Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

Farrell, Helen E.; Bruce, Kimberley; Lawler, Clara; Cardin, Rhonda D.; Davis-Poynter, Nicholas; Stevenson, Philip G.

doi:10.1371/journal.ppat.1006069

Cited by 28 publications

(24 citation statements)

References 55 publications

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“…Innate immune pressure may also limit the efficiency of CMV spread. Important differences in routes of infection and hosts notwithstanding, murine CMV studies have revealed that macrophages and natural killer cells induce a bottleneck and restrict systemic spread from the draining lymph nodes after inoculation by footpad injection (33,34). While vaccines that induce neutralizing antibodies may prevent infection of cells altogether, other vaccines, such as those that induce T-cell or antibody-dependent cell-mediated cytotoxicity responses, allow viral replication and antigen expression within at least one cell prior to virus elimination (35,36).…”

Section: Discussionmentioning

confidence: 99%

Transient Oral Human Cytomegalovirus Infections Indicate Inefficient Viral Spread from Very Few Initially Infected Cells

Mayer

Krantz

Swan

et al. 2017

J Virol

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Cytomegalovirus (CMV) is acquired by the oral route in children, and primary infection is associated with abundant mucosal replication, as well as the establishment of latency in myeloid cells that results in lifelong infection. The efficiency of primary CMV infection in humans following oral exposure, however, is unknown. We consistently detected self-limited, low-level oral CMV shedding events, which we termed transient CMV infections, in a prospective birth cohort of 30 highly exposed CMV-uninfected infants. We estimated the likelihood of transient oral CMV infections by comparing their observed frequency to that of established primary infections, characterized by persistent high-level shedding, viremia, and seroconversion. We developed mathematical models of viral dynamics upon initial oral CMV infection and validated them using clinical shedding data. Transient infections comprised 76 to 88% of oral CMV shedding events. For this high percentage of transient infections to occur, we identified two mathematical prerequisites: a very small number of initially infected oral cells (1 to 4) and low viral infectivity (Ͻ1.5 new cells infected/cell). These observations indicate that oral CMV infection in infants typically begins with a single virus that spreads inefficiently to neighboring cells. Thus, although the incidence of CMV infection is high during infancy, our data provide a mechanistic framework to explain why multiple CMV exposures are typically required before infection is successfully established. These findings imply that a sufficiently primed immune response could prevent CMV from establishing latent infection in humans and support the achievability of a prophylactic CMV vaccine.IMPORTANCE CMV infects the majority of the world's population and is a major cause of birth defects. Developing a vaccine to prevent CMV infection would be extremely valuable but would be facilitated by a better understanding of how natural human CMV infection is acquired. We studied CMV acquisition in infants and found that infections are usually brief and self-limited and are successfully established relatively rarely. Thus, although most people eventually acquire CMV infection, it usually requires numerous exposures. Our analyses indicate that this is because the virus is surprisingly inefficient, barely replicating well enough to spread to neighboring cells in the mouth. Greater knowledge of why CMV infection usually fails may provide insight into how to prevent it from succeeding. KEYWORDS Epstein-Barr virus, basic reproduction number, cytomegalovirus, founder population, herpes simplex virus, human herpesviruses, mathematical modeling, oral shedding, transient infection

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Section: Discussionmentioning

confidence: 99%

Transient Oral Human Cytomegalovirus Infections Indicate Inefficient Viral Spread from Very Few Initially Infected Cells

Mayer

Krantz

Swan

et al. 2017

J Virol

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“…NK and NKT cells are an essential effector arm of innate immunity that participates in the control of viral infections [42][43][44][45]. IL-10 has been shown to promote NK cell proliferation, cytokine production, and cytotoxicity in vitro [46][47][48][49][50], although in some in vivo settings it could modulate NK cell activity [51,52].…”

