Flavivirus Pathogenesis

Flaviviruses include important human pathogens, such as dengue virus, Zika virus, West Nile virus, and yellow fever virus, plus many more viruses that circulate in nature and have the potential to emerge as new human pathogens. Projects in our lab include:
Immune mechanisms that control Zika virus and other congenital infections ZIKV is unusual among flaviviruses in its ability to cross the placental barrier and cause congenital infections. We use mouse models to study the immune mechanisms that control transplacental transmission and the balance between protective and pathogenic immune responses during pregnancy. We found that IFN-λ can have either protective or pathogenic effects depending on the stage of pregnancy but both effects occur through signaling specifically in maternal tissues (Casazza 2022 mBio) and ongoing work seeks to define the mechanisms by which this occurs.
Zika virus infection in the female reproductive tract ZIKV mainly is transmitted by mosquitoes, but also can be sexually transmitted, which requires the virus to target distinct tissues and overcome distinct immune responses compared to mosquito-borne transmission. We found that hormonal status is a key component of ZIKV infection in a mouse vaginal infection model (Lopez 2022 J Virol) and ongoing work seeks to define the mechanism by which this occurs. Sexual transmission also is important in the context of ZIKV congenital infection as it creates the potential for ascending infection, in addition to hematogenous transplacental transmission. We are using mouse models to understand how the route of transmission impacts the outcome of ZIKV congenital infection.
Host genetic determinants of neuroinvasive flavivirus pathogenesis Flavivirus infections produce heterogeneous disease presentations, with most infections being asymptomatic and only a subset presenting with severe disease. We are using genetically diverse mice (Collaborative Cross) to understand how host genetic differences contribute to the outcome of infection with neuroinvasive flaviviruses, including West Nile virus, Japanese encephalitis virus, and Powassan virus (Jasperse 2023 J Virol).
Viral and host mechanisms that control flavivirus infection in the skin The skin is the initial site of infection for arboviruses so the immune environment of the skin has the potential to set the stage for subsequent events in flavivirus pathogenesis. The skin also is a site with the potential for distinct responses to mosquito-borne versus tick-borne flaviviruses, owing to the distinct feeding behavior of their arthropod vectors. We are investigating skin-specific effects of IFN-λ in controlling flavivirus pathogenesis.
Viral determinants of Zika virus pathogenesis We found that two closely-related ZIKV strains (H/PF/2013 and PRVABC59) have distinct virulence phenotypes in mice and that this difference is attributable to a set of 6 nucleotide differences, rather than a difference in the amino acid sequence between these two strains (Carbaugh 2020 J Virol). Ongoing work seeks to define the mechanism by which these nucleotide differences affect ZIKV pathogenesis. We also are working with collaborators in the Dept of Biochemistry & Biophysics to understand how the stablity of RNA structures affects flavivirus replication. In another project we found that envelope protein glycosylation mediates ZIKV pathogenesis (Carbaugh 2019 J Virol) and now are working to understand how glycosylation affects replication, pathogenesis, and antibody sensitivity of flaviviruses more broadly.
No-known-vector flaviviruses While the best-known flaviviruses are vector-borne human pathogens, “no-known-vector flaviviruses” have never been found in an arthropod and many of these viruses don’t replicate in mosquito cells in culture. These viruses have been isolated from bats, rodents, and fish and while many of them have been known for decades, they are largely unstudied. NKV flaviviruses are found in 3 distinct clades within the flavivirus phylogeny, suggesting that there have been multiple instances in flavivirus evolution in which vector-borne viruses gained the ability to transmit by a vector-independent route. Our work seeks to define the mechanisms that control the host range and tropism of NKV flaviviruses with the goal of understanding the factors that control host range specificity of flaviviruses more broadly and implications for the emergence of obscure flaviviruses as new human pathogens.

IFN-λ mediated antiviral immunity

IFN-λ (type III interferon) activates an antiviral response similar to the IFN-αβ (type I IFN) response, but the IFN-λ response typically is less potent, less inflammatory and most evident at epithelial tissues, leading to the model that IFN-λ provides front-line protection at anatomic barriers. Projects in our lab include:
IFN-λ mediated immunity at the maternal-fetal interface We found that IFN-λ can have either protective or pathogenic effects depending on the stage of pregnancy but both effects occur through signaling specifically in maternal tissues (Casazza 2022 mBio) and ongoing work seeks to define the mechanisms by which this occurs.
IFN-λ mediated immunity in the skin The effects of IFN-λ have been best studied in the respiratory and gastrointestinal tracts but its effects in another important epithelial barrier, the skin, have not been investigated extensively. We have identified skin-specific effects of IFN-λ in restricting infection by flaviviruses and in controlling skin lesions produced by herpes simplex virus. Ongoing work seeks to define the cell types that mediate IFN-λ responses in the skin and the mechanisms by which IFN-λ restricts viral infection and immune pathology at this epithelial barrier.
Defining IFN-λ specific antiviral responses In general the transcriptional response induced by IFN-λ is very similar to the response induced by IFN-αβ; we are interested in understanding how these cytokines nonetheless elicit distinct immune responses and how their signaling pathways and transcriptional responses differ in distinct cell types.

Herpes simplex virus pathogenesis

Although they are not related viruses, HSV and flaviviruses target some of the same tissues, including the skin, vagina, and neurons, making for interesting pathogenic comparisons. Projects in our lab include:
IFN-λ mediated control of HSV skin disease We found that IFN-λ restricts the severity of HSV skin lesions, in a manner distinct from limiting viral replication. Ongoing work seeks to define the IFN-λ responsive cells that control HSV pathogenesis in the skin in the context of both acute and recurrent disease.
Hormonal control of HSV vaginal infection Mouse models of HSV vaginal infection typically require pre-treatment with progesterone, but the mechanism by which this enhances susceptibility to HSV infection is not well understood. Ongoing work seeks to understand how progesterone affects cell intrinsic and extrinsic immune responses in the vagina and how that influences susceptibility to viral infection.
HSV infection and trafficking in neurons We have developed a new model of HSV reactivation in mice which is simpler and more tractable than other commonly used systems. We are using this system to study differences between acute and recurrent HSV disease, as well as to understand the stimuli that drive HSV reactivation from latency.

Our research is supported by: