In situ apoptosis of adaptive immune cells and the cellular escape of rabies virus in CNS from patients with human rabies transmitted by Desmodus rotundus

Fernandes, Elaine Aparecida; Andrade, Heitor Franco de; Lancellotti, Carmen Lúcia Penteado; Quaresma, Juarez Antônio Simões; Demachki, Sâmia; Vasconcelos, Pedro Fernando da Costa; Duarte, Maria Irma Seixas

doi:10.1016/j.virusres.2011.01.006

Cited by 34 publications

(35 citation statements)

References 28 publications

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“…The correlation between pathogenesis and apoptosis is consistent with observations of apoptosis in inflammatory cells, microglia and macrophages in natural RABV infections in humans and dogs [23,79]. Therefore, non-lethal strains are cleared from the CNS by infiltrating T cells—despite evidence of RABV antigen in the brain—whereas lethal strains destroy these T cells and are thus free to replicate and spread throughout the CNS [56,87,90]. In support of this hypothesis, several apoptotic pathways are involved in RABV infections that have specific ligands and receptors directly involved with the destruction or inhibition of T cells.…”

Section: Apoptosis: Detrimental or Beneficial To The Host?supporting

confidence: 82%

“…There have been observations of mild numbers of inflammatory cells, macrophages and oligodendrocytes, as well as a large number of infiltrating T cells, undergoing apoptosis in infected tissues during natural RABV infection [87,88,89], suggesting that these may be the targets of RABV-induced apoptosis. The inherent differences in pathogenicity between non-lethal and lethal strains of RABV may be due to the ability of non-lethal strains to induce apoptosis in neurons, as opposed to the lethal strains inducing programmed death in infiltrating T cells (Figure 1) [56,82,87,90,91], as fewer infiltrating lymphocytes have been detected in the brains of animals infected with pathogenic strains [92]. Similarly, HIV has been shown to sensitize T cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)- and CD95(Fas/APO-1)-ligand (CD95L)-mediated apoptosis [93].…”

Section: Apoptosis: Detrimental or Beneficial To The Host?mentioning

confidence: 99%

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Subversion of the Immune Response by Rabies Virus

Scott

Nel

2016

Viruses

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Rabies has affected mankind for several centuries and is one of the oldest known zoonoses. It is peculiar how little is known regarding the means by which rabies virus (RABV) evades the immune response and kills its host. This review investigates the complex interplay between RABV and the immune system, including the various means by which RABV evades, or advantageously utilizes, the host immune response in order to ensure successful replication and spread to another host. Different factors that influence immune responses—including age, sex, cerebral lateralization and temperature—are discussed, with specific reference to RABV and the effects on host morbidity and mortality. We also investigate the role of apoptosis and discuss whether it is a detrimental or beneficial mechanism of the host’s response to infection. The various RABV proteins and their roles in immune evasion are examined in depth with reference to important domains and the downstream effects of these interactions. Lastly, an overview of the means by which RABV evades important immune responses is provided. The research discussed in this review will be important in determining the roles of the immune response during RABV infections as well as to highlight important therapeutic target regions and potential strategies for rabies treatment.

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Section: Apoptosis: Detrimental or Beneficial To The Host?supporting

confidence: 82%

Section: Apoptosis: Detrimental or Beneficial To The Host?mentioning

confidence: 99%

Subversion of the Immune Response by Rabies Virus

Scott

Nel

2016

Viruses

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“…What impact these cytokines have on neuronal integrity is unclear. Though CD8+ T cells have been found in brain sections of human rabies victims [50], their deletion appears to have no significant effect on the survival of challenged mice [4].…”

Section: Discussionmentioning

confidence: 99%

Immune Clearance of Attenuated Rabies Virus Results in Neuronal Survival with Altered Gene Expression

et al. 2012

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Rabies virus (RABV) is a highly neurotropic pathogen that typically leads to mortality of infected animals and humans. The precise etiology of rabies neuropathogenesis is unknown, though it is hypothesized to be due either to neuronal death or dysfunction. Analysis of human brains post-mortem reveals surprisingly little tissue damage and neuropathology considering the dramatic clinical symptomology, supporting the neuronal dysfunction model. However, whether or not neurons survive infection and clearance and, provided they do, whether they are functionally restored to their pre-infection phenotype has not been determined in vivo for RABV, or any neurotropic virus. This is due, in part, to the absence of a permanent “mark” on once-infected cells that allow their identification long after viral clearance. Our approach to study the survival and integrity of RABV-infected neurons was to infect Cre reporter mice with recombinant RABV expressing Cre-recombinase (RABV-Cre) to switch neurons constitutively expressing tdTomato (red) to expression of a Cre-inducible EGFP (green), permanently marking neurons that had been infected in vivo. We used fluorescence microscopy and quantitative real-time PCR to measure the survival of neurons after viral clearance; we found that the vast majority of RABV-infected neurons survive both infection and immunological clearance. We were able to isolate these previously infected neurons by flow cytometry and assay their gene expression profiles compared to uninfected cells. We observed transcriptional changes in these “cured” neurons, predictive of decreased neurite growth and dysregulated microtubule dynamics. This suggests that viral clearance, though allowing for survival of neurons, may not restore them to their pre-infection functionality. Our data provide a proof-of-principle foundation to re-evaluate the etiology of human central nervous system diseases of unknown etiology: viruses may trigger permanent neuronal damage that can persist or progress in the absence of sustained viral antigen.

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“…28 This inefficacy occurs because the virus can induce a significant production of calcitonin, somatostatin, and vasoactive intestinal peptides in infected cells, thus limiting the activity of T cells 29 ; further, the virus can even induce T cell apoptosis 30,31 Immunohistochemical studies of RABV-infected brains and spinal cords demonstrated that neurons showed a large amount of RABV antigen with intact morphology and that migrating T cells showed evidence of undergoing the apoptotic process. 30,32,33 In contrast to infections caused by highly pathogenic strains, T cells are important in controlling those caused by attenuated viruses, in which infected neurons are successfully eliminated by apoptosis and T cells remain intact. 9,34,35 Differences in the pathogenicity of RABV strains are associated not only with viral replication and the cellular infection rate but also with the level and duration of cytokine expression, in addition to the induction of apoptosis in immune cells.…”

Section: Introductionmentioning

confidence: 99%

Profile of Cytokines and Chemokines Triggered by Wild-Type Strains of Rabies Virus in Mice

Appolinário

Allendorf

Peres

et al. 2016

The American Society of Tropical Medicine and Hygiene

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Abstract. Rabies is a lethal infectious disease that causes 55,000 human deaths per year and is transmitted by various mammalian species, such as dogs and bats. The host immune response is essential for avoiding viral progression and promoting viral clearance. Cytokines and chemokines are crucial in the development of an immediate antiviral response; the rabies virus (RABV) attempts to evade this immune response. The virus's capacity for evasion is correlated with its pathogenicity and the host's inflammatory response, with highly pathogenic strains being the most efficient at hijacking the host's defense mechanisms and thereby decreasing inflammation. The purpose of this study was to evaluate the expression of a set of cytokine and chemokine genes that are related to the immune response in the brains of mice inoculated intramuscularly or intracerebrally with two wild-type strains of RABV, one from dog and the other from vampire bat. The results demonstrated that the gene expression profile is intrinsic to the specific rabies variant. The prompt production of cytokines and chemokines seems to be more important than their levels of expression for surviving a rabies infection.

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In situ apoptosis of adaptive immune cells and the cellular escape of rabies virus in CNS from patients with human rabies transmitted by Desmodus rotundus

Cited by 34 publications

References 28 publications

Subversion of the Immune Response by Rabies Virus

Subversion of the Immune Response by Rabies Virus

Immune Clearance of Attenuated Rabies Virus Results in Neuronal Survival with Altered Gene Expression

Profile of Cytokines and Chemokines Triggered by Wild-Type Strains of Rabies Virus in Mice

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