodman

2019

Nucleic Acid Sensing and Immunity - Part B

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Innate immunity, the first line of defense against invading pathogens, is an ancient form of host defense found in all animals, from sponges to humans. During infection, innate immune receptors recognize conserved molecular patterns, such as microbial surface molecules, metabolites produces during infection, or nucleic acids of the microbe’s genome. When initiated, the innate immune response activates a host defense program that leads to the synthesis proteins capable of pathogen killing. In mammals, the induction of cytokines during the innate immune response leads to the recruitment of professional immune cells to the site of infection, leading to an adaptive immune response. While a fully functional innate immune response is crucial for a proper host response and curbing microbial infection, if the innate immune response is dysfunctional and is activated in the absence of infection, autoinflammation and autoimmune disorders can develop. Therefore, it follows that the innate immune response must be tightly controlled to avoid an autoimmune response from host-derived molecules, yet still unencumbered to respond to infection. In this review, we will focus on the innate immune response activated from cytosolic nucleic acids, derived from the microbe or host itself. We will depict how viruses and bacteria activate these nucleic acid sensing pathways and their mechanisms to inhibit the pathways. We will also describe the autoinflammatory and autoimmune disorders that develop when these pathways are hyperactive. Finally, we will discuss gaps in knowledge with regard to innate immune response failure and identify where further research is needed.

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Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling

Cited by 32 publications

References 61 publications

Myeloid Dendritic Cells Repress Human Cytomegalovirus Gene Expression and Spread by Releasing Interferon-Unrelated Soluble Antiviral Factors

Myeloid Dendritic Cells Repress Human Cytomegalovirus Gene Expression and Spread by Releasing Interferon-Unrelated Soluble Antiviral Factors

Intratumoral CpG-B Promotes Antitumoral Neutrophil, cDC, and T-cell Cooperation without Reprograming Tolerogenic pDC

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

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