Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment

McCarthy, Mary K.; Davenport, Bennett; Reynoso, Glennys V.; Lucas, Erin D; May, Nicholas; Elmore, Susan A.; Tamburini, Beth A.J.; Hickman, Heather D.; Morrison, Thomas E.

doi:10.1172/jci.insight.121100

Cited by 28 publications

(41 citation statements)

References 62 publications

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“…To ensure stability of the inserted sequences and limit reversion, 4 copies of the miR-206 target sequence were placed in tandem and in-frame into the structural ORF of virulent CHIKV strain SL15649 within coding sequences of the viral E3 glycoprotein ( Figure 1, A and B). This site was chosen because it can accommodate insertions of exogenous sequences without compromising replication capacity (37,38). A mismatch control virus was engineered containing silent mutations at synonymous nucleotide positions in miRNA target sequences to alleviate restriction by miR-206 ( Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

Chikungunya virus replication in skeletal muscle cells is required for disease development

Lentscher¹,

McCarthy²,

May³

et al. 2020

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Chikungunya virus replication in skeletal muscle cells is required for disease development

Lentscher¹,

McCarthy²,

May³

et al. 2020

Journal of Clinical Investigation

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“…Although the effect of CHIKV/malaria co-infections in humans remains unclear, mouse studies suggest that malaria infection can ameliorate chikungunya-related arthropathy 80 . In mice, CHIKV infection can compromise lymph node function 81 and alter CD8 T cell trafficking 82 , with such CHIKV-mediated changes potentially modulating adaptive immunity and thus immunopathology in co-infection settings.…”

Section: Box 1 | Diagnosis Of Chikungunyamentioning

confidence: 99%

Rheumatic manifestations of chikungunya: emerging concepts and interventions

2019

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Chikungunya virus (CHIKV) is a member of a group of globally distributed, mosquito-transmitted arthritogenic alphaviruses that cause sporadic outbreaks of primarily rheumatic disease every 2-50 years 1-4. The largest epidemic of CHIKV disease (hereafter simply referred to as chikungunya) ever recorded began on Lamu Island, Kenya, in 2004 (Fig. 1). The epidemic expanded across four continents, with cases still being reported in 2019 (Fig. 1; Supplementary Table 1). Three major genotypes of CHIKV are now recognized-the Asian, the West African and the Asian and East-Central South African (ECSA) genotypes 5-but a new lineage, the Indian Ocean Lineage (IOL), also emerged from the ECSA genotype during the 2004-2019 epidemic 6. The epidemic reached >100 countries (Supplementary Table 1), caused >10 million cases (Supplementary Table 2), and might arguably be called a pandemic. An estimated 1.3 billion people are at risk of chikungunya 7. Climate change modelling suggests that many more areas of the world (including parts of China, sub-Saharan Africa, South America and the United States) might become able to accommodate transmission of CHIKV in the future 8,9. Chikungunya was previously often viewed as (and for many patients remains) a relatively benign and selflimiting rheumatic disease. However, a considerably more complex spectrum of less common atypical and severe manifestations is now recognized in subgroups of patients, with chikungunya often complicated by comorbidities and co-infections. Hospitalization rates for chikun gunya range from 0.6% to 13% 10-14 and estimates of chikungunya-related mortality range from 0.024% to 0.7% 10,12,15-17. In addition, many patients develop protracted rheumatic disease lasting many months, occasionally years, with a number of sequelae now also recognized 18-22. Estimates for the total economic costs (direct and indirect) of chikungunya have ranged from a median of US$67 for adults and $258 for children in Columbia 23 , to a mean of $150 per outpatient and $3,300 per inpatient in 2006 in Réunion Island 11. In a large study of a chikungunya outbreak in Bangladesh in 2017, >10 days of productivity were lost in ~30% of patients with chikung unya because of severe arthropathy 24. Such costs might be viewed as relatively modest by Western standards; however, the occasionally high attack rate of chikungunya, with up to 30-75% of a given population affected by chikungunya disease at any one time 1,25 , can result in a substantial economic burden, especially in resource-poor communities that are often affected by the disease 26. Considerable research in patients and animal models has now provided extensive insights into the complex Pandemic An epidemic of disease that has spread across a large region; for instance, multiple continents, or even worldwide. Attack rate The total number of new cases of a disease divided by the total population (that is, the percentage of a defined population that is affected by a disease).

