Animal models of alphavirus infection and human disease

Lucas, Cormac J.; Morrison, Thomas E.

doi:10.1016/bs.aivir.2022.07.001

Cited by 3 publications

(3 citation statements)

References 288 publications

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“…Microscopic analysis of muscle and joint biopsies from alphavirus-infected patients has been employed for diagnosis in addition to molecular techniques. In CHIKV-infected humans, some of these microscopic findings have included synovial hyperplasia, muscle degeneration and necrosis, and mononuclear to mixed inflammation with indication of a change in cellular infiltration profiles between acute, subacute, and chronic infections [ 98 , 99 ]. Of the extensive tissue sets sampled in our study, the fingers, wrists, ankles, and toes were the most consistent sites for inflammation and perivascular lymphocytic infiltration.…”

Section: Discussionmentioning

confidence: 99%

Mayaro virus pathogenesis and immunity in rhesus macaques

Weber,

Labriola,

Kreklywich

et al. 2023

PLoS Negl Trop Dis

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Mayaro virus (MAYV) is a mosquito-transmitted alphavirus that causes debilitating and persistent arthritogenic disease. While MAYV was previously reported to infect non-human primates (NHP), characterization of MAYV pathogenesis is currently lacking. Therefore, in this study we characterized MAYV infection and immunity in rhesus macaques. To inform the selection of a viral strain for NHP experiments, we evaluated five MAYV strains in C57BL/6 mice and showed that MAYV strain BeAr505411 induced robust tissue dissemination and disease. Three male rhesus macaques were subcutaneously challenged with 105 plaque-forming units of this strain into the arms. Peak plasma viremia occurred at 2 days post-infection (dpi). NHPs were taken to necropsy at 10 dpi to assess viral dissemination, which included the muscles and joints, lymphoid tissues, major organs, male reproductive tissues, as well as peripheral and central nervous system tissues. Histological examination demonstrated that MAYV infection was associated with appendicular joint and muscle inflammation as well as presence of perivascular inflammation in a wide variety of tissues. One animal developed a maculopapular rash and two NHP had viral RNA detected in upper torso skin samples, which was associated with the presence of perivascular and perifollicular lymphocytic aggregation. Analysis of longitudinal peripheral blood samples indicated a robust innate and adaptive immune activation, including the presence of anti-MAYV neutralizing antibodies with activity against related Una virus and chikungunya virus. Inflammatory cytokines and monocyte activation also peaked coincident with viremia, which was well supported by our transcriptomic analysis highlighting enrichment of interferon signaling and other antiviral processes at 2 days post MAYV infection. The rhesus macaque model of MAYV infection recapitulates many of the aspects of human infection and is poised to facilitate the evaluation of novel therapies and vaccines targeting this re-emerging virus.

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Section: Discussionmentioning

confidence: 99%

Mayaro virus pathogenesis and immunity in rhesus macaques

Weber,

Labriola,

Kreklywich

et al. 2023

PLoS Negl Trop Dis

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“…The study of these complex VBDs systems has relied heavily on live animal or human feedings [ 8 , 9 , 10 , 11 , 12 ]. While vertebrate animals offers several advantages, such as providing a natural physiological environment for the arthropods and offering insights into host–pathogen interactions [ 13 , 14 ], ethical and practical concerns exist [ 8 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Artificial Feeding Systems for Vector-Borne Disease Studies

Olajiga,

Jameson,

Carter

et al. 2024

Biology

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This review examines the advancements and methodologies of artificial feeding systems for the study of vector-borne diseases, offering a critical assessment of their development, advantages, and limitations relative to traditional live host models. It underscores the ethical considerations and practical benefits of such systems, including minimizing the use of live animals and enhancing experimental consistency. Various artificial feeding techniques are detailed, including membrane feeding, capillary feeding, and the utilization of engineered biocompatible materials, with their respective applications, efficacy, and the challenges encountered with their use also being outlined. This review also forecasts the integration of cutting-edge technologies like biomimicry, microfluidics, nanotechnology, and artificial intelligence to refine and expand the capabilities of artificial feeding systems. These innovations aim to more accurately simulate natural feeding conditions, thereby improving the reliability of studies on the transmission dynamics of vector-borne diseases. This comprehensive review serves as a foundational reference for researchers in the field, proposing a forward-looking perspective on the potential of artificial feeding systems to revolutionize vector-borne disease research.

