Failure to Thrive, Wasting Syndrome, and Immunodeficiency in Rabies: A Hypophyseal/Hypothalamic/Thymic Axis Effect of Rabies Virus

Torres-Anjel, M J; Volz, David C.; Torres, Manuel J. R.; Turk, Margaret A.; Tshikuka, Jose Gaby

doi:10.1093/clinids/10.supplement_4.s710

Cited by 29 publications

(14 citation statements)

References 21 publications

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“…This lower T cell infiltration probably leads to less efficient RABV elimination in LGP2 TG mice than that in B7-H1 Ϫ/Ϫ mice. The exact mechanisms causing death in rabies are not well understood, and some may be related to neuronal exhaustion and hormonal deregulation resulting in a lethal "stress" (53). A delay in viral clearance such as that observed in LGP2 TG mice may result in exposure to RABV-mediated "stress" for long enough to cause host death.…”

Section: Discussionmentioning

confidence: 99%

“…Different mechanisms have been proposed to explain the inefficiency of the immune response against RABV infection (24). RABV infection induces immune unresponsiveness (6,53), limits T cell infiltration into the NS (44), and keeps the blood-brain barrier tightly closed (37,45). It also promotes the destruction of migratory CD8 ϩ T cells in the NS through the upregulation of immunoevasive proteins such as B7-H1 (1,27,28).…”

mentioning

confidence: 99%

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Ambivalent Role of the Innate Immune Response in Rabies Virus Pathogenesis

Chopy

Pothlichet

Lafage

et al. 2011

J Virol

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The neurotropic rabies virus (RABV) has developed several evasive strategies, including immunoevasion, to successfully infect the nervous system (NS) and trigger a fatal encephalomyelitis. Here we show that expression of LGP2, a protein known as either a positive or negative regulator of the RIG-I-mediated innate immune response, is restricted in the NS. We used a new transgenic mouse model (LGP2 TG) overexpressing LGP2 to impair the innate immune response to RABV and thus revealed the role of the RIG-I-mediated innate immune response in RABV pathogenesis. After infection, LGP2 TG mice exhibited reduced expression of inflammatory/ chemoattractive molecules, beta interferon (IFN-␤), and IFN-stimulated genes in their NS compared to wild-type (WT) mice, demonstrating the inhibitory function of LGP2 in the innate immune response to RABV. Surprisingly, LGP2 TG mice showed more viral clearance in the brain and lower morbidity than WT mice, indicating that the host innate immune response, paradoxically, favors RABV neuroinvasiveness and morbidity. LGP2 TG mice exhibited similar neutralizing antibodies and microglia activation to those of WT mice but showed a reduction of infiltrating CD4؉ T cells and less disappearance of infiltrating CD8 ؉ T cells. This occurred concomitantly with reduced neural expression of the IFN-inducible protein B7-H1, an immunoevasive protein involved in the elimination of infiltrated CD8 ؉ T cells. Our study shows that the host innate immune response favors the infiltration of T cells and, at the same time, promotes CD8؉ T cell elimination. Thus, to a certain extent, RABV exploits the innate immune response to develop its immunoevasive strategy.Rabies virus (RABV) is a negative-strand RNA virus that infects mainly neurons and exploits the nervous system (NS) network to ensure its progression from the site of entry (bite site) to the site of exit, the salivary glands. The virulence of RABV relies on several factors, such as its capacity to avoid premature death of infected neurons and its property of escaping the immune response. Different mechanisms have been proposed to explain the inefficiency of the immune response against RABV infection (24). RABV infection induces immune unresponsiveness (6, 53), limits T cell infiltration into the NS (44), and keeps the blood-brain barrier tightly closed (37,45). It also promotes the destruction of migratory CD8 ϩ T cells in the NS through the upregulation of immunoevasive proteins such as B7-H1 (1, 27, 28). B7-H1 (also known as PD-1 ligand and CD274) is interferon (IFN) inducible and is usually expressed by immune cells. It contributes to dampening proliferation, cytokine production, and cytolytic activity (20,28,48).During its migration in the NS, RABV has to deal with the first line of defense against pathogens: the host innate immune response. RABV infection activates the innate immune sensor RIG-I, and likely also 22), and triggers classical type I IFN, chemoattractive, and inflammatory responses in infected cells, which could be responsible for set...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Ambivalent Role of the Innate Immune Response in Rabies Virus Pathogenesis

