A Murid Gamma-Herpesviruses Exploits Normal Splenic Immune Communication Routes for Systemic Spread

Frederico, Bruno; Chao, Brittany; May, Janet S.; Belz, Gabrielle T.; Stevenson, Philip G.

doi:10.1016/j.chom.2014.03.010

Cited by 57 publications

(84 citation statements)

References 59 publications

(70 reference statements)

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“…Each infection depends on seeding from an upstream site but can then be autonomous. For example, the B cells MuHV-4 infects in the spleen are distinct from those infected in the SCLN (17). Spleens and SCLN showed correspondingly independent AFC responses: splenic responses peaked later, and most splenic AFCs were still IgM ϩ when most SCLN AFCs were IgG ϩ .…”

Section: Discussionmentioning

confidence: 99%

“…MuHV-4 and HSV-1 infect alert mice nasally rather than orally (4,17) and spread from the olfactory neuroepithelium to establish long-term latency in B cells and trigeminal neurons, respectively, without causing significant disease. Therefore, this is a plausible natural entry portal about which we need to know more.…”

Section: Discussionmentioning

confidence: 99%

“…At day 10, the SCLN contained substantial numbers of IgG ϩ AFCs, while splenic AFCs were almost entirely IgM ϩ and only later became IgG ϩ . Thus, the focus of the antibody response followed that of infection, as it spread from SCLN to the spleen (17), with evidence of a new IgM response to splenic antigen in addition to the ongoing, IgG-dominated SCLN response.…”

Section: Antibody Response Of Balb/c Mice To Neuroepithelial Muhv-4 Imentioning

confidence: 99%

“…It is considered analogous to human tonsils and provides an immune induction site for respiratory epithelial infections (15,16). However, neuroepithelial infection may be different: MuHV-4 exploits immune communications to spread (17), implying that it follows the normal pathways of antigen-specific immune induction, and after intranasal (i.n.) inoculation, it reaches B cells first in the superficial cervical lymph nodes (SCLN).…”

mentioning

confidence: 99%

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B Cell Response to Herpesvirus Infection of the Olfactory Neuroepithelium

Tan

Stevenson

2014

J Virol

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Viruses commonly infect the respiratory tract. Analyses of host defense have focused on the lungs and the respiratory epithelium. Spontaneously inhaled murid herpesvirus 4 (MuHV-4) and herpes simplex virus 1 (HSV-1) instead infect the olfactory epithelium, where neuronal cilia are exposed to environmental antigens and provide a route across the epithelial mucus. We used MuHV-4 to define how B cells respond to virus replication in this less well-characterized site. Olfactory infection elicited generally weaker acute responses than lung infection, particularly in the spleen, reflecting slower viral replication and spread. Few virus-specific antibody-forming cells (AFCs) were found in the nasal-associated lymphoid tissue (NALT), a prominent response site for respiratory epithelial infection. Instead, they appeared first in the superficial cervical lymph nodes. The focus of the AFC response then moved to the spleen, matching the geography of virus dissemination. Little virus-specific IgA response was detected until later in the bone marrow. Neuroepithelial HSV-1 infection also elicited no significant AFC response in the NALT and a weak IgA response. Thus, olfactory herpesvirus infection differed immunologically from an infection of the adjacent respiratory epithelium. Poor IgA induction may help herpesviruses to transmit via long-term mucosal shedding. IMPORTANCEHerpesviruses are widespread, persistent pathogens against which vaccines have had limited success. We need to understand better how they interact with host immunity. MuHV-4 and HSV-1 inhaled by alert mice infect the olfactory neuroepithelium, suggesting that this is a natural entry route. Its immunology is almost completely unknown. The antibody response to neuroepithelial herpesvirus infection started in the cervical lymph nodes, and unlike respiratory influenza virus infection, did not significantly involve the nasal-associated lymphoid tissue. MuHV-4 and HSV-1 infections also elicited little virus-specific IgA. Therefore, vaccine-induced IgA might provide a defense that herpesviruses are ill-equipped to meet.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Antibody Response Of Balb/c Mice To Neuroepithelial Muhv-4 Imentioning

confidence: 99%

mentioning

confidence: 99%

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B Cell Response to Herpesvirus Infection of the Olfactory Neuroepithelium

Tan

Stevenson

2014

J Virol

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“…To reach the lymphoid reservoir of latency, gammaherpesviruses infect multiple cell types, including dendritic cells and macrophages (83,84). Some of the mechanisms by which the gammaherpesviruses impair and subvert the inflammatory response have only recently come to light, and the inhibition of il1␤ mRNA in response to extrinsic LPS stimulation and bacterial coinfection reveals a novel mechanism of viral interference with inflammatory signaling in a reservoir of infection in the host.…”

