La Crosse Virus Shows Strain-Specific Differences in Pathogenesis

Wilson, Sarah N.; López, Krisangel; Coutermash-Ott, Sheryl; Auguste, Dawn I.; Porier, Danielle L.; Armstrong, Philip M.; Andreadis, Theodore G.; Eastwood, Gillian; Auguste, Albert J.

doi:10.3390/pathogens10040400

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…Dulbecco's Modified Eagle Media (DMEM) containing 2% Fetal Bovine Serum (FBS), 100 units of Penicillin and 0.1 mg Streptomycin), for virus quantification by plaque assay. Mice were immediately euthanized when moribund or upon weight loss greater than or equal to 20% of their original body weight, as previously described [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

Novel murine models for studying Cache Valley virus pathogenesis and in utero transmission

López

Wilson

Coutermash-Ott

et al. 2021

Emerging Microbes & Infections

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Cache Valley virus (CVV) is a prevalent emerging pathogen of significant importance to agricultural and human health in North America. Emergence in livestock can result in substantial agroeconomic losses resulting from the severe embryonic lethality associated with infection during pregnancy. Although CVV pathogenesis has been well described in ruminants, small animal models are still unavailable, which limits our ability to study its pathogenesis and perform preclinical testing of therapeutics. Herein, we explored CVV pathogenesis, tissue tropism, and disease outcomes in a variety of murine models, including immune -competent and -compromised animals. Our results show that development of CVV disease in mice is dependent on innate immune responses, and type I interferon signalling is essential for preventing infection in mice. IFN-αβR -/- mice infected with CVV present with significant disease and lethal infections, with minimal differences in age-dependent pathogenesis, suggesting this model is appropriate for pathogenesis-related, and short- and long-term therapeutic studies. We also developed a novel CVV in utero transmission model that showed high rates of transmission, spontaneous abortions, and congenital malformations during infection. CVV infection presents a wide tissue tropism, with significant amplification in liver, spleen, and placenta tissues. Immune-competent mice are generally resistant to infection, and only show disease in an age dependent manner. Given the high seropositivity rates in regions of North America, and the continuing geographic expansion of competent mosquito vectors, the risk of epidemic and epizootic emergence of CVV is high, and interventions are needed for this important pathogen.

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Section: Methodsmentioning

confidence: 99%

Novel murine models for studying Cache Valley virus pathogenesis and in utero transmission

López

Wilson

Coutermash-Ott

et al. 2021

Emerging Microbes & Infections

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“…Therefore, we hypothesized we could use the M swap viruses to better understand how LACV replicates in vivo . Since La Crosse virus is the leading etiological agent of pediatric arboviral encephalitis in the United States and causes hospitalized instances of disease in humans less than 16 years old, the murine model we chose to study our LACV reassortants disease utilizes C57BL6/J neonatal mice (20). To test the neuroinvasive capacity of the M segments from our two LACV strains, we infected 6-day old mice with 50 PFU of S 1978 M 1960 L 1978 or WT LACV 1978 ( Figure 5A-C ) and 5-day old mice with 50 PFU of S 1960 M 1978 L 1960 or WT LACV 1960 ( Figure 5D-F ).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown that different La Crosse virus (LACV) strains exhibited differences in viral growth kinetics and pathogenesis (19) (20). However, the molecular determinants driving these phenotypes are not well-defined.…”

Section: Two Genetically Similar La Crosse Virus Strains Confer Diffe...mentioning

confidence: 99%

Section: Segment Reassortants Alter Clinical Outcomes and Virulence I...mentioning

confidence: 99%

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La Crosse virus reassortants highlight genomic determinants of infection and pathogenesis

Rondeau,

Spector,

Thannickal

et al. 2024

Preprint

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The genomic determinants that contribute to orthobunyavirus infection and pathogenesis are not well-defined. In this study, we harnessed the process of reassortment to understand which viral factors drive change in the replication and pathogenesis of La Crosse virus (LACV). We systematically reassorted the genomic segments of two genetically similar Lineage I LACV isolates into six unique reassortants. Despite the parental isolates having high levels of RNA and protein consensus, the reassortants demonstrate how minimal changes in RNA and protein structure can have significant changes in viral growth and reproduction in vitro in mammalian and insect models. We observed that swapping the S segment between isolates led to differences in replication and assembly resulting in one non-rescuable reassortant and one viable reassortant that exhibited an increase in viral growth dynamics. Switching the M segment led to changes in viral plaque phenotype and growth kinetics. L segment reassortants similarly differed in changes in viral growth dynamics. We further explored the M segment reassortants in a neonate mouse model and observed a role for the M segment in neuroinflammation and virulence. Through reassortment of the La Crosse virus genomic segments, we are able to further understand how genomic determinants of infection and pathogenesis operate in orthobunyaviruses. Future investigations will focus on identifying the specific molecular elements that govern the observed phenotypes in vitro and in vivo.

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“…Wild-type strains of mice have been used to study the neurovirulence of a wide range of viruses, as they are susceptible to many different viral infections. Neonatal mice are acutely susceptible to many viruses and have been used extensively to study specific aspects of virus neurovirulence [ 63 , 64 , 65 , 66 ]. Their susceptibility makes them a promising model for highly sensitive neurovirulence screening.…”

Section: Animal Models For Testing Vaccine Neurovirulencementioning

confidence: 99%

Live Viral Vaccine Neurovirulence Screening: Current and Future Models

Fulton¹,

Bailey²

2021

Vaccines

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Live viral vaccines are one of the most successful methods for controlling viral infections but require strong evidence to indicate that they are properly attenuated. Screening for residual neurovirulence is an important aspect for live viral vaccines against potentially neurovirulent diseases. Approximately half of all emerging viral diseases have neurological effects, so testing of future vaccines will need to be rapid and accurate. The current method, the monkey neurovirulence test (MNVT), shows limited translatability for human diseases and does not account for different viral pathogenic mechanisms. This review discusses the MNVT and potential alternative models, including in vivo and in vitro methods. The advantages and disadvantages of these methods are discussed, and there are promising data indicating high levels of translatability. There is a need to investigate these models more thoroughly and to devise more accurate and rapid alternatives to the MNVT.

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La Crosse Virus Shows Strain-Specific Differences in Pathogenesis

Cited by 6 publications

References 23 publications

Novel murine models for studying Cache Valley virus pathogenesis and in utero transmission

Novel murine models for studying Cache Valley virus pathogenesis and in utero transmission

La Crosse virus reassortants highlight genomic determinants of infection and pathogenesis

Live Viral Vaccine Neurovirulence Screening: Current and Future Models

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