Section: Early Il-10 Induction and Effects On Innate Immunitymentioning

confidence: 99%

IL-10: A Multifunctional Cytokine in Viral Infections

Rojas

Avia

Martı́n

et al. 2017

Journal of Immunology Research

299

268

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The anti-inflammatory master regulator IL-10 is critical to protect the host from tissue damage during acute phases of immune responses. This regulatory mechanism, central to T cell homeostasis, can be hijacked by viruses to evade immunity. IL-10 can be produced by virtually all immune cells, and it can also modulate the function of these cells. Understanding the effects of this multifunctional cytokine is therefore a complex task. In the present review we discuss the factors driving IL-10 production and the cellular sources of the cytokine during antiviral immune responses. We particularly focus on the IL-10 regulatory mechanisms that impact antiviral immune responses and how viruses can use this central regulatory pathway to evade immunity and establish chronic/latent infections.

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“…Thus, counting of red and green plaques reveals the extent of viral passage through cre ϩ cells. SSM express lysM (14) and CD11c (29), and DC express CD11c but rarely express lysM (30). MHV-RG passing from noses to SCLN switches more in CD11c-cre than in lysM-cre mice (19), consistent with DC providing the main route to B cells (13).…”

Section: Ifnar Blockade Does Not Change the Predominant Route Of Inmentioning

confidence: 79%

“…3a, SSM are not detectably CD11c ϩ , their lower level expression level is evident only at a high magnification ( Fig. 4a) (29), and the CD11c hi cells visible in LN at a low magnification are predominantly DC. Both anti-IFNAR-treated and control LN contained CD11c ϩ GFP ϩ cells, but the former had significantly more of these cells.…”

Section: Ifn-i Protects the Nasal Respiratory Epitheliummentioning

confidence: 84%

Type I Interferon Signaling to Dendritic Cells Limits Murid Herpesvirus 4 Spread from the Olfactory Epithelium

Lawler

Stevenson

2017

J Virol

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Murid herpesvirus 4 (MuHV-4) is a B cell-tropic gammaherpesvirus that can be studied Despite viral evasion, type I interferons (IFN-I) limit its spread. After MuHV-4 inoculation into footpads, IFN-I protect lymph node subcapsular sinus macrophages (SSM) against productive infection; after peritoneal inoculation, they protect splenic marginal zone macrophages, and they limit MuHV-4 replication in the lungs. While invasive infections can be used to test specific aspects of host colonization, it is also important to understand natural infection. MuHV-4 taken up spontaneously by alertmice enters them via olfactory neurons. We determined how IFN-I act in this context. Blocking IFN-I signaling did not increase neuronal infection but allowed the virus to spread to the adjacent respiratory epithelium. In lymph nodes, a complete IFN-I signaling block increased MuHV-4 lytic infection in SSM and increased the number of dendritic cells (DC) expressing viral green fluorescent protein (GFP) independently of lytic infection. A CD11c cell-directed signaling block increased infection of DC only. However, this was sufficient to increase downstream infection, consistent with DC providing the main viral route to B cells. The capacity of IFN-I to limit DC infection indicated that viral IFN-I evasion was only partly effective. Therefore, DC are a possible target for IFN-I-based interventions to reduce host colonization. Human gammaherpesviruses infect B cells and cause B cell cancers. Interventions to block virus binding to B cells have not stopped their infection. Therefore, we must identify other control points that are relevant to natural infection. Human infections are difficult to analyze. However, gammaherpesviruses colonize all mammals. A related gammaherpesvirus of mice reaches B cells not directly but via infected dendritic cells. We show that type I interferons, an important general antiviral defense, limit gammaherpesvirus B cell infection by acting on dendritic cells. Therefore, dendritic cell infection is a potential point of interferon-based therapeutic intervention.

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Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

Cited by 28 publications

References 55 publications

Transient Oral Human Cytomegalovirus Infections Indicate Inefficient Viral Spread from Very Few Initially Infected Cells

Transient Oral Human Cytomegalovirus Infections Indicate Inefficient Viral Spread from Very Few Initially Infected Cells

IL-10: A Multifunctional Cytokine in Viral Infections

Type I Interferon Signaling to Dendritic Cells Limits Murid Herpesvirus 4 Spread from the Olfactory Epithelium

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