Section: Discussionmentioning

confidence: 99%

Murine Gammaherpesvirus 68 Pathogenesis Is Independent of Caspase-1 and Caspase-11 in Mice and Impairs Interleukin-1β Production upon Extrinsic Stimulation in Culture

Cieniewicz

Dong

et al. 2015

J Virol

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Gammaherpesviruses establish lifelong infections that are associated with the development of cancer. These viruses subvert many aspects of the innate and adaptive immune response of the host. The inflammasome, a macromolecular protein complex that controls inflammatory responses to intracellular danger signals generated by pathogens, is both activated and subverted during human gammaherpesvirus infection in culture. The impact of the inflammasome response on gammaherpesvirus replication and latency in vivo is not known. Caspase-1 is the inflammasome effector protease that cleaves the proinflammatory cytokines interleukin-1␤ (IL-1␤) and IL-18. We infected caspase-1-deficient mice with murine gammaherpesvirus 68 (MHV68) and observed no impact on acute replication in the lung or latency and reactivation from latency in the spleen. This led us to examine the effect of viral infection on inflammasome responses in bone marrow-derived macrophages. We determined that infection of macrophages with MHV68 led to a robust interferon response but failed to activate caspase-1 or induce the secretion of IL-1␤. In addition, MHV68 infection led to a reduction in IL-1␤ production after extrinsic lipopolysaccharide stimulation or upon coinfection with Salmonella enterica serovar Typhimurium. Interestingly, this impairment occurred at the proIL-1␤ transcript level and was independent of the RTA, the viral lytic replication and transcription activator. Taken together, MHV68 impairs the inflammasome response by inhibiting IL-1␤ production during the initial stages of infection. IMPORTANCEGammaherpesviruses persist for the lifetime of the host. To accomplish this, they must evade recognition and clearance by the immune system. The inflammasome consists of proteins that detect foreign molecules in the cell and respond by secreting proinflammatory signaling proteins that recruit immune cells to clear the infection. Unexpectedly, we found that murine gammaherpesvirus pathogenesis was not enhanced in mice lacking caspase-1, a critical inflammasome component. This led us to investigate whether the virus actively impairs the inflammasome response. We found that the inflammasome was not activated upon macrophage cell infection with murine gammaherpesvirus 68. Infection also prevented the host cell inflammasome response to other pathogen-associated molecular patterns, indicated by reduced production of the proinflammatory cytokine IL-1␤ upon bacterial coinfection. Taken together, murine gammaherpesvirus impairment of the inflammatory cytokine IL-1␤ in macrophages identifies one mechanism by which the virus may inhibit caspase-1-dependent immune responses in the infected animal. G ammaherpesviruses establish lifelong latent infections that are associated with significant morbidity and the development of malignancies (1-3). Gammaherpesviruses initially infect the mucosal tissues of naive hosts and undergo productive replication prior to colonization of latency reservoirs, including B lymphocytes and macrophages (4-6). Murine gammaherpes...

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Dynamic bidirectional regulation of NLRC3 and gammaherpesviruses during viral latency in B lymphocytes

Kang,

Han,

et al. 2024

Journal of Medical Virology

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While most NOD‐like receptors (NLRs) are predominately expressed by innate immune cells, NLRC3, an inhibitory NLR of immune signaling, exhibits the highest expression in lymphocytes. The role of NLRC3 or any NLRs in B lymphocytes is completely unknown. Gammaherpesviruses, including human Epstein–Barr virus (EBV) and murine gammaherpesvirus 68 (MHV‐68), establish latent infection in B lymphocytes, which requires elevated NF‐κB. This study shows that during latent EBV infection of human B cells, viral‐encoded latent membrane protein 1 (LMP1) decreases NLRC3 transcript. LMP1‐induced‐NF‐κB activation suppresses the promoter activity of NLRC3 via p65 binding to the promoter. Conversely, NLRC3 inhibits NF‐κB activation by promoting the degradation of LMP1 in a proteasome‐dependent manner. In vivo, MHV‐68 infection reduces Nlrc3 transcripts in splenocytes, and Nlrc3‐deficient mice show greater viral latency than controls. These results reveal a bidirectional regulatory circuit in B lymphocytes, where viral latent protein LMP1 reduces NLRC3 expression, while NLRC3 disrupts gammaherpesvirus latency, which is an important step for tumorigenesis.

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A Murid Gamma-Herpesviruses Exploits Normal Splenic Immune Communication Routes for Systemic Spread

Cited by 57 publications

References 59 publications

B Cell Response to Herpesvirus Infection of the Olfactory Neuroepithelium

B Cell Response to Herpesvirus Infection of the Olfactory Neuroepithelium

Murine Gammaherpesvirus 68 Pathogenesis Is Independent of Caspase-1 and Caspase-11 in Mice and Impairs Interleukin-1β Production upon Extrinsic Stimulation in Culture

Dynamic bidirectional regulation of NLRC3 and gammaherpesviruses during viral latency in B lymphocytes

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