Chopy

Pothlichet

Lafage

et al. 2011

J Virol

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“…It is known that pathogenic strains of RV infect the hypothalamus and alter HPA activity (24,29), resulting in the elevated production of steroid hormones and the reduced production of growth hormones (29). These changes may be responsible for the lymphoid organ atrophy and altered immune function (29,31) seen during the late stages of rabies. Compared to other strains, mice with an SJL background (i) have reduced HPA axis activity (2), (ii) develop more extensive CNS inflammation FIG.…”

Section: Discussionmentioning

confidence: 99%

Lethal Silver-Haired Bat Rabies Virus Infection Can Be Prevented by Opening the Blood-Brain Barrier

Roy

Hooper

2007

J Virol

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Silver-haired bat rabies virus (SHBRV) infection induces a strong virus-specific immune response in the periphery of the host, but death is common due to the failure to open the blood-brain barrier (BBB) and deliver immune effectors to central nervous system (CNS) tissues. Mice with an SJL background are less susceptible to lethal infection with rabies viruses. In addition, these animals are known to have reduced hypothalamuspituitary-adrenal (HPA) axis activity and an elevated capacity to mediate CNS inflammatory responses. We show here that approximately one-half of PLSJL mice survive an SHBRV infection that is invariably lethal for 129/SvEv mice. This difference is associated with the elevated capacity of PLSJL mice to mediate BBB permeability changes in response to the infection. The induction of more extensive BBB permeability and CNS inflammation in these animals results in greater virus clearance and improved survival. On the other hand, treatment of SHBRV-infected PLSJL mice with the steroid hormone dehydroepiandrosterone reduced BBB permeability changes and caused greater mortality. We conclude that the infiltration of immune effectors across the BBB is critical to surviving a rabies virus infection and that HPA axis activity may influence this process.Fluid exchange and the entry of circulating cells and macromolecules into central nervous system (CNS) tissues are regulated by the blood-brain barrier (BBB), a specialization of the neurovasculature (11). While the loss of BBB integrity is often associated with pathological changes in the CNS tissues (1, 12, 25), transiently increased BBB permeability can be therapeutic. An example is when immune effectors are delivered to CNS tissues to clear an infection with the attenuated rabies virus (RV) strain CVS-F3 (21). The clearance of this virus from the CNS of 129/SvEv mice occurs without signs of disease and is associated with enhanced BBB permeability which is largely restricted to the cerebellum (21). The absence of this beneficial enhancement of BBB permeability can lead to a CNS infection becoming lethal, as is evidently the case for infection with the highly pathogenic silver-haired bat-associated RV (SHBRV) (23), the virus that is currently responsible for the majority of human deaths from rabies in the United States and Canada (18). Despite the normal development of RV-specific immunity in peripheral lymphoid organs, increased BBB permeability and immune cell invasion do not occur in the CNS tissues of SHBRV-infected 129/SvEv mice (23). Consequently, the virus is not cleared, and the animals die (23).While the antiviral immune response cannot clear SHBRV from the CNS tissues of 129/SvEv mice, immune cells adoptively transferred from these animals are capable of causing elevated BBB permeability as well as CNS inflammation and clearance of CVS-F3 from the CNS of rag2 Ϫ/Ϫ mice (23). We therefore speculated that the BBB in the cerebellum of SHBRV-infected animals becomes refractory to the signals that trigger enhanced permeability, and the virus-clearin...

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“…The reason why CD4+ and CD8+ cell populations did not decrease in parallel with a decrease of the number of spleen cells was uncertain; however, the emergence of CD8+ suppressor cells which was revealed from the co-culture experiments of 1088 spleen cells with ERA spleen cells (Table 1) would be one of the possible explanations. A marked decrease of the total number of mononuclear cells in spleen during the street rabies virus infection has been postulated to be ascribable to the hypophyseal-hypothalamic-thymic axis effect of rabies virus (17). According to this model, reduction of growth hormone production and altered ACTH secretion caused by rabies virus infection of pituitary can lead to excess production of lymphotoxic glucocorticoids.…”

Section: No Evidence Of Virus Infection In the Thymus And Spleen Of 1mentioning

confidence: 99%

“…Elucidation of the underlying mechanisms may help the understanding of the significance of CMI and allow further improvement of the regimens of post-exposure vaccination and reveal ways of circumventing the virus-induced immunosuppression. TorresAnjel et al (17) and Perry et al (11) have recently provided a great impact on the problem by demonstrating that immunodepletion can be prevented by adrenalectomy and results from a hormonal dysregulation based on the street rabies virus infection of pituitary gland. However, the overall features of the suppression of CMI by street rabies virus infection are still unclear.…”

mentioning

confidence: 99%