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“…CHIKV infection elicits antigen-specific CD8 ؉ T cell responses. CHIKV(OVA)-AF is a recombinant virus engineered to encode the H-2K b -restricted ovalbumin OVA 257-264 epitope (K b OVA 257 ; SIINFEKL) and the I-A d /I-A b -restricted OVA 323-339 epitope (ISQAVH AAHAEINEAGR) in-frame with the viral structural polyprotein in the genome of the pathogenic CHIKV strain AF15561 (46). Four-week-old wild-type (WT) C57BL/6 male mice were mock inoculated or inoculated via subcutaneous (s.c.) injection with 10 3 PFU of CHIKV(OVA)-AF in the left rear footpad, and CD8 ϩ T cell responses were interrogated during both the acute and the chronic phases at 5, 10, 14, 21, and 28 days postinoculation (dpi).…”

Section: Resultsmentioning

confidence: 99%

“…This study was conducted in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals (99) Viruses. CHIKV AF15561 (CHIKV-AF) and the recombinant CHIKV-AF strain encoding immunodominant CD8 (SIINFEKL) and CD4 (ISQAVHAAHAEINEAGR) [CHIKV(OVA)-AF] T cell epitopes for ovalbumin have been described previously (46). CHIKV(OVA)-AF with a single N-to-K amino acid substitution at position 4 of the SIINFEKL epitope (SIIKFEKL) [CHIKV(OVA4K)-AF] was generated by site-directed mutagenesis.…”

Section: Methodsmentioning

confidence: 99%

“…The substitution of K for N at position 4 of the SIINFEKL epitope preserves peptide binding to H-2K b yet greatly diminishes the stimulation of CD8 ϩ T cells (80). Virus stocks were generated by electroporation of BHK-21 cells with viral RNA transcribed in vitro from plasmid DNA templates as described previously (46,101). LCMV-Arm (clone 53b) and LCMV-cl13 stocks were propagated by a single passage in BHK-21 cells.…”

Section: Methodsmentioning

confidence: 99%

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Chikungunya Virus Evades Antiviral CD8⁺T Cell Responses To Establish Persistent Infection in Joint-Associated Tissues

Davenport

Bullock

McCarthy

et al. 2020

J Virol

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Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes explosive epidemics of a febrile illness characterized by debilitating arthralgia and arthritis that can endure for months to years following infection. In mouse models, CHIKV persists in joint tissues for weeks to months and is associated with chronic synovitis. Using a recombinant CHIKV strain encoding a CD8+ T cell receptor epitope from ovalbumin, as well as a viral peptide-specific major histocompatibility complex class I tetramer, we interrogated CD8+ T cell responses during CHIKV infection. Epitope-specific CD8+ T cells, which were reduced in Batf3−/− and Wdfy4−/− mice with known defects in antigen cross-presentation, accumulated in joint tissue and the spleen. Antigen-specific ex vivo restimulation assays and in vivo killing assays demonstrated that CD8+ T cells produce cytokine and have cytolytic activity. Despite the induction of a virus-specific CD8+ T cell response, the CHIKV burden in joint-associated tissues and the spleen were equivalent in wild-type (WT) and CD8α−/− mice during both the acute and the chronic phases of infection. In comparison, CD8+ T cells were essential for the control of acute and chronic lymphocytic choriomeningitis virus infection in the joint and spleen. Moreover, adoptive transfer of virus-specific effector CD8+ T cells or immunization with a vaccine that induces virus-specific effector CD8+ T cells prior to infection enhanced the clearance of CHIKV infection in the spleen but had a minimal impact on CHIKV infection in the joint. Collectively, these data suggest that CHIKV establishes and maintains a persistent infection in joint-associated tissue in part by evading CD8+ T cell immunity. IMPORTANCE CHIKV is a reemerging mosquito-transmitted virus that in the last decade has spread into Europe, Asia, the Pacific Region, and the Americas. Joint pain, swelling, and stiffness can endure for months to years after CHIKV infection, and epidemics have a severe economic impact. Elucidating the mechanisms by which CHIKV subverts antiviral immunity to establish and maintain a persistent infection may lead to the development of new therapeutic strategies against chronic CHIKV disease. In this study, we found that CHIKV establishes and maintains a persistent infection in joint-associated tissue in part by evading antiviral CD8+ T cell immunity. Thus, immunomodulatory therapies that improve CD8+ T cell immune surveillance and clearance of CHIKV infection could be a strategy for mitigating chronic CHIKV disease.

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Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment

Cited by 28 publications

References 62 publications

Chikungunya virus replication in skeletal muscle cells is required for disease development

Chikungunya virus replication in skeletal muscle cells is required for disease development

Rheumatic manifestations of chikungunya: emerging concepts and interventions

Chikungunya Virus Evades Antiviral CD8⁺T Cell Responses To Establish Persistent Infection in Joint-Associated Tissues

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Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment

Cited by 28 publications

References 62 publications

Chikungunya virus replication in skeletal muscle cells is required for disease development

Chikungunya virus replication in skeletal muscle cells is required for disease development

Rheumatic manifestations of chikungunya: emerging concepts and interventions

Chikungunya Virus Evades Antiviral CD8+T Cell Responses To Establish Persistent Infection in Joint-Associated Tissues

Contact Info

Product

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Chikungunya Virus Evades Antiviral CD8⁺T Cell Responses To Establish Persistent Infection in Joint-Associated Tissues