Insights into the pathogenesis of herpes simplex encephalitis from mouse models

Mancini, Mathieu; Vidal, Silvia M.

doi:10.1007/s00335-018-9772-5

Cited by 46 publications

(63 citation statements)

References 152 publications

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“…inoculation routes, and virus strains of variable neurovirulence have been developed to investigate the pathogenesis of viral infections in vivo [20]. So far, mostly intranasal or intracerebral infection models have been used to study HSE in mice [21][22][23], whereas HSV-1 latency is established mainly by corneal scarification [21].…”

Section: Plos Pathogensmentioning

confidence: 99%

An improved animal model for herpesvirus encephalitis in humans

et al. 2020

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Herpesviral encephalitis caused by Herpes Simplex Virus 1 (HSV-1) is one of the most devastating diseases in humans. Patients present with fever, mental status changes or seizures and when untreated, sequelae can be fatal. Herpes Simplex Encephalitis (HSE) is characterized by mainly unilateral necrotizing inflammation effacing the frontal and mesiotemporal lobes with rare involvement of the brainstem. HSV-1 is hypothesized to invade the CNS via the trigeminal or olfactory nerve, but viral tropism and the exact route of infection remain unclear. Several mouse models for HSE have been developed, but they mimic natural infection only inadequately. The porcine alphaherpesvirus Pseudorabies virus (PrV) is closely related to HSV-1 and Varicella Zoster Virus (VZV). While pigs can control productive infection, it is lethal in other susceptible animals associated with severe pruritus leading to automutilation. Here, we describe the first mutant PrV establishing productive infection in mice that the animals are able to control. After intranasal inoculation with a PrV mutant lacking tegument protein pUL21 and pUS3 kinase activity (PrV-ΔUL21/US3Δkin), nearly all mice survived despite extensive infection of the central nervous system. Neuroinvasion mainly occurred along the trigeminal pathway. Whereas trigeminal first and second order neurons and autonomic ganglia were positive early after intranasal infection, PrV-specific antigen was mainly detectable in the frontal, mesiotemporal and parietal lobes at later times, accompanied by a long lasting lymphohistiocytic meningoencephalitis. Despite this extensive infection, mice showed only mild to moderate clinical signs, developed alopecic skin lesions, or remained asymptomatic. Interestingly, most mice exhibited abnormalities in behavior and activity levels including slow movements, akinesia and stargazing. In summary, clinical signs, distribution of viral antigen and inflammatory pattern show striking analogies to human encephalitis caused by HSV-1 or VZV not observed in other animal models of disease.

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Section: Plos Pathogensmentioning

confidence: 99%

An improved animal model for herpesvirus encephalitis in humans

et al. 2020

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“…However, these data suggest that a deficiency in the lectin pathway results in a lack of control of viral replication leading to an exacerbated inflammatory response in the brain, that results in an increased mortality rate in mice infected with HSV-1. The mouse model of intranasal infection used in this study is not expected to induce HSV-1 viremia and spread to internal organs in WT animals [62,63]; yet, one cannot exclude that such spread would have been observed in MBL deficient mice. MASP-2 deficient mice were protected by a patent and not available for this study, so that MBL-A x MBL-C deficient mice (only one MBL gene is expressed in humans whereas two closely related proteins MBL-A and MBL-C are produced in mice) were used instead of MASP-2 deficient mice to test the role of the lectin pathway in susceptibility to HSE.…”

Section: Discussionmentioning

confidence: 94%

Herpes simplex encephalitis in adult patients with MASP-2 deficiency

et al. 2019

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We report here two cases of Herpes simplex virus encephalitis (HSE) in adult patients with very rare, previously uncharacterized, non synonymous heterozygous G634R and R203W substitution in mannan-binding lectin serine protease 2 (MASP2), a gene encoding a key protease of the lectin pathway of the complement system. None of the 2 patients had variants in genes involved in the TLR3-interferon signaling pathway. Both MASP2 variants induced functional defects in vitro, including a reduced (R203W) or abolished (G634R) protein secretion, a lost capability to cleave MASP-2 precursor into its active form (G634R) and an in vivo reduced antiviral activity (G634R). In a murine model of HSE, animals deficient in mannose binding lectins (MBL, the main pattern recognition molecule associated with MASP-2) had a decreased survival rate and an increased brain burden of HSV-1 compared to WT C57BL/6J mice. Altogether, these data suggest that MASP-2 deficiency can increase susceptibility to adult HSE. Author summaryHuman herpes virus type 1 (HSV-1) infects a large number of individuals during their life, with manifestations usually limited to mild and self-limiting inflammation of the oral mucosa (cold sore). However, HSV-1 can cause a very severe disease of the brain called Herpes simplex encephalitis (HSE) in 1 out of 250'000-500'000 individuals per year. The reasons why HSV-1 can cause such a devastating disease in a very limited number of individuals are unknown. Increasing evidence suggests that susceptibility to HSE in children can results from genetic variations in the immune system, in particular in a viral detection PLOS Pathogens | https://doi.pathway called the Toll-like receptor 3 (TLR3)-interferon (IFN) axis. Fewer data are available to explain HSE in adult patients. Here, we describe two adult patients with HSE who carry mutations in a gene called mannan-binding lectin serine protease 2 (MASP2), which is part of an immune pathway different from the TLR3-IFN axis, called the lectin pathway of the complement system. We demonstrate that MASP2 mutations induce functional defects in immune defense against HSV-1 that prevent viral replication. Mice deficient in the lectin pathway have higher mortality compared to wild-type mice after HSV-1 infection. Altogether, our study suggests that susceptibility to HSE in adults relies of immune deficiencies that are different from those causing HSE in children.Herpes simplex encephalitis and MASP-2 deficiency PLOS Pathogens | https://doi.

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“…Viral shedding can appear either in the presence of lesions as a clinical reactivation or with very moderate or no symptoms as subclinical reactivation. Shedding from mucosal surfaces drives transmission to other sexual partners and, in some cases, infection with HSV can be transferred from mother to infant at delivery [20,21].…”

Section: Epidemiology and Pathogenesis Of Hsv Infectionmentioning

confidence: 99%

Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development

Treml

Gazdová

Šmejkal

et al. 2020

Viruses

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Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance crisis has been attributed to the overuse of these medications, as well as the lack of new drug development by the pharmaceutical industry due to reduced economic inducements and challenging regulatory requirements. Therefore, the development of novel antiviral drugs against HSV infections would be a step forward in improving global combat against these infections. The incorporation of biologically active natural products into anti-HSV drug development at the clinical level has gained limited attention to date. Thus, the search for new drugs from natural products that could enter clinical practice with lessened resistance, less undesirable effects, and various mechanisms of action is greatly needed to break the barriers to novel antiherpetic drug development, which, in turn, will pave the road towards the efficient and safe treatment of HSV infections. In this review, we aim to provide an up-to-date overview of the recent advances in natural antiherpetic agents. Additionally, this paper covers a large scale of phenolic compounds, alkaloids, terpenoids, polysaccharides, peptides, and other miscellaneous compounds derived from various sources of natural origin (plants, marine organisms, microbial sources, lichen species, insects, and mushrooms) with promising activities against HSV infections; these are in vitro and in vivo studies. This work also highlights bioactive natural products that could be used as templates for the further development of anti-HSV drugs at both animal and clinical levels, along with the potential mechanisms by which these compounds induce anti-HSV properties. Future insights into the development of these molecules as safe and effective natural anti-HSV drugs are also debated.

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Insights into the pathogenesis of herpes simplex encephalitis from mouse models

Cited by 46 publications

References 152 publications

An improved animal model for herpesvirus encephalitis in humans

An improved animal model for herpesvirus encephalitis in humans

Herpes simplex encephalitis in adult patients with MASP-2 deficiency

Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development

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