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“…Alphavirus-induced encephalomyelitis can be studied in a mouse model of infection with Sindbis virus (SINV), the prototypic alphavirus, which causes widespread infection of neurons. Acute disease consists of weight loss, hunched posture, and paralysis, with severity depending on both host genetics and the strain of SINV ( 10 – 14 ). Recovery from SINV infection of the central nervous system (CNS) involves resident neural cells and infiltrating leukocytes from the periphery ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Phenotypic and transcriptional changes in peripheral blood mononuclear cells during alphavirus encephalitis in mice

Nguyen,

Bartlett,

Troisi

et al. 2024

mBio

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Sindbis virus (SINV) infection of mice provides a model system for studying the pathogenesis of alphaviruses that infect the central nervous system (CNS) to cause encephalomyelitis. While studies of human viral infections typically focus on accessible cells from the blood, this compartment is rarely evaluated in mice. To bridge this gap, single-cell RNA sequencing (scRNAseq) was combined with flow cytometry to characterize the transcriptional and phenotypic changes of peripheral blood mononuclear cells (PBMCs) from SINV-infected mice. Twenty-one clusters were identified by scRNAseq at 7 days after infection, with a unique cluster and overall increase in naive B cells for infected mice. Uninfected mice had fewer immature T cells and CCR9 + CD4 T cells and a unique immature T cell cluster. Gene expression was most altered in the Ki67 + CD8 T cell cluster, with chemotaxis and proliferation-related genes upregulated. Global analysis indicated metabolic changes in myeloid cells and increased expression of Ccl5 by NK cells. Phenotypes of PBMCs and cells infiltrating the CNS were analyzed by flow cytometry over 14 days after infection. In PBMCs, CD8 and Th1 CD4 T cells increased in representation, while B cells showed a transient decrease at day 5 in total, Ly6a + , and naive cells, and an increase in activated B cells. In the brain, CD8 T cells increased for the first 7 days, while Th1 CD4 T cells and naive and Ly6a + B cells continued to accumulate for 14 days. Therefore, dynamic immune cell changes can be identified in the blood as well as the CNS during viral encephalomyelitis. IMPORTANCE The outcome of viral encephalomyelitis is dependent on the host immune response, with clearance and resolution of infection mediated by the adaptive immune response. These processes are frequently studied in mouse models of infection, where infected tissues are examined to understand the mechanisms of clearance and recovery. However, studies of human infection typically focus on the analysis of cells from the blood, a compartment rarely examined in mice, rather than inaccessible tissue. To close this gap, we used single-cell RNA sequencing and flow cytometry to profile the transcriptomic and phenotypic changes of peripheral blood mononuclear cells (PBMCs) before and after central nervous system (CNS) infection in mice. Changes to T and B cell gene expression and cell composition occurred in PBMC and during entry into the CNS, with CCL5 being a differentially expressed chemokine. Therefore, dynamic changes occur in the blood as well as the CNS during the response of mice to virus infection, which will inform the analysis of human studies.

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Animal models of alphavirus infection and human disease

Cited by 3 publications

References 288 publications

Mayaro virus pathogenesis and immunity in rhesus macaques

Mayaro virus pathogenesis and immunity in rhesus macaques

Artificial Feeding Systems for Vector-Borne Disease Studies

Phenotypic and transcriptional changes in peripheral blood mononuclear cells during alphavirus encephalitis in mice

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